Abstract
The escalating global burden of pancreatic ductal adenocarcinoma (PDAC) is imposing a critical health burden as a major cause of cancer-related mortality. Survival rates are low due to late-stage diagnosis and complex tumor microenvironments. The review discusses the multifaceted approach required for effective management, including the latest therapeutic approaches, and highlights the critical role of the tumor microenvironment in therapy response. Innovations in targeted therapies and immunotherapies are emphasized, with a focus on genetic mutations such as BRCA and KRAS that influence treatment outcomes. Furthermore, the article explores emerging therapeutic strategies, including the utilization of novel drug combinations. The review underscores the necessity for ongoing research to improve diagnostic techniques, develop more effective therapies, and ultimately enhance patient outcomes in pancreatic cancer.
Introduction
The global burden of pancreatic cancer has increased dramatically over the past few decades and incidence is expected to rise, representing a leading cause of cancer-related mortality and a crucial health issue. The risk of death from pancreatic cancer increases significantly with age, from < 2 deaths per 100,000 person-years for individuals in the USA aged 35–39 years to > 90 deaths per 100,000 person-years for individuals aged > 80 years [1, 2]. Incidence is higher in males compared to females, with pancreatitis, smoking, alcohol, and obesity being commonly associated risk factors with the disease. In addition, numerous genes have been strongly linked to tumorigenesis of pancreatic cancer such as KRAS, ATM, BRCA1, BRCA2, MLH, MSH2, MSH6 and PR53 [3–5]. Approximately 90% of pancreatic malignancies are pancreatic ductal adenocarcinomas (PDACs). Pancreatic cancer has significantly high mortality rate of approximately 90% and a dismal survival rate of 5 years in ~ 15–25% of patients who undergo surgery [6]. This is primarily due to several factors including ineffective screening methods, late-stage diagnosis, and the challenging tumor microenvironment.
Management of pancreatic cancer is complex and requires multidisciplinary care. Multimodality therapy with surgical resection, chemotherapy, and occasionally radiation constitutes the mainstay of curative intent therapy offered to the patients with resectable (RPC) and borderline resectable pancreatic cancer (BRPC) [7]. Surgery remains the cornerstone therapy in patients with resectable stages I-III PDAC. Major determinant of resection in localized disease is involvement of the blood vessels posterior to the pancreas [8, 9].
In addition, micro-metastatic disease is pivotal in the progression and prognosis of PDAC, often leading to relapse post-surgery due to early dissemination of tumor cells into the bloodstream and lymphatics. This early spread results in occult metastases, detectable through circulating tumor cells (CTCs) and cell-free DNA (cfDNA) before clinical signs appear [10, 11]. Thus, both neoadjuvant and adjuvant therapies are critical in targeting these tumor cells to improve outcomes. Systemic therapy used in these settings includes gemcitabine or combination therapies such as FOLFIRINOX or gemcitabine-capecitabine, which have shown improvement in overall survival compared to gemcitabine monotherapy [12]. In metastatic or locally advanced PDAC, combination chemotherapy regimen is considered standard of care in patients with good performance status. Gemcitabine monotherapy has been the standard treatment for advanced PDAC, offering a median overall survival (OS) of approximately 6 months. To enhance efficacy, combination regimens such as FOLFIRINOX (a combination of folinic acid, fluorouracil, irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel have been developed. In the MPACT trial, the addition of nab-paclitaxel to gemcitabine improved median OS to 8.5 months compared to 6.7 months with gemcitabine alone, with 1-year survival rates of 35% versus 22%, respectively. However, this combination was associated with increased toxicities, including myelosuppression and peripheral neuropathy [13]. Gemcitabine plus abraxane and mFOLFIRINOX demonstrated improved median OS, 8.5 and 11.1 months respectively, compared to gemcitabine alone [14, 15]. More recently, NALIRIFOX demonstrated superior median OS benefit over gemcitabine-abraxane in a phase III randomized NAPOLI-3 trial [16].
The advent of next-generation sequencing and targeted therapies has resulted in a paradigm shift in the therapeutic approach for PDAC. This article discusses recent advances and milestones in PDAC treatment, along with the exploration of emerging therapies that require further evidence to confirm their efficacy.
Tumor microenvironment
Understanding tumor microenvironment and its implication on the biology and response to therapy for PDAC has been a major focus of research in the past decade. Pancreatic cancer is distinguished by its fibrotic stroma or desmoplasia which constitutes a variety of cell types, including inflammatory cells, blood vessels and nerve cells and cancer-associated fibroblasts (CAF) that produce collagen, fibronectin, laminin and hyaluronic acid when activated [17]. The stiffness and elevated hydrostatic pressures due to extracellular matrix deposition, coupled with poor vascularization in pancreatic tumors, create barriers to effective drug delivery, prompting research into overcoming these stromal barriers to improve therapeutic efficacy [18].
CAFs,which constitute up to 90% of tumor mass, play a significant rolein tumorigenesis through interacting with specific genetic mutations andpromoting tumor growth. CAFs have different subtypes. For example, myoepithelial variants function to restrain and inhibit cancer progression while inflammatory CAFs tend to promote cancer growth, invasion and resistance. Targeting stroma to enhance chemotherapeutic drug delivery and activity has not yet yielded a therapeutic breakthrough in PDAC. Targeting the Sonic Hedgehog Signaling (SHH) pathway, which is vital in pancreatic tumorigenesis, with saridegib and vismodegib have also been disappointing, highlighting the complexity of the disease and the need for continued research to find more effective treatments [19, 20]. Preclinical models demonstrated that SHH may be preferentially expressed in myoepithelial CAFs which is believed to be a major reason for the unfavorable outcomes despite targeting this pathway.
Preclinical studies on modified hyaluronidase molecule, PEGPH20, showed promising results by decreasing tumor hyaluronic acid content, reducing interstitial fluid pressures, and enhancing tumor vascularity. These findings led to clinical trials combining PEGPH20 with nab-paclitaxel and gemcitabine or FOLFIRINOX. A phase IB/II trial compared PEGPH20 plus FOLFORINOX against FOLFORINOX alone. Results showed that the addition of PEGPH20 did not improve overall survival (OS) and was associated with higher toxicity. In addition, median OS for patients receiving combination was significantly lower at 7.7 months, compared to 14.4 months with modified FOLFORINOX [21]. Similarly, the addition of PEGPH20 to nab-paclitaxel and gemcitabine did not improve OS or progression-free survival (PFS), with both groups demonstrating a median OS and PFS of approximately 11 and 7.1 months respectively. Treatment with PEGPH20 resulted in a higher objective response rate (ORR). However, it did not enhance the duration of response. Adverse events were more frequent in the PEGPH20 group, particularly grade 3 treatment related adverse events (TRAEs) like fatigue and muscle spasms [22].
Integrin αVβ3 is preferentially expressed on inflammatory CAFs and neoangiogenic endothelial cells in PDAC and was therefore considered as a potential therapeutic target [23]. ProAgio is a monoclonal antibody that targets integrin αVβ3 leading to apoptosis of cellsthat express this marker. It is currently under clinical investigation in a phase I trial in combination with gemcitabine and nab-paclitaxel for treating metastatic PDAC. The primary endpoint of this study is safety of the combination regimen with additional focus on assessing its pharmacokinetics, pharmacodynamics, and overall treatment efficacy (NCT06182072).
The complex dense stromal microenvironment also plays a crucial role in acquired resistance to therapies, whether chemotherapies , targeted therapies or immune-modulating treatments. Several factors have been studied as vital determinants of PDAC microenvironment that contribute to treatment resistance.
Hypovascularity: PDAC is characterized by low microvascular density which reflects the dense fibrotic reaction that is characteristic of PDAC microenvironment and may trap proangiogenic molecules in the stroma, thereby limiting their capacity to trigger angiogenesis [24]. A proteogenomic analysis of PDAC demonstrated an inverse correlation between vascularity and cellular infiltration [25]. Hypovascularity hinders the penetration and distribution of drugs into the tumor microenvironment, thereby limiting their efficacy. Moreover, poor vascularization deprives cancer cells from nutrients for proliferation. In order to adapt, cancer cells activate autophagy which allows them to recycle their own cellular components and sustain metabolic functions. This adaptation not only supports continued tumor growth under adverse conditions but also increases resistance to chemotherapy and radiationas autophagy helps cancer cells survive the cellular damage induced by these therapies. Autophagy has also been found to promote immune evasion by causing degradation of major histocompatibility complex (MHC) class I molecules in pancreatic cancer cells, which are necessary for recognition by CD8 + cytotoxic T cells. In mouse models, inhibiting autophagy was shown to reverse this process, sensitizing PDAC to immunotherapy [26, 27].
Fibrosis: Dense fibrosis is frequently described as a physical barrier to therapeutic effectiveness in PDAC. Fibroblasts produce extracellular matrix (ECM) components, which lead to fibrosis. Additionally, CAFs mediate collagen cross-linking, which modifies tumor stiffness, promotes tumor growth and cancer cell migration through remodeling stromal microenvironment. Single-cell analyses of PDAC tumors have identified distinct CAF subsets, each with unique transcriptional profiles and spatial organization. These subsets interact with cancer cells based on their differentiation status: alpha smooth muscle actin (α-SMA) + CAFs are located near well-differentiated cancer cell nests, while Fibroblast activating protein (FAP) + CAFs cluster around poorly differentiated tumor regions [28].
The PDAC stromal microenvironment is enriched with markers such as collagen, FAP, or α-SMA, each of which is linked to different survival outcomes and molecular features, highlighting the complexity and heterogeneity of the tumor stroma [29]. CD105 + CAFs, which include both myofibroblastic and inflammatory types, are tumor-promoting, supporting cancer progression and suppressing antitumor immune responses. In contrast, CD105-negative (CD105⁻) CAFs have tumor-restrictive functions, showing lower expression of FAP and higher expression of MHC class II antigen machinery, which allows them to present antigens and potentially enhance adaptive immune responses. This antigen-presenting CAF subset may strengthen the immune system’s ability to suppress tumors, unlike other CAF populations that impair immune-mediated tumor control. This highlights the diverse and complex roles of CAF subsets in regulating both tumor progression and immune activity [30].
Immune Evasion: Immune evasiveness of PDAC is multifactorial and influenced by intrinsic and extrinsic mechanisms. The lack of potent immunogenic tumor antigens and immunogenicity (ineffective antigen presentation), which hinders T cell priming, leads to immunotherapy resistance. Additionally, PDAC is characterized by exclusion of leukocyte populations (e.g., T cells and dendritic cells) that are necessary for immune recognition. On the other hand, PDAC is known for its recruitment of myeloid and fibroblast populations that possess immune suppressive and tumor-promoting features. Systemic factors, including inflammation, reduced dendritic cells, and dysfunctional peripheral T cells further weaken immune responses. Elevated neutrophil-to-lymphocyte ratios, linked to systemic inflammation, also reduce chemotherapy efficacy. These multifactorial mechanisms collectively drive PDAC’s immune evasiveness and therapy resistance [31, 32].
Remodeling of the tumor microenvironment: Tumor microenvironment in PDAC acts as a barrier to effective therapy, but it is also adaptable, offering potential for therapeutic reprogramming. By targeting key components of the TME such as myeloid cells, fibroblasts, or extracellular matrix (ECM) the resistance of PDAC to cytotoxic and immune-based therapies can be reduced. For example, depleting Colony-Stimulating Factor 1 Receptor (CSF1R+) myeloid cells enhances T cell infiltration improving chemotherapy outcomes in both mouse models and some patients [33]. Additionally, inhibiting focal adhesion kinase (FAK) reduces immunosuppressive leukocytes like myeloid and regulatory T cells (Tregs), thereby sensitizing PDAC tumors to chemotherapy and immunotherapy in mice [34]. These findings highlight that although therapeutic resistance in PDAC is driven by multiple mechanisms within the TME, disrupting specific components could improve treatment responses.
Novel therapeutic advancements
PDAC is characterized by several key genetic mutations that drive its development and progression. The most prevalent include KRAS, TP53, CDKN2A and SMAD4 [35]. Understanding these mutations has been pivotal in developing targeted therapeutic strategies. Almost 90% of PDAC patients harbor KRAS mutations which led to the development of several targeted strategies [36]. Similarly, TP53 mutation, a tumor suppressor gene is detected in 50–75% of PDAC cases [37]. Therapeutic approaches aiming to restore p53 function or exploit its pathways are under investigation. The CDKN2A gene and SMAD4, involved in the TGF-β signaling pathway are also common in PDAC with several studies investigating their potentials as therapeutic targets in PDAC [38]. Although these are the most common mutations detected in PDAC, there are other mutations such as BRCA1/2 mutations have been identified in subsets of PDAC patients. These findings have led to the use of PARP inhibitors, which have shown efficacy in BRCA-mutated PDAC [39]..
RAS targeted therapy
The RAS gene family plays an indispensable role in regulating cell division, growth, and differentiation. Mutations in KRAS, HRAS and NRAS are the most frequently mutated RAS-genes with the predominance of KRAS mutation in PDAC in up to 90% of cases [40]. Sotorasib (AMG 510) is a first-in-class orally available, selective and irreversible inhibitor of KRAS G12C mutation, which has a 1–2% incidence in PDAC [41]. It has been FDA-approved for the treatment of advanced NSCLC, based on the phase II CodeBreaK-100 trial (n-38 PDAC patients). Although activity of sotorasib in PDAC was not as effective compared to NSCLC, it demonstrated an objective response rate (ORR) of 21% (95% CI, 10–37), disease control rate (DCR) of 84.2% (95% CI, 68.7–93.9), median progression free survival (PFS) of 4.0 months (95% CI 2.8–5.6) and median OS of 6.9 months (95% CI 5.0–9.1) [42]. Adagrasib (MRTX849), another direct KRASG12C inhibitor with a longer half-life than sotorasib at 23 h, has been investigated in KRYSTAL-1 trial [42]. ORR was 33.3% (95% CI 14.6–57.0) and DCR was 81% (17/21) in the PDAC cohort (n = 21). Median PFS was 5.4 months (95% CI, 3.9–8.2) and median OS was 8.0 months (95% CI 5.2–11.8). Divarasib (GDC-6036) is another KRASG12C inhibitor which demonstrated activity in metastatic PDAC patients. In a phase I trial of 137 patients with advanced KRASG12C mutated solid tumors, 7 had PDAC and 43% (3/7) and 57% (4/7 patients) experienced partial response and stable disease respectively [43]. The majority of reported adverse events were gastrointestinal, such as nausea, vomiting, diarrhea, and abdominal pain, while Grade 3 and 4 events included transaminitis and hepatitis [44].
Sotorasib, adagrasib, and divarasib are groundbreaking targeted therapies of KRAS G12C mutation which was previously considered “undruggable.” They function by irreversibly binding to and inactivating the mutated KRAS protein, thus blocking its ability to trigger downstream signaling pathways essential for cancer cell growth and survival. This targeted approach has shown effectiveness in clinical trials across solid tumors with KRAS G12C mutation (Table 1). These therapies represent a significant advancement in personalized cancer treatment, paving the way for further potential targets to be investigated.
Table 1.
Novel RAS inhibitors under development
| Trial ID | Drug | Phase/N | Mechanism of action | Aim of the study | Results |
|---|---|---|---|---|---|
| KRASG12C Inhibitors | |||||
| NCT03785249 (Recruting) | Adagrasib | Phase I/II/822 | Orally-available small molecule inhibitor of KRAS G12C. | Evaluating safety, tolerability, pharmacokinetics, and clinical activity of adagrasib in patients with advanced solid tumors with KRAS G12C mutation |
No maximum tolerated dose was formally defined 8 of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with KRASG12C-mutant NSCLC achieved PR -The median DOR was 16.4 months (95% CI, 3.1 to not estimable) The median PFS was 11.1 months (95% CI, 2.6 to not estimable). 4 One of two patients with KRASG12C-mutant CRC achieved a PR (DOR, 4.2 months) The most common TARE (any grade) were nausea (80 0.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3–4 TARE was fatigue (15.0%) No results for PDAC patients are published yet |
| NCT03600883 (CodeBreaK100) (Active, not recruiting) | Sotorasib | Phase I/II/713 | Selectively and irreversibly inhibits KRASG12C | Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Sotorasib | Sotorasib produced an ORR was 41%, median DOR was 12.3 Sotorasib was well tolerated, with few late-onset treatment-related toxicities, none of which led to treatment discontinuation. Results on PDAC Patients are not yet published |
| NCT04185883 (CodeBreaK101) (Recruiting) | Sotorasib | Phase I/II/1200 | Selectively and irreversibly inhibits KRASG12C. | Evaluating the safety, tolerability, pharmacokinetics, and efficacy of sotorasib monotherapy and in combination in advanced Solid tumors with KRAS p.G12C mutation |
Among 48 patients with chemotherapy-refractory KRAS G12C-mutated CRC (ORR): 30.0% (95% CI: 16.6–46.5%) (PFS): 5.7 months (95% CI: 4.2–7.7) (OS): 15.2 months (95% CI: 12.5–not estimable) Safety: TRAEs occurred in 94% of patients, with 27% experiencing grade ≥ 3 TRAEs. Among 37 NSCLC patients Confirmed ORR: 65%Safety: The most common treatment- (TRAEs) included: Neutropenia/Neutrophil count decreased: 48%, Anemia: 41%,Nausea: 41%,Thrombocytopenia/Platelet count decreased: 40%,Asthenia: 33% Grade ≥ 3 TRAEs reported in 49% of patients, with the most common being neutropenia and anemia. No fatal TRAEs were reported |
| NCT05178888 (KRYSTAL-16) (Completed) | Adagrasib | Phase I/11 | Selectively and irreversibly binds to the cysteine residue locking KRAS G12C in its inactive state, thereby inhibiting downstream signaling pathways and leading to tumor cell death | Evaluating pharmacokinetics and preliminary clinical activity of adagrasib in combination with palbociclib in patients with advanced solid tumor malignancies | Results have not been published yet |
| NCT04973163 (Active, not recruiting) | BI-1823911 | Phase I/30 | Has potent anti-proliferative activity in a panel of KRASG12C mutant cancer cell lines | Evaluating safety, pharmacokinetics and preliminary efficacy of BI 1,823,911 as a monotherapy and in combination in patients with advanced or metastatic solid tumors with KRAS G12Cmutation | Results have not been published uet |
| NCT04449874 (Recruiting) | Divarasib | Phase I/498 | Binding to the KRAS G12C mutation, trapping the mutated protein in an inactive state, preventing it from sending pro-growth signals within the cell and ultimately inhibiting tumor growth | Evaluating the safety, pharmacokinetics, and activity of divarasib monotherapy or in combination in patients with advanced or metastatic solid tumors with KRAS G12C. |
No dose-limiting toxic effects or treatment-related deaths were reported. TARE occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 e0vent in 1 patient (1%). TARE resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). In NSCLC cohort, (60 patients) The confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), The median PFS was 13.1 months (95% CI, 8.8 to could not be estimated). In CRC cohort, (55 patients) The confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), The median PFS was 5.6 months (95% CI, 4.1 to 8.2). No results published in PDAC patients have been published yet. |
| NCT05002270 (Recruiting) | Glecirasib | Phase I/II/48 | Binding to the mutated cysteine residue on the KRAS G12C protein, effectively trapping it in an inactive state | Evaluate the safety, tolerability, pharmacokinetics, and preliminary evidence of antitumor activity of glecirasib in patients with advanced solid tumors with KRAS G12C mutation | Among 28 pts with PDAC, 13 achieved PR with the ORR of 46.4% (13/28) and DCR of 96.4%; the DOR and PFS were 4.1 months and 5.5 months (95%CI 1.2, 13.1), respectively. TRAE of any grade occurred in 89.6% (43/48) pts; the most common (≥ 10%) TRAE were anemia (52.1%), blood bilirubin increased (39.6%), white blood cell count decreased (18.8%), ≥Grade 3 TRAE occurred in 25% (12/48) pts; no TRAE were fatal or led to treatment discontinuation |
| NCT05379946 (Active, not recruiting) | Garsorasib | Phase I/II/92 | KRASG12C inhibitor | Evaluate safety, tolerability, pharmacokinetics and efficacy of garsorasib in patients with advanced solid tumors with KRAS G12C mutation | Among 79 NSCLC treated patients, 75 patients (94.9%) reported TARE with 30 patients experiencing grade 3 or 4 events (38.0%). Among 74 patients assessable for efficacy analysis, 30 patients had a PR and 38 had SD with ORR and DCR of 40.5% and 91.9%, respectively. The median PFS was 8.2 months, and the median duration of response DOR was 7.1 months. Among 62 in phase 2 PR oc- curred in 24 patients (ORR, 38.7%) and SD in 32 patients (DCR, 90.3%). The median PFS and DOR were 7.6 months and 6.9 months, respectively. In patients with brain metastasis, ORR and DCR were 17% and 100%, respectively |
| KRASG12D Inhibitors | |||||
| NCT05382559 (Recruiting) | ASP3082 | Phase I/651 | Binds to and targets KRASG12D for proteasome-mediated degradation | Evaluations of safety and tolerability of ASP3082 in patients withadvanced solid tumors with KRAS G12D mutation called KRAS G12D. |
111 participants were enrolled for all dose levels, including 74 with PDAC, 16 with CRC, and 19 with NSCLC. All patients were pretreated with a median of two prior lines of therapy For patients with PDAC and NSCLC who received 300 to 600 mg of ASP3082 as follows: In the PDAC group, 6 of 27 participants remained on treatment, and five participants had PR, with a median time to response of 2.6 months. In the NSCLC group, 8 of 13 remained on treatment Three participants had PR, with a median time to response of 1.4 months DOR and PFS were not mature. Common Adverse Events: Fatigue (15%), infusion-related reactions (14%), and elevated liver enzymes (AST and ALT increases in 7% and 6% of patients, respectively) Grade 3 Adverse Events: Observed in 5% of patients |
| NCT05533463 (Recruiting) | HRS-4642 | Phase I/108 | KRASG12D inhibitor | Evaluate the safety, Tolerability, and pharmacokinetics of HRS-4642 in patients with advanced solid tumors with KRAS G12D mutation | Results have not been published yet |
| NCT06428500 (Recruiting) | QTX3046 | Phase I |
Orally bioavailable KRASG12D inhibitor, picomolar-level binding affinity (0.01nM) to inactive KRASG12D |
To determine the safety and tolerability of QTX3046 as a single agent or in combination with cetuximab | Results have not been published yet |
| NCT06227377 (Recruiting) | QTX3034 | Phase I/250 | Selective, orally bioavailable, and picomolar-level binding affinity (0.6 nM) to GDP-bound KRASG12D | Evaluating the safety, tolerability, and efficacy of QTX3034 in patients with solid tumors with KRASG12D mutation | Results have not been published yet |
| NCT05737706 (Terminated) | MRTX1133 | Phase I/63 | Selective KRASG12D inhibitor that binds to GDP-bound state, with a nanomolar-level IC50 | Exploration of MRTX1133 dose and regimen, and collecting sufficient safety and PK information | No clinical efficacy or safety data for MRTX1133 from this trial have been publicly released. The study was terminated prior to initiating Phase 2, and only Phase 1 was conducted. Therefore, detailed results regarding the outcomes of the trial are not available |
| Non-selective KRAS inhibitors | |||||
| NCT06625320 (Recruiting) | RMC-6236 | Phase III/460 | Oral RAS (ON) multi-selective tri-complex inhibitor | Comparing (PFS) and OS in patients on RMC-6236 compared to standard trearment in metastatic PDAC patients treated with 5-flurouracil (5-FU) or gemcitabine based regimen will improve (PFS) or (OS) compared to investigator’s choice of standard of care chemotherapy in patients with metastatic PDAC who were previously treated with one prior line of therapy with 5-fluorouracil (5-FU) based or gemcitabine-based regimen | No Results have been published yet |
| NCT06078800 (Recruiting) | YL-17,231 | Phase I/80 | Pan-RAS inhibitor has potent anti-proliferative activity on tumor cells |
-Evaluate the safety and tolerability of YL-17,231 Determine the MTD and recommended Phase 2 dose (RP2D) |
No Results have been published yet |
| NCT06096974 (Recruiting) | YL-17,231 | Phase I/60 | Pan-RAS inhibitor has potent anti-proliferative activity on tumor cells | Evaluate safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of Pan-RAS Inhibitor YL-17,231 in patients with advanced solid tumors with mutations in KRAS, HRAS, or NRAS | No Results have been published yet |
ORR Objective response rate, AE Adverse events, PR Partial response, DCR Disease control rate, DOR Duration of response, PFS progression-free survival, TARE Treatment related adverse events, CRC Colorectal cancer, NSCLC non-small cell lung carcinoma, OS Overall Survival, SD: Stable Disease, PK Pharmacokinetics, MTD Maximum tolerated dose
Pan-RAS and Ras-selective allele targeted therapies represent cutting-edge strategies in PDAC management. These treatments target specific Ras alleles or the broader family of Ras proteins respectively to inhibit their function and disrupt the signaling pathways that drive tumor growth and survival. RMC-4630 is a SHP2 inhibitor and a novel pan-RAS therapy that is currently under investigation in a multicenter open-label phase 1 study to evaluate its safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles (NCT03634982). SOS1 inhibitors (e.g., BI 1701963) are pan-RAS targeted therapeutic agents that have been studied both as a monotherapy and in combination with MEK inhibitors to enhance efficacy against RAS-mutated cancers. Early trial results have shown that BI 1,701,963 can inhibit RAS pathway signaling safely and effectively, leading to improved disease control rates in patients with advanced solid tumors with RAS mutations. These findings suggest a potential therapeutic role for SOS1 inhibition in managing PDAC, though further confirmatory studies are needed to strengthen the evidence (NCT04111458) (Fig. 1).
Fig. 1.
Targeted therapeutic strategies across the RAS signaling pathway. This figure illustrates the RAS–MAPK and PI3K–AKT–mTOR pathways. Therapeutic approaches include mutant KRAS inhibitors (e.g., sotorasib, MRTX849), SHP2 inhibitors (e.g., SHP099), RAF/MEK/ERK inhibitors, PI3K/mTOR pathway inhibitors, RAS–SHP2–GRB2 disruptors (e.g., RMC-6236). Immunotherapeutic modalities such as anti-cancer vaccines and KRAS-targeted therapies are also demonstrated
MRTX1133 is a notable noncovalent inhibitor designed to target the KRAS G12D mutation, prevalent in various cancers, including PDAC. Through extensive structure-based drug design, MRTX1133 was identified as a potent and selective inhibitor, demonstrating high-affinity binding to KRAS G12D with a dissociation constant (Ka) of approximately 0.2 pM and an inhibitory concentration (IC₅₀) below 2 nM. In preclinical studies, MRTX1133 effectively suppressed KRAS G12D signaling, leading to significant tumor regression in xenograft models, including those derived from PDAC. These findings suggest that MRTX1133 holds promise as a therapeutic agent against KRAS G12D-driven malignancies [45].
Although KRAS is the most common mutation in PDAC, NRAS similarly leads to constitutive activation of MAPK (RAF–MEK–ERK) and PI3K–AKT pathways, all of which drive tumor proliferation and survival [46]. STK19 kinase was recently reported to be a novel activator of NRAS and a potential therapeutic target for NRAS-mutant melanomas. Chelidonine, a potent and selective inhibitor of STK19 kinase activity, demonstrated inhibition of NRAS signaling, cell proliferation and induction of apoptosis in a panel of NRAS-mutant cancer cell lines, including melanoma, liver, lung, and gastric cancers [47]. Alternative therapeutic strategies for NRAS-mutant PDAC often target downstream pathway inhibition, such as MEK or ERK inhibitors, to block key effectors of the NRAS signaling cascade. Combination regimens, such as MEK plus CDK4/6 inhibition, are currently being studied in NRAS-mutant solid tumors, including PDAC, to overcome adaptive resistance [48].
Limitation of targeting KRAS mutation
Although sotorasib and adagrasib were approved for KRAS G12C-mutant NSCLC, they are relatively less effective in CRC and PDAC, with limited duration of response before disease progression [49, 50]. Resistance arises from two main mechanisms; mutations in KRAS itself, which alter its drug-binding or signaling ability, and secondary mutations in other parts of the tumor genome. Tumors evolve due to genetic instability, selecting resistant mutations and altering treatment sensitivity as they grow and metastasize. Another common resistance mechanism to KRAS inhibitors is mutant KRAS amplification which disrupts the balance between the drug and its target. In sotorasib-treated patients, 7% developed KRAS G12C amplifications, which increased during treatment, particularly in CRC. Additionally, some tumors escape therapy by losing the KRAS G12C mutation entirely and activating alternative cancer-driving pathways [51–53]. The reactivation of the MAPK pathway is one of the adaptive resistance mechanisms. This resistance arises from feedback loops where inhibition of KRAS or MEK leads to compensatory activation of upstream receptor tyrosine kinases, such as EGFR, resulting in sustained ERK signaling and tumor cell survival. For instance, studies have shown that combining KRAS or MEK inhibitors with mTORC1/2 inhibitors can overcome this resistance, leading to enhanced cytotoxicity and tumor regression in PDAC models [54].
TP53 targeting strategies
The tumor protein 53 (TP53) mutation is clinically recognized in 50–90% of patients with PDAC. TP53 mutations often co-occur with KRAS mutations, suggesting early KRAS involvement in pancreatic carcinogenesis [55]. Moreover, TP53 mutations affect PDAC microenvironment, influencing immune responses, T-cell differentiation and interactions with CAFs. Multiple studies demonstrated the role of p53 in tumor progression since its discovery. However, mutant forms of the tumor-suppressor p53 not only lose their tumor-suppressive properties but also frequently acquire tumor-promoting properties. Developing p53-targeted therapies can be challenging because the agent must specifically target mutp53 in cancer cells while having no effect on normal cells harboring wild type p53. Hence, major therapeutic strategies targeting p53 can be classified into two categories based on their p53 status either to restore wtp53 functions or eradicate mutp53 [56, 57].
Restoring p53 function: In cancers with intact wild-type TP53 (wtp53), p53’s tumor-suppressor function can be inhibited by mechanisms that rely on the action of Mouse Double Minute 2(MDM2), its major negative regulator. MDM2 prevents p53 from entering the nucleus, inhibiting its DNA-binding capacity, and promoting its degradation [58]. A study using data from The Cancer Genome Atlas (TCGA) confirmed that MDM2 overexpression often correlates with intact p53 across various cancer types. This finding has led to the development of MDM2 inhibitors as a potential therapeutic approach for cancer harboring wtp53. Nutlin-3a, class of cis-imidazoline analogs, blocks the p53-MDM2 interaction and has spurred extensive research into their clinical applications. By preventing MDM2 from inhibiting p53, these inhibitors aim to restore p53’s tumor-suppressive functions [59, 60].
Nutlins are preclinical drugs designed to inhibit tumor growth by reactivating (wtp53). In clinical trials, patients achieved stable disease on RG7112 (RO5045337). Although nutlins work by strongly activating the p53 pathway in tumors with MDM2 overexpression, they are ineffective in cancers that overexpress Mouse Double Minute X (MDMX), a related protein that also inhibits p53 but through a different p53-binding pocket [61]. To overcome this limitation, dual inhibitors targeting both MDM2 and MDMX were developed. ALRN-6924 is the first and only dual MDM2/MDMX inhibitor to enter clinical trials after preclinical studies demonstrated its significant antitumor effects. Since MDM2 and MDMX suppress p53 via different mechanisms. Dual antagonism therapy is believed to have greater therapeutic potential by simultaneously targeting two different pathways to restore p53 activity in tumors with high levels of either MDM2 or MDMX. [62]
Since p53 is often mutated (mutp53) in cancers, therapies that prevent p53 degradation by targeting MDM2/MDMX only work in cancers with wtp53, which limits their clinical application. Thus, studies aimed to directly target and restore the function of mutated p53 are vital. Theoretically, the restoration of mutp53 is as follows: [1] Some mutp53 proteins can regain normal (wild type) activity at certain “permissive” temperatures [2]. A second-site suppressor mutation can adapt to deleterious mutations and restore wild-type activities, and [3] A synthetic peptide, such as CDB3, derived from p53-interacting proteins (e.g., 53BP2), can bind to the mutant p53 core and help it recover its DNA-binding ability, thus restoring its tumor-suppressing function [63]. Table 2 summarizes novel compounds that have been discovered with the ability to reactivate mutp53.
Table 2.
Compounds known to reactivate mutant p53 (mutp53),
| Compound name | Mechanism | Mutant p53 target | References |
|---|---|---|---|
| CP-31,398 | Binds to the denatured DNA-binding domain of mutp53 and restores nature p53 conformation | V173A, S241F, R249S, R273H | [64] |
| PRIMA-1 | Enhances wtp53 stability at 37 °C, and restores their DNA binding ability | R175H, R273H | [65] |
| STIMA-1 | Binds to the core domain of mutant p53 and results in the stabilization of wtp53 conformation | R175H, R273H | [66] |
| P53R3 | Restores sequence-specific DNA-binding ability of several mutp53 | R175H, M237I, R273H | [67] |
| ZMC1 | Provides addition Zn2+ to cancer with mutp53 for proper folding | R175H, R172H | [68] |
Depletion of mutant p53: Another strategy focuses on targeting mutant p53 to slow tumor progression is based on two key observations; depleting mutp53 reduces cancer growth, according to studies silencing mutp53 using RNA-based methods, such as small interfering RNA (siRNA) or short hairpin RNA (shRN) can suppress its ability to drive cancer progression. Additionally, unlike wild type p53, mutp53 tends to be naturally unstable and degrades quickly unless stabilized by specific mechanisms in cancer cells. Thus, numerous compounds have been developed with a main goal to limit the production of mutp53 and enhance its degradation, consequently limiting its cancer-promoting effect [69, 70]. Table 3 summarizes some of the compounds developed that directly target mutp53.
Table 3.
Compounds directly targeting mutp53
| Compound name | Mechanism | Target | References |
|---|---|---|---|
| Gambogic acid | Increases wtp53 proteins levels, inhibits mutp53-Hsp90 complex and induces CHIP-mediated degradation | R175H, G266E, R273H, R280K | [71] |
| Spautin-1 | Inhibits macro-autophagy to induce mutp53 degradation via chaperone-mediated autophagy | P98S, P151H, A161T, R175C, R175D, R175H, L194F, S227K, S227R, G245C, R248L, R248W, E258K, R273H, R273L, R280K, and R282W | [72] |
| NSC59984 | Promotes MDM-mediated mutp53 protein degradation and stimulating p73 | R175L, R175H, S241F, R273H/P309F | [73] |
| HDAC inhibitor | Inhibits HDAC-regulated transcription and disrupts HDAC6/Hsp90/mutp53 complex | R175H, R280K, V247F/P223L | [74] |
Wtp53: Wild type p53, Hsp90: heat shock protein 90, CHIP (carboxyl terminus of Hsp70-interacting protein), HDAC: histone deacetylase
Limitations of P53 targeting therapies: Directly targeting mutp53 is far more challenging due to the structural diversity of mutp53, which makes it challenging to develop a single compound that can target al.l p53 mutations. Moreover, restoring p53 activity can lead to side effects because the p53 pathway is highly complex and can impact normal tissues. For example, hematological toxicities have been reported in some patients on the MDM2 inhibitor RG7112. ‘; [57, 59]
Cyclin-Dependent kinase inhibitor 2 A (CDKN2A) mutation target therapy
CDKN2A gene is a critical tumor suppressor gene, playing pivotal roles in the regulation of cell growth and division. The encoded proteins exert their tumor-suppressive effects by inhibiting cell-cycle progression, promotes apoptosis, senescence and inhibits cancer-associated processes like cell-in-cell structure formation and anchorage-independent growth, while it modulates anti-tumor immunity by influencing immune-cell infiltration. CDKN2A mutations play a significant role in pancreatic tumors, with somatic mutations present in up to 95% of pancreatic tumors and a genetic predisposition observed in familial cases. Targeting the CDKN2A pathway presents several therapeutic opportunities, although indirect targeting is often necessary due to the difficulty of directly restoring tumor suppressor function [75].
Neuregulin 1 (NRG1)
Neuregulin 1 (NRG1) fusions are rare oncogenic drivers that have been detected in NSCLC, PDAC and constitute less than 1% of solid tumors [76]. The FDA recently granted accelerated approval for a novel targeted therapy, zenocutuzumab IV 750 mg every 2 weeks, for advanced PDAC or NSCLC that harbor NRG1 gene fusion. This approval was based on the promising results of a phase 2 clinical trial in patients with refractory locally advanced unresectable or metastatic solid tumors with NRG1 gene fusion. Thirty adults with advanced or metastatic NRG1 fusion-positive PDAC were included in the study. Objective response rate, the primary end point of the study, was 40% (95% CI, 23-59%) and median DOR was 11.1 months (95% CI, 7.4 to 12.9) in 30 patients with PDAC. The most common (≥ 10%) treatment related adverse effects (TRAEs) were diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema, while the most common Grade 3 or 4 laboratory abnormalities were increased gamma-glutamyl transferase, anemia, thrombocytopenia, and hyponatremia [77].
TGF-β targeted therapy
TGF-β plays a critical role in tumor suppression by promoting apoptosis, controlling the cell cycle and enhancing TME by stimulating stromal growth. Bone Morphogenetic Protein2 (BMP2), which is upregulated in PDAC, particularly affects cancer cells with SMAD mutations by promoting their growth and facilitating epithelial-mesenchymal transition (EMT) [78, 79]. It has been demonstrated that BMP signaling contributes to epithelial-mesenchymal transition (EMT) which is regulated by Gremlin 1 (Grem1). Grem1 binds to BMP ligands, preventing them from activating BMP receptors on the cell surface causing cellular heterogeneity within the tumor microenvironment, as it prevents cells from undergoing EMT simultaneously, thus preserving a mix of epithelial and mesenchymal traits. This impacts multiple aspects of cancer progression, including response to treatment, ability to metastasize and resistance to treatment [80]. Additionally, studies have demonstrated that Grem1 is expressed by activated fibroblasts and that higher expression is linked to a more advanced stage of the tumor [81].
Other pathways that have been investigated with disappointing results include the WNT signaling pathway which plays a critical role in regulating cell growth, differentiation, and survival; alterations in this pathway contribute to cancer initiation, progression, and resistance to therapy. Approximately 5 to 7% of PDAC cases involve mutations in the ring finger protein 43 (RNF43), which normally inhibits WNT signaling by promoting degradation of FZD receptors and LRP5/6 co-receptors. Inactivation of RNF43 leads to an increased dependency on WNT ligands for cell growth. Despite the potential of targeting WNT signaling, therapies aimed at inhibiting WNT ligands or blocking FZD receptors have been largely unsuccessful, primarily due to severe side effects such as bone density loss. Simultaneously, the NOTCH pathway that is overactivated in pancreatic cancer stem cells, known for their role in drug resistance, is targeted through treatments like γ-secretase inhibitors (GSI) and anti-Notch antibodies, aiming to mitigate the stem cells’ impact on tumor persistence and therapy resistance [82, 83]. Table 4 summarizes ongoing clinical trials investigating novel therapeutic targets for PDAC.
Table 4.
Clinical trials on novel therapeutic targets in PDAC
| Clinical Trial | Target | Study | Regimen/Agent | Mechanism of Action | Results |
|---|---|---|---|---|---|
| NCT01839487 | PEGPH20 Hyaluronidase | III | Combined with chemotherapy (e.g., nab-paclitaxel, gemcitabine) | Targets hyaluronic acid in tumor matrix to enhance drug delivery |
Median OS: 11.2 Months for the PEGPH20 arm vs. 11.5 months for the placebo arm Median PFS: 7.1 months in both arms (HR, 0.97; 95% CI, 0.75 to 1.26) ORR: 47% in the PEGPH20 arm vs. 36% in the placebo arm (ORR ratio, 1.29; 95% CI, 1.03 to 1.63) |
| NCT04291079 | TGFβ1 | I | SRK-181 administered alone or in combination with anti-PD-(L)1 | Inhibits latent TGFβ1 activation |
SRK-181 was generally well tolerated across all tested doses No dose-limiting toxicities (DLTs) were observed up to 3000 mg every 3 weeks (q3w) or 2000 mg every 2 weeks (q2w) as monotherapy, and up to 2400 mg q3w in combination with anti–PD-(L)1 therapy |
| NCT04888312 | CD40 Agonists | Ib/2 | Mitazalimab + modified FOLFIRINOX (mFOLFIRINOX) | Modulates tumor immune microenvironment |
(ORR): The confirmed ORR was 42.1%, with an unconfirmed ORR of 54.4% among evaluable patients (DOR): The median DOR was 12.6 months (PFS): The median PFS was 7.7 months, with a 12-month PFS rate of 35.1% (OS): The median OS was 14.9 months, and the 18-month OS rate was 36.2% 24-Month Survival: At a median follow-up of 25.4 months, the 24-month survival rate was 29.4%, compared to historical rates of 8% with FOLFIRINOX alone |
| NCT03454035 | CDK4/6 | I | Palbociclib + Ulixertinib | Cell cycle arrest | PFS was 2.05 months |
| NCT02912949 | ERBB3 | I/II | Zenocutuzumab | HER2, HER3 bispecific antibody, reduces cell growth in NRG1 cancer cell lines and induces durable clinical responses in patients with NRG1 fusion–positive tumors |
ORR: Among 158 patients with measurable disease, the ORR was 30% (95% CI, 23–37%) DoR: The median DoR across all tumor types was 11.1 months (95% CI, 7.4–12.9) PFS: The median PFS was 6.8 months (95% CI, 5.5–9.1) |
| NCT01485744 | Integrin αvβ8 and αvβ1 | I | PLN-101,095 | Prevents activation of TGF-β and enhance response to chemotherapy | Not yet published |
| NCT06182072 | αvβ3 | I/Ib | ProAgio in combination with Gemcitabine and nab paclitaxel | Targets cancer-associated pancreatic stellate cells to induce apoptosis | Not yet published |
| NCT03821935 | GARP-TGF-β1 | I | Livmoniplimab (ABBV-151) or combined with Budigalimab | Enhances the immunogenicity of PDAC TME by activation of TGF-β1 | Not yet published |
| I | |||||
| NCT01485744 | Sonic Hedgehog (SHH) Pathway | Ib | Sonidegib in combination of with fluorouracil, leucovorin, oxaliplatin, and irinotecan | Blocks activation of SHH pathway by inhibiting Smoothened (SMO) protein | Not yet published |
| NCT03093116 | TRK | I/II | Repotrectinib | Inhibits the activity of ROS1 and TRK and preventing uncontrolled cell proliferation | Not yet published |
GARP-TGF-β1 glycoprotein-A repetitions predominant, TGF Tumor Growth Factor, Smo Smoothened protein, HER Human Epidermal growth factor receptor, TRK tropomyosin receptor kinase
Immunotherapy
The emergence of immune checkpoint inhibitors (ICIs) have significantly advanced the treatment landscape of various solid tumors and demonstrated notable success in gastrointestinal cancers. However, results in PDAC have been less encouraging, with ICIs generally showing limited efficacy [84]. Despite this, ongoing research into the TME and predictive biomarkers is beginning to identify PDAC patient subsets that could benefit from ICI. Current studies are also focused on overcoming resistance and increasing tumor immunogenicity, aiming for effective immunotherapeutic strategies in PDAC in the future (Table 5) [85].
Table 5.
Trials on immune checkpoint inhibitors
| Trial | Agent | Target | Combination therapy | Phase/N | Results |
|---|---|---|---|---|---|
| NCT04060342 | Atezolizumab + Selicrelumab (CD40 agonist) + Bevacizumab + Tiragolumab + Tocilizumab | PD-L1, CD40, VEGF, TIGIT, IL-6R | Nab-Paclitaxel + Gemcitabine + Oxaliplatin + Leucovorin + Cobimetinib + Fluorouracil + PEGPH20 + BL-8040 (CXCR4 antagonist) + RO6874281 + AB928 + LSTA1 | I, II/340 | ORR was 6.1% in atezolizumab plus PEGPH20 group (arm A) vs 2.4%in chemotherapy3-4 AEs grade reported was 65.2% (arm A) vs 61.9% (arm B) |
| NCT03006302 | Pembrolizumab | PD-1 | Epacadostat (INCB24360) + CRS207 + GVAX cancer vaccine | II/40 | Determining the recommended dose of epacadostat. Results were not published |
| NCT02758587 | Pembrolizumab | PD-1 | Defactinib | I, II/59 |
1. Safety and tolerability 2. Objective response rate (ORR), Duration of response (DOR). ORR was 21% and DCR of 71%. (PFS) was 5.0 months, and median (OS) was 9.9 months |
| NCT05630183 | Botensilimab (AGEN1181) | CTLA-4 | Gemcitabine + Nab-paclitaxel | II/78 | Results haven’t been published yet |
| NCT03744468 | BGB-A425 + Tislelizumab (BGB-A317) + LBL-007 | TIM-3, PD-1, LAG-3 | N/A | I, II/ 114 | Results haven’t been published yet |
PDL-1 Programmed death ligand-1, VEGF Vascular endothelial growth factor, TIGIT T cell immunoreceptor with immunoglobulin and ITIM domain, IL-6R Interleukin-6 receptor, ORR Objective response, AE Adverse event, CTLA-4 Cytotoxic T-Lymphocyte-Associated Protein 4, PFS Progression-free survival, DOR Duration of response, DCR: Disease control rate, LAG-3 Lymphocyte activation gene 3, TIM-3 T-cell immunoglobulin and mucin domain 3
Microsatellite instability-high (MSI-H) in PDAC represents a promising area of development, particularly with the use of ICIs. Deficient mismatch repair (dMMR) and/or MSI-H is rather uncommon in PDAC with an incidence of 0.8% [86]. MSI-H status can be assessed by circulating tumor DNA (ctDNA)-based tumor genomic profiling and tissue-based tumor genomic profiling [87] In a study including 86 patients with twelve different tumor types exhibiting dMMR/MSI-H, two achieved complete response (CR) and three partial response (PR) out of 8 patients with advanced/refractory PDAC [87] A phase-2 KEYNOTE-158 trial also assessed the efficacy of pembrolizumab in dMMR/MSI-H advanced solid tumors, four (18.2%) out of 22 PDAC patients responded to treatment, achieving one CR and three PRs, with median PFS of 4.1 months (95% CI, 2.4–4.9 months) and median OS of 23.5 months (95% CI, 13.5 months to not reached) [88].
The food and Drug Administration (FDA) has provided a tissue-agnostic accelerated approval of pembrolizumab in May 2017 for the treatment of unresectable or metastatic dMMR/MSI-H tumors [41]. Approval was extended in June 2020 to include tumors with a high mutational burden (TMB-H), defined as ≥ 10 mutations per megabase, which demonstrated a significantly higher objective response rate (ORR) of 29.4% (95% CI: 20.8–39.3) compared to 6.3% (95% CI: 4.6, 8.3) in non-TMB-H patients when treated with pembrolizumab [89]. However, no PDAC patients were included in this data set. Following this, the 2020 ASCO guidelines for metastatic PDAC recommended pembrolizumab as a second-line therapy for tumors exhibiting dMMR/MSI-H, citing strong evidence and recommendation levels [90]. While MSI-H/dMMR and TMB-H are established predictive biomarkers for ICI’s across various cancer types, their practical application in PDAC remains limited and underexplored. The extremely low prevalence of MSI-H/dMMR in PDAC poses a major limitation to widespread screening utility and therapeutic relevance [91]. As such, while patients harboring these alterations may experience durable responses to pembrolizumab, the overall impact is clinically negligible on the broader PDAC population. Moreover, identifying MSI-H/dMMR often requires sufficient tissue for PCR-based or immunohistochemical assays, which can be difficult to obtain in PDAC due to tumor location and desmoplastic stroma [92]. On the other hand, TMB is rarely high in PDAC, and no universally accepted threshold or testing standard exists across platforms. The use of circulating tumor DNA (ctDNA) to measure TMB in a non-invasive manner introduces further complications: ctDNA yields in PDAC are often low, especially in early or poorly vascularized tumors, making reliable quantification difficult [93]. Compounding this issue is the lack of standardized pre-analytical processing, sequencing depth, panel size, and data interpretation pipelines, which significantly impairs reproducibility and limits clinical trust in ctDNA-derived TMB scores. These challenges must be addressed through assay harmonization, cross-platform validation, and PDAC-specific prospective studies to realize the full potential of these biomarkers in clinical practice.
Chimeric antigen receptor (CAR-T) cell therapy in PDAC
Chimeric Antigen Receptor (CAR) T-cell therapy, a cutting-edge cancer treatment approach, is being explored in PDAC with promising early results. CAR-T involves genetically engineering patient’s T cells to express CARs that specifically target cancer-associated antigens which are overexpressed in pancreatic cancer cells. Initial studies and clinical trials have shown that these modified T cells can effectively recognize and kill tumor cells, leading to significant anti-tumor responses in some patients (Table 6) [94]. Mesothelin (MSLN) is a protein overexpressed in PDAC and CAR T therapy targeting MSLN has modified T cells from the patient’s blood to recognize and attack cancer cells that express MSLN. These engineered T cells, especially a version called hYP218, are particularly effective in infiltrating and persisting within tumors, thereby enhancing their ability to combat PDAC [95]. Furthermore, combining MSLN-targeting CAR T cells with other therapies, like oncolytic viruses that carry additional immune-activating agents, has led to significant tumor shrinkage in animal studies. Early clinical trials in humans have also been promising. A phase 1 trial with patients suffering from advanced, treatment-resistant PDAC showed that the treatment was safe and provided disease control. This indicates a strong potential for MSLN-targeting CAR-T therapy to treat advanced PDAC effectively. Another phase 1 study included 6 treatment-refractory metastatic PDAC patients who were treated with CAR T cells three times per week for three weeks [96]. The treatment showed a decent safety profile with no dose-limiting toxicity, cytokine release syndrome (CRS), or neurologic toxicities. The best response was stable disease, lasting 3.8 and 5.4 months in two patients. Positron-emission tomography (PET) imaging showed dramatic metabolic activity reduction in the liver lesion of one patient, highlighting the potential anti-tumor activity [96].
Table 6.
Trials on CAR T cell therapy
| Trial ID | Target | Agent | Combination therapy | Phase/N | Aims/ | Results |
|---|---|---|---|---|---|---|
| NCT04511871 (Completed) | HER2 | CCT303-406 | N/A | I/15 | Safety,tolerability, DLTs and MTD |
Median PFS: 8 weeks 12-month OS:45.5%DOR: Not reached at 36 weeks of follow up |
| NCT04404595 (Recruiting) | Claudin18.2 | CT041 | N/A | Ib/14 | Evaluate the safety and efficacy of autologous claudin 18.2 chimeric antigen receptor T-cell therapy in patients with advanced gastric or PDAC | ORR: 33%, no ORR, mDOR and PFS are not reported in pancreatic cancer cohort |
| NCT04581473 | Claudin 18.2 | CT041 | Anti-PD-1 + Paclitaxel or Irinotecan or Apatinib | I/14 | Evaluating the safety and efficacy of CT041 (satricel) in advanced gastric adenocarcinoma and PDAC |
SD: 2 patients PR: 8 patients mPFS: 5.6 months (95%CI 1.9,7.4), mOS:10.8 months (95%CI 5.1,NE) |
| NCT03323944 (Completed) | Mesothelin | huCART-meso cells | N/A | I/18 | Determining AEs, ORR, PFS, and OS |
Preliminary results showed that combination therapy was well-tolerated. However, two patients experienced severe pulmonary toxicity. SD is reported in 57% of patients. |
| NCT03013712 | EpCAM | Anti-EpCAM CAR T cells | N/A | I, II/60 | Investigating toxicity profile, and efficacy of CAR T cells | Preclinical studies showed effective tumor growth inhibition in mouse models. Results have not been published yet |
|
(on going) |
CD22 | CAR-T/CAR-TILs cells with anti-CD22 CAR and a ScFv fragment of anti-PD-L1 | N/A | I/30 | ORR, PFS, OS, and AEs | Not yet published |
ROR2 Receptor tyrosine kinase-like orphan receptor 2, DLTs Dose-limiting toxicities, EGFR Epidermal growth factor receptor, EpCAM Epithelial cell adhesion molecule, MSLN Mesothelin, MTD Maximum tolerated dose, N/A: Not applicable, ORR Overall response rate, OS: Overall survival, PFS Progression-free survival, SD stable disease
Claudin18.2 (CLDN18.2), primarily located in the gastric epithelium, contributes to the tight junctions that seal the spaces between epithelial cells, maintaining selective permeability and preventing the leakage of ions and molecules and thereby preserving the environment necessary for proper gastric function [97]. It is highly expressed in various cancers, including PDAC, making it a promising target for therapy. Recent studies on CT041, a therapy involving autologous T cells genetically modified to target CLDN18.2, have shown positive outcomes in treating gastrointestinal malignancies. Two metastatic PDAC patients, previously unresponsive to standard treatments, were treated with this anti-CLDN18.2 CAR T cell therapy. Both patients experienced CRS managed with tocilizumab and demonstrated significant tumor control; one had a partial response while the other achieved a complete response [98]. An increase in CD8 + T cells and Treg cells, a decrease in CD4 + T cells and B cells, higher IL-8 levels, and reduced TGF-β1 were observed, indicating effective immune modulation and sustained tumor suppression with anti-CLDN18.2 CAR T cell therapy. Although CAR T-cell therapy has advanced within the last decade, its application as a treatment for PDAC remains debatable. Major obstacles for CAR T-cell therapies in PDAC include immunosuppressive TMEs and desmoplasia. However, therapeutic combination of CAR T cells targeting immunosuppressive cells with tumor-targeting CAR T cells could potentially overcome the TME barrier. Ongoing research is needed to construct CAR T cells that improve survival outcomes while minimizing off-target toxicities.
Nanoparticle-based therapeutic strategies for PDAC
The emergence of nanoparticles was a game changer in overcoming the complex TME of PDAC and regulating the immune system. Nano-albumin-bound (Nab)-paclitaxel, a nano-based drug commonly used in PDAC treatment, was proven to deplete the tumor stroma through the interaction between the albumin and secreted protein acid. Additionally, the size of the nanoparticles is adjustable. Small-sized nanoparticles can pass through the tumor stroma where molecular drugs cannot penetrate, which enables nanoparticles to deliver immunomodulatory agents. The use of nano drug delivery devices coupled with stroma depletion has emerged as a promising treatment for PDAC. Furthermore, numerous studies have tested nanoparticle-based photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), and sonodynamic therapy (SDT) for treatment of PDAC, and the results were promising in the preclinical models [99].
Nanoparticle-based Immunogenic cell death strategies for enhanced PDAC immunotherapy
Immunogenic cell death (ICD) is a specific type of cancer cell death. When the tumor cells are stimulated by external stimuli, the dying tumor cells release damage-associated molecular patterns (DAMPs) that activate tumor-specific immune responses and boost antitumor responses. ICD leads to activation and recruitment of cytotoxic T cell lymphocytes (CTLs). Therefore, ICDs could work synergistically with ICIs to increase the patient immune response rates. Some chemotherapeutic drugs, oncolytic viruses, physicochemical therapies, photodynamic therapies, and radiotherapies can induce ICD. Nanomedicines can reportedly enhance ICD-inducible agents to exert stronger immune effects, owing to their proven advantages in drug delivery. This is especially suitable for solid tumors with poor drug delivery, such as PDAC [100].
Oxaliplatin is a common chemotherapeutic agent for PDAC treatment and is an ICD-inducible agent. Compared to free oxaliplatin treatment, studies showed that pancreatic tumor cells treated with nanoparticles encapsulating oxaliplatin release more DAMPs inducing stronger dendritic cell immune responses and a higher percentage of tumor-infiltrating activated cytotoxic T lymphocytes. Furthermore, mesoporous silica nanoparticles (MSNPs) were developed to efficiently deliver high doses of platinum-based chemotherapy drugs directly to pancreatic tumors. In PDAC mouse model with Kras mutations, MSNPs improved therapeutic delivery into tumor cells. The nanoparticles also helped keep the drug stable in the bloodstream after injection and reduced side effects. This approach enhances the drug’s effectiveness while minimizing toxicity to healthy tissues [101].
Nanoparticle-based immune modulation strategies for enhanced PDAC immunotherapy
Nanoparticles have been exploited in boosting immune system by targeting tumor immune microenvironment (TIME). These nanoparticles can deliver immunomodulatory cytokines more effectively. For instance, nanoparticles that co-load chemokine C-X-C motif ligand 12 (CXCL12) traps with Interleukin-10 (IL-10) or PD-L1 traps were developed to synergistically modify the immunosuppressive TIME to allow the host’s immune system to kill the tumor cells [102]. Another approach involves nanoparticles delivering RNA that activates retinoic acid-inducible gene I (RIG-I) receptors, which trigger the release of pro-inflammatory signals to boost the immune response and slow tumor growth. Since traditional drugs struggle to reach deep tumors and lymph nodes near the tumor, nanoparticles help deliver drugs directly to these areas. For example, combining Interleukin-12 (IL-12) microspheres with targeted radiotherapy allows continuous drug release, reaching tumor lymph nodes and leading to better tumor control. This nanoparticle strategy improves drug delivery and enhances the immune system’s ability to fight cancer [103]. While nanomedicine demonstrated promising hopes for boosting responses to therapies in PDAC, some challenges should be put into consideration including toxicity, selection of the right particle carrier, and translating results from preclinical studies to a clinical setting. Solving these problems may help nanomedicine improve the efficacy of immunotherapy and OS of patients with PDAC [104, 105].
Gene therapy in PDAC
RNAi therapy in PDAC
RNA interference (RNAi) is a gene-silencing process that regulates target genes by using double-stranded RNAs (dsRNAs) to degrade complementary mRNAs, thus preventing protein production. The three main RNAi molecules are small interfering RNA (siRNA), microRNA (miRNA), and short hairpin RNA (shRNA) [106]. RNAi is initiated when the Dicer enzyme processes dsRNA into small fragments (~ 22 nucleotides) which are incorporated into RNA-induced silencing complexes (RISCs). RNAi-based therapies, like Patisiran, the first FDA-approved RNAi therapy, has shown to improve symptoms for some diseases such as hereditary transthyretin-mediated amyloidosis (HTA). However, challenges like RNA degradation in body fluids and inefficient delivery limit their effectiveness. To overcome these issues, nanocarriers have been developed, offering safer, more efficient delivery compared to viral vectors. Nanocarriers include organic complexes like lipid complexes, polymers and inorganic nanoparticles like magnetic nanoparticles, quantum dots, carbon nanotubes, and gold nanoparticles [107].
RNAi using SiRNAs
MicroRNAs (miRNAs) are small non-coding RNA molecules, 18–25 nucleotides long, that bind to complementary mRNA sequences to either degrade the target mRNA or stop it from making proteins. Unlike siRNAs, which target a single mRNA, miRNAs can regulate multiple mRNAs at once. They play key role in cancer processes, including tumor growth, spread, drug resistance, and treatment response [108]. Cancer cells can also release miRNAs in exosomes to influence other cells in TME. In PDAC, abnormal miRNA expression is linked to cancer development, progression, and invasion. miR-21, which is a microRNA, is a small, non-coding RNA molecule that plays a significant role in cancer cell proliferation and differentiation which makes it a promising potential therapy for PDAC. Studies show that miR-21, miR-196a, miR-196b, and let-7i are highly expressed and strongly associated with low survival in patients with PDAC [109]. Hence, researchers developed anti-miR-21 nanoparticles (TPN-21) to better penetrate tumors. These nanoparticles combine a cell-penetrating peptide (iRGD) and a fatty acid group for stability. TPN-21 reduces miR-21 expression, boosting tumor-suppressing effects of proteins like PTEN and PDCD4 consequently inhibiting cancer cells growth. In another study, Li and colleagues developed nanoparticles made of polyethylene glycol, polyethyleneimine, and magnetic iron oxide, linked to antibodies targeting PDAC cells. These nanoparticles deliver both anti-miR-21 and gemcitabine leading to cancer cell death, reduced tumor growth, and lower metastasis in pre-clinical studies, highlighting the combined power of gene silencing and chemotherapy [110].
Crisper/Cas gene editing
CRISPR functions as a natural immune system in bacteria like E. coli, where it defends against viral infections by recognizing and cutting foreign genetic material [111]. This system has been adapted as a powerful gene-editing tool due to its precision, efficiency, and simplicity compared to earlier methods like zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). CRISPR/Cas9 is an RNA-guided endonuclease that consists of the Cas9 protein and a guide RNA (sgRNA), which directs DNA cleavage at specific target sequences. The DNA damage caused by Cas9 is repaired through either non-homologous end joining (NHEJ) or homology-directed repair (HDR) [112]. Variants of CRISPR have been developed for specific applications: base editors (cysteine and adenine base editors) introduce precise point mutations, Cas13 edits RNA to minimize DNA damage, and prime editing uses a DNA nickase and reverse transcriptase to make base changes without double-strand breaks. However, effective delivery remains a challenge, with viral vectors (e.g., retrovirus, adenovirus, adeno-associated virus) being common but limited due to risks like immune responses, potential immunogenicity, and insertional mutations [112]. An ideal delivery system would enhance target specificity, reduce off-target effects, and avoid immune complications. Given the high prevalence of oncogenic mutations in PDAC, such as KRAS, TP53, CDKN2A, and SMAD4, CRISPR/Cas9 can potentially correct these genetic aberrations or inhibit key oncogenic pathways driving tumor progression. Researchers have explored CRISPR/Cas9 to knock out mutant KRAS, a hallmark mutation in PDAC, which has shown tumor-suppressive effects in preclinical studies. Additionally, CRISPR-based disruption of genes associated with chemoresistance and immunosuppressive signaling in the tumor microenvironment (TME) offers avenues to enhance the efficacy of existing treatments, such as chemotherapy and immunotherapy. Emerging CRISPR variants, like base and prime editors, further expand therapeutic potential by allowing precise base substitutions without inducing double-strand DNA breaks, thus reducing off-target effects. However, challenges remain, including safe and efficient delivery of CRISPR components to deep pancreatic tumors, minimizing off-target mutations, and overcoming tumor heterogeneity. Ongoing research into nanoparticle-based delivery systems and innovative targeting strategies aims to address these hurdles and pave the way for the clinical translation of CRISPR/Cas9-based therapeutics in PDAC [113, 114].
Despite CRISPR’s promise, effective delivery systems remain a challenge, especially in cancer treatment. Viral vectors (e.g., retrovirus, adenovirus, adeno-associated virus) are widely used in gene therapy due to their efficient delivery, but they have limitations, such as triggering immune responses, gene insertion mutations, and risks from neutralizing antibodies. Therefore, an ideal CRISPR delivery vehicle should achieve target specificity, minimize off-target effects, and avoid immune-related complications for safer and more effective therapeutic applications [115].
Patient derived xenografts and organoids in gene editing
Patient derived xenografts are created by implanting human tumor tissues into immunodeficient mice, preserving the original tumor’s characteristics. The integration of CRISPR/Cas9 in PDX models has enabled targeted genome editing directly within these in vivo systems [115]. This approach facilitates the analysis of genetic dependencies and mechanisms of drug resistance in cancer, enhancing the utility of PDXs as programmable models for human malignancies. In PDAC, PDX models are created by implanting human pancreatic tumor tissues into immunodeficient mice, effectively preserving the original tumor’s histological and genetic characteristics. PDX models help maintain the morphological and genetic features of the tumor enabling effective studying of tumor biology and therapeutic responses which consequently allow better assessment of drug therapeutic efficacy. In addition, PDX models have been correlated with patient prognosis. Specifically, successful engraftment is associated with a higher risk of disease recurrence post-surgery, suggesting its potential as a prognostic indicator [116].
Despite their significant advantages, they have their limitations. Human stromal and immune components are gradually replaced by murine equivalents, especially after multiple passages which limits the study of immune-tumor and stroma-tumor interactions. Moreover, PDX models are expensive and can take months to be done. Moreover, these procedures are performed in immunodeficient mice, which restricts the accurate assessment of immunotherapies and the understanding of immune evasion mechanisms, both of which are crucial for the development of PDAC treatments. Compared to other cancers, PDAC tends to have a lower success rate of engraftment, likely because of its dense desmoplastic stroma and low vascularity [117].
Organoids are three-dimensional (3D) miniaturized structures derived from patient tumor tissues that recapitulate key aspects of the original tumor’s histology and genetics. In PDAC, patient-derived organoids (PDOs) have emerged as valuable preclinical models due to their ability to mimic the architecture, molecular characteristics, and drug responses of pancreatic tumors. Thus, they have been used in testing therapeutic agents, enabling prediction of drug response which helps in personalized treatment regimens in real-time clinical practice. They can also be used in studying specific genes and pathways in PDAC allowing better understanding of its pathogenesis, progression and development of drug resistance. Organoids can also be cryopreserved and expanded over time, allowing building biobanks that support long-term studies and retrospective analyses. However, organoid generation can be time consuming and its formation depends on the tumor type and quality of biopsy which can limit its use in acute clinical decisions [118].
Vaccines
Vaccine therapy boosts immune system’s response against cancer via exposing cancer-associated antigens to T cells [119]. Although conventional immunotherapy showed efficacy against tumors with identifiable surface antigens, vaccines can target a broader range of antigens. In addition, there are multiple forms of cancer vaccines such as DNA, mRNA, peptide and DC vaccines. Till date, sipuleucel-T (PROVENGE), is the only FDA approved therapeutic cancer vaccine for prostate cancer. Other agents are still under investigation such as GVAX (pancreatic cell lines altered with Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and CRS207 (a live attenuated strain of Listeria monocytogenes that expresses MSLN) either alone or in combination with a mAb targeting the CD40 molecule to activate APCs [120].
Autogene cevumeran, an adjuvant personalized mRNA neoantigen vaccine, has been recently investigated in a phase I clinical trial to evaluate its efficacy in PDAC patients and its impact on T cell activity. Results showed that the addition of a personalized neoantigen vaccine to combination of atezolizumab and mFOLFIRINOX is safe, and yielded significant neoantigen-specific T cells in 50% of the participants with resectable PDAC. Notably, the vaccine-expanded T cells remained functional for up to two years after. These initial results advocate for further comprehensive studies on tailored mRNA neoantigen vaccines in PDAC [121]. Existing trials on novel cancer vaccine in PDAC are summarized in Table 7.
Table 7.
Cancer vaccine studies in PDAC
| Trial ID | Agent | Target | Combination therapy | Phase/N | Results |
|---|---|---|---|---|---|
| NCT04161755 (on gong) | RO7198457 (Autogene Cevumeran/BNT122) | TSAs and TAAs | Atezolizumab + FOLFIRINOX | I/29 |
Longer median recurrence-free survival in vaccine group (P = 0.003) at 18-month median follow-up Grade 3 AE: 6% (1/16) |
| NCT04853017 | ELI-002/ELI-002 2P | KRAS-G12D, KRAS-G12R | N/A | I/25 |
No dose-limiting toxicities Median relapse-free survival = 16.33 months 84% (21/25) patients showed mKRAS-specific T cell responses |
| NCT02600949 (On going) | Personalized synthetic peptide vaccine | TSAs and TAAs | Imiquimod (TLR7 agonist) + Pembrolizumab + Sotigalimab (APX005M; a CD40 agonist) | I/150 | Results have not been published yet |
TSA Tumor specific antigen, TAA Tumor associated antigen, AE Adverse events, OS Overall survival, PFS Progression-free survival
In trial (NCT04853017) 25 participants were enrolled. Results showed that Median Recurrence-Free Survival (mRFS): 16.3 months. Median OS: 28.9 months. T Cell Response Correlation: Patients with above-median mKRAS-specific T cell responses had not reached mRFS at the time of analysis, whereas those with below-median responses had a mRFS of 4.0 months. Safety Profile: ELI-002 was well-tolerated, with no Grade 3/4 treatment-emergent adverse events, dose-limiting toxicities, or cases of cytokine release syndrome were observed.
Homologous recombinant deficiency and therapeutic strategies in PDAC
The interplay between mutations and TME is key for the advancement of targeted therapeutic management of PDAC patients. Major players in the TME are CAFs, which comprises up to 90% of the tumor mass in pancreatic cancer. The association between CAFs and certain mutations, especially Breast Cancer Susceptibility Gene (BRCA): BRCA1, BRCA2, and ATM have been one of the active research focuses in recent years for their role in genomic instability, which can drive cancer initiation and progression [122]. A study on the stromal microenvironment of pancreatic cancer revealed that tumors with BRCA mutations (BRCA-mut) differ significantly in their composition of cancer-associated fibroblasts (CAFs) compared to their counterparts (BRCA-WT). Specifically, BRCA-mut tumors have a higher presence of clusterin-positive (CLU+) CAFs, which are known to regulate immune responses. Additionally, these tumors exhibit increased activity of Heat Shock Factor 1 (HSF1), a transcription factor involved in stress response, which correlates with higher clusterin expression in CAFs. This suggests that HSF1 may reprogram CAFs in BRCA-mutated pancreatic cancers, potentially impacting the tumor’s response to DNA repair-targeting therapies like PARP inhibitors and platinum-based chemotherapies [123].
The phase III POLO study (n-154 patients) evaluated olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, as maintenance therapy against placebo in patients with metastatic PDAC harboring a germline BRCA mutation, following first-line platinum-based chemotherapy. Although the study did not show a statistically significant improvement in median OS with olaparib (18.9 months vs. 18.1 months; HR: 0.91; 95% CI, 0.56 to 1.46; P = 0.68), it demonstrated improvement in PFS (HR, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life (between-group difference, − 2.47 points; 95% CI, − 7.27 to 2.33). The study’s recruitment challenges suggest a need for future research on a larger scale with a focus on identifying the appropriate patient population that could benefit from novel targeted approaches. While BRCA and ATM mutations appear in a subset of PDAC, they share an underlying homologous recombination deficiency (HRD) that can significantly impact tumor behavior, therapy responsiveness, and TME. Understanding how these mutations shape the TME is crucial for developing more effective immunotherapies and combination treatments [124, 125].
Despite the improvement in PFS, the POLO trial did not show a significant increase in the OS. This may be due to cross-over effect, where patients initially on placebo later received other therapies, or because PARP inhibitors may not prevent eventual disease progression in advanced PDAC. PARP inhibitors show efficacy primarily in patients with HRD, particularly those with BRCA1/2 or PALB2 mutations [125]. However, these mutations occur in only about 5–7% of PDAC cases, limiting the drug’s applicability to a small subset of patients. Moreover, resistance mechanisms, such as secondary reversion mutations that restore BRCA function or up regulation of alternative DNA repair pathways (e.g., RAD51-mediated repair), can develop during treatment, reducing long-term efficacy. Additionally, studies reported adverse events, including anemia, fatigue, nausea, and increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) [126]. To address these limitations, ongoing research focuses on combination strategies, such as pairing PARP inhibitors with immune checkpoint inhibitors, DNA-damage response (DDR) inhibitors, or anti-angiogenic agents, to enhance efficacy and counteract resistance mechanisms. Additionally, more robust biomarker discovery efforts are needed to expand the population of PDAC patients who may benefit from PARP inhibitor therapy [127].
Peroxisome proliferator-activated receptor (PPAR) inhibitors and their combinations with immunotherapy are being extensively explored for their dual roles in cancer treatment. PPAR, a receptor involved in fat metabolism, has been shown to have an impact on cancer cell proliferation and immune regulation. PPAR activation leads to the degradation of PD-L1. This is achieved either through lysosomal pathways or by inhibiting c-Myc, a regulator that typically increases PD-L1 expression. Furthermore, PPAR agonists like rosiglitazone can suppress pro-tumor inflammation mediated by Gpr132 in macrophages and enhance T cell activity, boosting the immune response against tumors. These mechanisms highlight the complex role of PPARγ in modulating the TME and immune system’s response to cancer, presenting a promising opportunity for enhancing the efficacy of cancer immunotherapy [128] [128]. Moreover, thiazolidinediones have demonstrated the ability to reduce PD-L1 levels, thus improving the efficacy of immune checkpoint inhibitors in preclinical models. This effect appears to be mediated through both transcriptional and post-transcriptional mechanisms, although the precise pathways remain an area of active investigation [129].
Given the immune-suppressive nature of PDAC, PPARγ-based therapies hold therapeutic promise, particularly when used in combination with ICIs. In preclinical studies, combining PPARγ agonists with ICIs, such as anti-PD-1 or anti-PD-L1 antibodies, has shown synergistic effects, leading to enhanced tumor regression and prolonged survival. Moreover, targeting PPARγ may also help to overcome the immunosuppressive stroma that characterizes PDAC, thus improving the tumor’s responsiveness to ICI. The ongoing clinical trials exploring the combination of PPARγ modulators with ICIs are promising, but further research is necessary to define optimal dosing regimens and patient selection criteria [130].
Neurotrophic tyrosine receptor kinase (NTRK) mutation in PDAC
Although KRAS is the most common mutation documented in PDAC, other mutations such as TP53, CDKN2A and SMAD4 are also prevalent. Although NTRK fusions are relatively rare in PDAC, their identification remains clinically important. In a cohort of 400 resected or locally advanced/metastatic PDAC patients, NTRK fusions were identified in three cases—two with EML4-NTRK3 fusions (both KRAS wild-type) and one with a novel KANK1-NTRK3 fusion [131]. Larotrectinib is one of the key selective TRK inhibitors approved for NTRK fusion-positive solid tumors, demonstrating high response rates and durable disease control in pediatric and adult patients. Entrectinib is a multi-targeted inhibitor that blocks TRK, ROS1, and ALK is approved for NTRK fusion-positive cancers, particularly effective in managing brain metastases due to its CNS penetration. Next-generation TRK inhibitors (e.g., Selitrectinib, Repotrectinib) are developed to overcome resistance caused by acquired mutations (e.g., TRK kinase domain mutations) that can emerge during treatment with first-line TRK inhibitors. This highlights the importance of using a combination of diagnostic approaches to accurately identify gene fusions for appropriate therapeutic targeting [132, 133].
Future directions in PDAC therapy
Despite significant advancements in understanding the molecular and immunologic landscape of PDAC, clinical translation remains limited due to the tumor’s profound heterogeneity, dense desmoplastic stroma, and immunosuppressive microenvironment. Future therapeutic strategies should integrate precision oncology, immunotherapy, and nanotechnology to overcome these barriers. Targeted therapies such as KRAS G12D inhibitors (e.g., MRTX1133) and stroma-modulating agents have shown promising preclinical results. However, it requires biomarker-driven patient stratification to enhance efficacy and reduce resistance [134]. Immunotherapies, specially ICIs and CAR-T cells, face challenges in PDAC due to T-cell exclusion and lack of tumor immunogenicity; thus, combinational strategies with oncolytic viruses or agents that modulate the tumor microenvironment are essential for enhancing immune infiltration [135] Additionally, nanomedicine-based drug delivery systems can improve intratumoral drug accumulation while minimizing systemic toxicity, holding potential for synergistic effects with chemo- and immunotherapies [136]. Figure 2 summarizes emerging therapeutic targets and novel agents in PDAC. Bringing these innovations to the clinic requires robust multidisciplinary translational pipelines, more sophisticated preclinical models—such as patient-derived organoids and xenografts—and the use of adaptive trial designs. Overcoming therapeutic resistance, inter-patient variability, and drug delivery limitations will shape the next phase of PDAC management, emphasizing the need for collaboration between academia, industry, and regulatory agencies. The ongoing trials with novel agents are summarized in Table 8.
Fig. 2.
Emerging therapeutic targets and novel agents in PDAC
This diagram illustrates key molecular targets and immune pathways, highlighting therapeutic strategies under clinical development or use. Some of the targeted agents are shown, such as HER2/HER3 TP53, and NRG1. Vaccine therapy and novel targets such as Mesothelin (huCART-meso cells) and other CAR-T therapies are depicted cancer vaccines. Novel targets such as Mesothelin (e.g., Amatuximab, hYP218 CAR-T) and other CAR-T therapies are also depicted
Figures 1 and 2 are original and created by Dr. Yara Sakr
Table 8.
Ongoing trials with novel agents
| Trial ID | Investigational agent | Phase | N | Primary end point |
|---|---|---|---|---|
| NCT06592664 | LSTA1 with gemcitabine and abraxane | Ib/IIa | 30 | Incidence of adverse events |
| NCT06411691 | KRAS vaccine combined with Balstilimab and Botensilimab | I | 54 | PFS |
| NCT03323944 | huCART-meso cells via intravenous infusion (IV) | Phase I | 18 | Treatment-related adverse events |
| NCT05141149 | Humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets and neutralizes PAUF | Phase1/IIIa | 80 |
Phase 1: To evaluate safety and tolerability of PBP1510 and dose limiting toxicity of PBP1510 Phase 2a: To establish safety and efficacy of PBP1510 in combination with gemcitabine |
| NCT06599502 | AZD0022 monotherapy vs. AZD0022 in combination with Cetuximab | Phase I/ II | 430 | Incidence of Dose-Limiting Toxicity (DLT), adverse events and ORR |
| NCT06625320 |
RMC-6236 vs. standard care of treatment of the investigator’s choice including 1. Gemcitabine and nab-paclitaxel (GnP) 2. Oxaliplatin, leucovorin, irinotecan, and 5-FU (mFOLFIRINOX) 3. Liposomal irinotecan (Nal-IRI + 5-FU/LV) 4. Oxaliplatin, leucovorin and 5-FU (FOLFOX) |
Phase III | 460 | PFS and OS in the RAS G12-mutant population |
| NCT06673017 | PTM-101, an absorbable drug product containing paclitaxel | Phase I | 26 | Number of subjects with PTM-101/PTM-101 placement-related adverse events |
| NCT05846516 | ATP150/ATP152, VSV-GP154 and Ezabenlimab (BI 754091) | Phase I | 85 | DLT and Disease-free survival (DFS) |
| NCT06639724 | Combination Product: Fostamatinib in combination with chemotherapy (gemcitabine and nab-paclitaxel) | Phase I | 36 | Surgical delay, as measured by the proportion of enrolled participants for whom pancreatic resection cannot be performed within 6 weeks of the last pre-operative treatment cycle |
Conclusion
The complex nature of PDAC imposes a challenge when it comes to its management. This paper highlights the pivotal role of the tumor microenvironment and the interplay with cancer-associated fibroblasts and the innovative targeted therapeutic approaches and immunotherapies that are being explored to overcome these barriers. The study underlines the importance of ongoing research to uncover effective treatments and improve diagnostic strategies to enhance the survival rates and quality of life for PDAC patients.
Author contributions
MM and YS wrote the main manuscript text. MA and BE reviewed the manuscript. GG updated the manuscript based on reviewer feedback along with tables.
Funding
There was no funding received for the work presented in this manuscript.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol. 2021;18(7):493–502. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Wang X, Liu C, Yang Y, Huang X, Yu J. Burden of pancreatic cancer in older adults globally, regionally, and in 204 countries: 1990–2019 and projections to 2030. J Gastrointest Surg. 2024;28(2):121–31. [DOI] [PubMed] [Google Scholar]
- 3.Shindo K, Yu J, Suenaga M, Fesharakizadeh S, Cho C, Macgregor-Das A, et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. J Clin Oncol. 2017;35(30):3382–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Hu C, Hart SN, Polley EC, Gnanaolivu R, Shimelis H, Lee KY, et al. Association between inherited germline mutations in Cancer predisposition genes and risk of pancreatic Cancer. JAMA. 2018;319(23):2401–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Stoffel EM, Brand RE, Goggins M. Pancreatic cancer: changing epidemiology and new approaches to risk assessment, early detection, and prevention. Gastroenterology. 2023;164(5):752–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Afghani E, Klein AP. Pancreatic adenocarcinoma: trends in epidemiology, risk factors, and outcomes. Hematol Oncol Clin North Am. 2022;36(5):879–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011–24. [DOI] [PubMed] [Google Scholar]
- 8.Tempero MA, Malafa MP, Al-Hawary M, Behrman SW, Benson AB, Cardin DB, et al. Pancreatic adenocarcinoma, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(4):439–57. [DOI] [PubMed] [Google Scholar]
- 9.Martin-Perez E, Domínguez-Muñoz JE, Botella-Romero F, Cerezo L, Matute Teresa F, Serrano T, et al. Multidisciplinary consensus statement on the clinical management of patients with pancreatic cancer. Clin Transl Oncol. 2020;22(11):1963–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371(11):1039–49. [DOI] [PubMed] [Google Scholar]
- 11.Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet. 2016;388(10039):73–85. [DOI] [PubMed] [Google Scholar]
- 12.Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25. [DOI] [PubMed] [Google Scholar]
- 13.Foschini F, Napolitano F, Servetto A, Marciano R, Mozzillo E, Carratù AC, et al. FOLFIRINOX after first-line gemcitabine-based chemotherapy in advanced pancreatic cancer: a retrospective comparison with FOLFOX and FOLFIRI schedules. Ther Adv Med Oncol. 2020;12:1758835920947970. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic Cancer. N Engl J Med. 2018;379(25):2395–406. [DOI] [PubMed] [Google Scholar]
- 15.Pusceddu S, Ghidini M, Torchio M, Corti F, Tomasello G, Niger M et al. Comparative effectiveness of gemcitabine plus Nab-Paclitaxel and FOLFIRINOX in the First-Line setting of metastatic pancreatic cancer: A systematic review and Meta-Analysis. Cancers (Basel). 2019;11(4).484 [DOI] [PMC free article] [PubMed]
- 16.Wainberg ZA, Melisi D, Macarulla T, Pazo Cid R, Chandana SR, De La Fouchardière C, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet. 2023;402(10409):1272–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Dougan SK. The pancreatic Cancer microenvironment. Cancer J. 2017;23(6):321–5. [DOI] [PubMed] [Google Scholar]
- 18.Ferrara B, Pignatelli C, Cossutta M, Citro A, Courty J, Piemonti L. The extracellular matrix in pancreatic cancer: description of a complex network and promising therapeutic options. Cancers (Basel). 2021;13(17).4442 [DOI] [PMC free article] [PubMed]
- 19.De Jesus-Acosta A, Sugar EA, O’Dwyer PJ, Ramanathan RK, Von Hoff DD, Rasheed Z, et al. Phase 2 study of vismodegib, a Hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma. Br J Cancer. 2020;122(4):498–505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Ho WJ, Jaffee EM, Zheng L. The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities. Nat Rev Clin Oncol. 2020;17(9):527–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Ramanathan RK, McDonough SL, Philip PA, Hingorani SR, Lacy J, Kortmansky JS, et al. Phase IB/II randomized study of FOLFIRINOX plus pegylated Recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J Clin Oncol. 2019;37(13):1062–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Van Cutsem E, Tempero MA, Sigal D, Oh DY, Fazio N, Macarulla T, et al. Randomized phase III trial of pegvorhyaluronidase Alfa with Nab-Paclitaxel plus gemcitabine for patients with Hyaluronan-High metastatic pancreatic adenocarcinoma. J Clin Oncol. 2020;38(27):3185–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kemper M, Schiecke A, Maar H, Nikulin S, Poloznikov A, Galatenko V, et al. Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression. J Exp Clin Cancer Res. 2021;40(1):214. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Sherman MH, Beatty GL. Tumor microenvironment in pancreatic Cancer pathogenesis and therapeutic resistance. Annu Rev Pathol. 2023;18:123–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Cao L, Huang C, Cui Zhou D, Hu Y, Lih TM, Savage SR, et al. Proteogenomic characterization of pancreatic ductal adenocarcinoma. Cell. 2021;184(19):5031–e5226. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Yamamoto K, Venida A, Yano J, Biancur DE, Kakiuchi M, Gupta S, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature. 2020;581(7806):100–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Hindson J. PDAC resistance to immunotherapy — a role for autophagy? Nat Reviews Gastroenterol Hepatol. 2020;17(7):382. [DOI] [PubMed] [Google Scholar]
- 28.Myo Min KK, Ffrench CB, Jessup CF, Shepherdson M, Barreto SG, Bonder CS. Overcoming the fibrotic fortress in pancreatic ductal adenocarcinoma: challenges and opportunities. Cancers (Basel). 2023;15(8).2354 [DOI] [PMC free article] [PubMed]
- 29.Mascharak S, Guo JL, Foster DS, Khan A, Davitt MF, Nguyen AT, et al. Desmoplastic stromal signatures predict patient outcomes in pancreatic ductal adenocarcinoma. Cell Rep Med. 2023;4(11):101248. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Manoukian P, Bijlsma M, van Laarhoven H. The cellular origins of Cancer-Associated fibroblasts and their opposing contributions to pancreatic Cancer growth. Front Cell Dev Biol. 2021;9:743907. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Martinez-Bosch N, Vinaixa J, Navarro P. Immune evasion in pancreatic cancer: from mechanisms to therapy. Cancers (Basel). 2018;10(1).6 [DOI] [PMC free article] [PubMed]
- 32.Guo S, Wang Z. Unveiling the immunosuppressive landscape of pancreatic ductal adenocarcinoma: implications for innovative immunotherapy strategies. Front Oncol. 2024;14:1349308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, et al. CSF1/CSF1R Blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74(18):5057–69. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Symeonides SN, Anderton SM, Serrels A. FAK-inhibition opens the door to checkpoint immunotherapy in pancreatic Cancer. J Immunother Cancer. 2017;5:17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Hu HF, Ye Z, Qin Y, Xu XW, Yu XJ, Zhuo QF, et al. Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications. Acta Pharmacol Sin. 2021;42(11):1725–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Luo J. KRAS mutation in pancreatic cancer. Semin Oncol. 2021;48(1):10–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Maddalena M, Mallel G, Nataraj NB, Shreberk-Shaked M, Hassin O, Mukherjee S, et al. TP53 missense mutations in PDAC are associated with enhanced fibrosis and an immunosuppressive microenvironment. Proc Natl Acad Sci U S A. 2021;118:(23):e2025631118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Dardare J, Witz A, Merlin JL, Gilson P, Harlé A. SMAD4 and the TGFβ pathway in patients with pancreatic ductal adenocarcinoma. Int J Mol Sci. 2020;21(10). [DOI] [PMC free article] [PubMed]
- 39.Lai E, Ziranu P, Spanu D, Dubois M, Pretta A, Tolu S, et al. BRCA-mutant pancreatic ductal adenocarcinoma. Br J Cancer. 2021;125(10):1321–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Lanfredini S, Thapa A, O’Neill E. RAS in pancreatic cancer. Biochem Soc Trans. 2019;47(4):961–72. [DOI] [PubMed] [Google Scholar]
- 41.Strickler JH, Satake H, George TJ, Yaeger R, Hollebecque A, Garrido-Laguna I, et al. Sotorasib in KRAS p.G12C-Mutated advanced pancreatic Cancer. N Engl J Med. 2023;388(1):33–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Blair HA, Sotorasib. First Approval Drugs. 2021;81(13):1573–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Sacher A, LoRusso P, Patel MR, Miller WH Jr., Garralda E, Forster MD, et al. Single-Agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N Engl J Med. 2023;389(8):710–21. [DOI] [PubMed] [Google Scholar]
- 44.Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRAS(G12C) Inhibition with Sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Wei D, Wang L, Zuo X, Maitra A, Bresalier RS. A small molecule with big impact: MRTX1133 targets the KRASG12D mutation in pancreatic Cancer. Clin Cancer Res. 2024;30(4):655–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.de Jesus VHF, Mathias-Machado MC, de Farias JPF, Aruquipa MPS, Jácome AA, Peixoto RD. Targeting KRAS in pancreatic ductal adenocarcinoma: the long road to cure. Cancers (Basel). 2023;15(20).5015 [DOI] [PMC free article] [PubMed]
- 47.Qian L, Chen K, Wang C, Chen Z, Meng Z, Wang P. Targeting NRAS-Mutant cancers with the selective STK19 kinase inhibitor chelidonine. Clin Cancer Res. 2020;26(13):3408–19. [DOI] [PubMed] [Google Scholar]
- 48.Yang X, Wu H. RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms. J Hematol Oncol. 2024;17(1):108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Santarpia M, Ciappina G, Spagnolo CC, Squeri A, Passalacqua MI, Aguilar A, et al. Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development-a narrative review. Transl Lung Cancer Res. 2023;12(2):346–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Liu J, Kang R, Tang D. The KRAS-G12C inhibitor: activity and resistance. Cancer Gene Ther. 2022;29(7):875–8. [DOI] [PubMed] [Google Scholar]
- 51.Ash LJ, Busia-Bourdain O, Okpattah D, Kamel A, Liberchuk A, Wolfe AL. KRAS: biology, inhibition, and mechanisms of inhibitor resistance. Curr Oncol. 2024;31(4):2024–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Reita D, Pabst L, Pencreach E, Guérin E, Dano L, Rimelen V et al. Direct targeting KRAS mutation in Non-Small cell lung cancer: focus on resistance. Cancers (Basel). 2022;14(5).1321 [DOI] [PMC free article] [PubMed]
- 53.Tanaka N, Lin JJ, Li C, Ryan MB, Zhang J, Kiedrowski LA, et al. Clinical acquired resistance to KRAS(G12C) Inhibition through a novel KRAS Switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov. 2021;11(8):1913–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Lee S, Rauch J, Kolch W. Targeting MAPK signaling in cancer: mechanisms of drug resistance and sensitivity. Int J Mol Sci. 2020;21(3).1102 [DOI] [PMC free article] [PubMed]
- 55.Voutsadakis IA. Mutations of p53 associated with pancreatic cancer and therapeutic implications. Ann Hepatobiliary Pancreat Surg. 2021;25(3):315–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.McCubrey JA, Yang LV, Abrams SL, Steelman LS, Follo MY, Cocco L et al. Effects of TP53 mutations and MiRs on immune responses in the tumor microenvironment important in pancreatic Cancer progression. Cells. 2022;11(14).2155 [DOI] [PMC free article] [PubMed]
- 57.Wang H, Guo M, Wei H, Chen Y. Targeting p53 pathways: mechanisms, structures and advances in therapy. Signal Transduct Target Therapy. 2023;8(1):92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Hamzehloie T, Mojarrad M, Hasanzadeh Nazarabadi M, Shekouhi S. The role of tumor protein 53 mutations in common human cancers and targeting the murine double minute 2-p53 interaction for cancer therapy. Iran J Med Sci. 2012;37(1):3–8. [PMC free article] [PubMed] [Google Scholar]
- 59.Hu J, Cao J, Topatana W, Juengpanich S, Li S, Zhang B, et al. Targeting mutant p53 for cancer therapy: direct and indirect strategies. J Hematol Oncol. 2021;14(1):157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Oliner JD, Saiki AY, Caenepeel S. The role of MDM2 amplification and overexpression in tumorigenesis. Cold Spring Harb Perspect Med. 2016;6(6).a026336 [DOI] [PMC free article] [PubMed]
- 61.Shen H, Maki CG. Pharmacologic activation of p53 by small-molecule MDM2 antagonists. Curr Pharm Des. 2011;17(6):560–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Saleh MN, Patel MR, Bauer TM, Goel S, Falchook GS, Shapiro GI, et al. Phase 1 trial of ALRN-6924, a dual inhibitor of MDMX and MDM2, in patients with solid tumors and lymphomas bearing Wild-type TP53. Clin Cancer Res. 2021;27(19):5236–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Lu Y, Wu M, Xu Y, Yu L. The development of p53-Targeted therapies for human cancers. Cancers (Basel). 2023;15(14).3560. [DOI] [PMC free article] [PubMed]
- 64.Tanner S, Barberis A. CP-31398, a putative p53-stabilizing molecule tested in mammalian cells and in yeast for its effects on p53 transcriptional activity. J Negat Results Biomed. 2004;3:5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Perdrix A, Najem A, Saussez S, Awada A, Journe F, Ghanem G et al. PRIMA-1 and PRIMA-1(Met) (APR-246): from mutant/wild type p53 reactivation to unexpected mechanisms underlying their potent Anti-Tumor effect in combinatorial therapies. Cancers (Basel). 2017;9(12).172 [DOI] [PMC free article] [PubMed]
- 66.Zache N, Lambert JM, Rökaeus N, Shen J, Hainaut P, Bergman J, et al. Mutant p53 targeting by the low molecular weight compound STIMA-1. Mol Oncol. 2008;2(1):70–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Weinmann L, Wischhusen J, Demma MJ, Naumann U, Roth P, Dasmahapatra B, et al. A novel p53 rescue compound induces p53-dependent growth arrest and sensitises glioma cells to Apo2L/TRAIL-induced apoptosis. Cell Death Differ. 2008;15(4):718–29. [DOI] [PubMed] [Google Scholar]
- 68.Blanden AR, Yu X, Wolfe AJ, Gilleran JA, Augeri DJ, O’Dell RS, et al. Synthetic metallochaperone ZMC1 rescues mutant p53 conformation by transporting zinc into cells as an ionophore. Mol Pharmacol. 2015;87(5):825–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Cordani M, Garufi A, Benedetti R, Tafani M, Aventaggiato M, D’Orazi G et al. Recent advances on mutant p53: unveiling novel oncogenic roles, degradation pathways, and therapeutic interventions. Biomolecules. 2024;14(6).649 [DOI] [PMC free article] [PubMed]
- 70.Ubby I, Krueger C, Rosato R, Qian W, Chang J, Sabapathy K. Cancer therapeutic targeting using mutant-p53-specific SiRNAs. Oncogene. 2019;38(18):3415–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Hatami E, Jaggi M, Chauhan SC, Yallapu MM. Gambogic acid: a shining natural compound to nanomedicine for cancer therapeutics. Biochim Biophys Acta Rev Cancer. 2020;1874(1):188381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Kunimasa K, Ikeda-Ishikawa C, Tani Y, Tsukahara S, Sakurai J, Okamoto Y, et al. Spautin-1 inhibits mitochondrial complex I and leads to suppression of the unfolded protein response and cell survival during glucose starvation. Sci Rep. 2022;12(1):11533. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Zhang S, Zhou L, Hong B, van den Heuvel AP, Prabhu VV, Warfel NA, et al. Small-Molecule NSC59984 restores p53 pathway signaling and antitumor effects against colorectal Cancer via p73 activation and degradation of mutant p53. Cancer Res. 2015;75(18):3842–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Kim HJ, Bae SC. Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res. 2011;3(2):166–79. [PMC free article] [PubMed] [Google Scholar]
- 75.Stefanoudakis D, Frountzas M, Schizas D, Michalopoulos NV, Drakaki A, Toutouzas KG. Significance of TP53, CDKN2A, SMAD4 and KRAS in pancreatic Cancer. Curr Issues Mol Biol. 2024;46(4):2827–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Nagasaka M, Ou SI. NRG1 and NRG2 fusion positive solid tumor malignancies: a paradigm of ligand-fusion oncogenesis. Trends Cancer. 2022;8(3):242–58. [DOI] [PubMed] [Google Scholar]
- 77.Kim DW, Schram AM, Hollebecque A, Nishino K, Macarulla T, Rha SY, et al. The phase I/II eNRGy trial: zenocutuzumab in patients with cancers harboring NRG1 gene fusions. Future Oncol. 2024;20(16):1057–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Giarratana AO, Prendergast CM, Salvatore MM, Capaccione KM. TGF-β signaling: critical nexus of fibrogenesis and cancer. J Transl Med. 2024;22(1):594. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79.Devico Marciano N, Kroening G, Dayyani F, Zell JA, Lee FC, Cho M et al. BRCA-Mutated pancreatic cancer: from discovery to novel treatment paradigms. Cancers (Basel). 2022;14(10).2453 [DOI] [PMC free article] [PubMed]
- 80.Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014;7(344):re8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.Kobayashi H, Gieniec KA, Wright JA, Wang T, Asai N, Mizutani Y, et al. The balance of stromal BMP signaling mediated by GREM1 and ISLR drives colorectal carcinogenesis. Gastroenterology. 2021;160(4):1224–e3930. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82.Ram Makena M, Gatla H, Verlekar D, Sukhavasi S, M KP KCP. Wnt/β-Catenin signaling: the culprit in pancreatic carcinogenesis and therapeutic resistance. Int J Mol Sci. 2019;20(17).4242 [DOI] [PMC free article] [PubMed]
- 83.Mustafa M, Abbas K, Alam M, Habib S, Zulfareen, Hasan GM, et al. Investigating underlying molecular mechanisms, signaling pathways, emerging therapeutic approaches in pancreatic cancer. Front Oncol. 2024;14:1427802. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84.Wei J, Li W, Zhang P, Guo F, Liu M. Current trends in sensitizing immune checkpoint inhibitors for cancer treatment. Mol Cancer. 2024;23(1):279. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85.Chouari T, La Costa FS, Merali N, Jessel MD, Sivakumar S, Annels N et al. Advances in immunotherapeutics in pancreatic ductal adenocarcinoma. Cancers (Basel). 2023;15(17).4265 [DOI] [PMC free article] [PubMed]
- 86.Eso Y, Shimizu T, Takeda H, Takai A, Marusawa H. Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against Gastrointestinal and hepatobiliary cancers. J Gastroenterol. 2020;55(1):15–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87.Chakrabarti S, Bucheit L, Starr JS, Innis-Shelton R, Shergill A, Dada H et al. Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer. J Immunother Cancer. 2022;10(6).e004485. [DOI] [PMC free article] [PubMed]
- 88.Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch Repair-Deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89.Marcus L, Fashoyin-Aje LA, Donoghue M, Yuan M, Rodriguez L, Gallagher PS, et al. FDA approval summary: pembrolizumab for the treatment of tumor mutational Burden-High solid tumors. Clin Cancer Res. 2021;27(17):4685–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 90.Zheng-Lin B, O’Reilly EM. Pancreatic ductal adenocarcinoma in the era of precision medicine. Semin Oncol. 2021;48(1):19–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.Luchini C, Brosens LAA, Wood LD, Chatterjee D, Shin JI, Sciammarella C, et al. Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications. Gut. 2021;70(1):148–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92.Hoskins EL, Samorodnitsky E, Wing MR, Reeser JW, Hopkins JF, Murugesan K, et al. Pan-cancer landscape of programmed death Ligand-1 and programmed death Ligand-2 structural variations. JCO Precis Oncol. 2023;7:e2200300. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 93.Sha D, Jin Z, Budczies J, Kluck K, Stenzinger A, Sinicrope FA. Tumor mutational burden as a predictive biomarker in solid tumors. Cancer Discov. 2020;10(12):1808–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94.Uscanga-Palomeque AC, Chávez-Escamilla AK, Alvizo-Báez CA, Saavedra-Alonso S, Terrazas-Armendáriz LD, Tamez-Guerra RS et al. CAR-T cell therapy: from the shop to Cancer therapy. Int J Mol Sci. 2023;24(21).15688. [DOI] [PMC free article] [PubMed]
- 95.Zhang GZ, Li TF, Han SY. Mesothelin-targeted CAR-T cells for adoptive cell therapy of solid tumors. Arch Med Sci. 2021;17(5):1213–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Farhangnia P, Khorramdelazad H, Nickho H, Delbandi AA. Current and future immunotherapeutic approaches in pancreatic cancer treatment. J Hematol Oncol. 2024;17(1):40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97.Chen J, Xu Z, Hu C, Zhang S, Zi M, Yuan L, et al. Targeting CLDN18.2 in cancers of the Gastrointestinal tract: new drugs and new indications. Front Oncol. 2023;13:1132319. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98.Qi C, Gong J, Li J, Liu D, Qin Y, Ge S, et al. Claudin18.2-specific CAR T cells in Gastrointestinal cancers: phase 1 trial interim results. Nat Med. 2022;28(6):1189–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 99.Watt J, Kocher HM. The desmoplastic stroma of pancreatic cancer is a barrier to immune cell infiltration. Oncoimmunology. 2013;2(12):e26788. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100.Duan X, Chan C, Lin W. Nanoparticle-Mediated Immunogenic cell death enables and potentiates Cancer immunotherapy. Angew Chem Int Ed Engl. 2019;58(3):670–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 101.Hou W, Yang B, Zhu H. Nanoparticle-Based therapeutic strategies for enhanced pancreatic ductal adenocarcinoma immunotherapy. Pharmaceutics. 2022;14(10).2033 [DOI] [PMC free article] [PubMed]
- 102.Shams F, Golchin A, Azari A, Mohammadi Amirabad L, Zarein F, Khosravi A, et al. Nanotechnology-based products for cancer immunotherapy. Mol Biol Rep. 2022;49(2):1389–412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 103.Das M, Shen L, Liu Q, Goodwin TJ, Huang L. Nanoparticle delivery of RIG-I agonist enables effective and safe adjuvant therapy in pancreatic Cancer. Mol Ther. 2019;27(3):507–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 104.Zhang C, Yan L, Wang X, Zhu S, Chen C, Gu Z, et al. Progress, challenges, and future of nanomedicine. Nano Today. 2020;35:101008. [Google Scholar]
- 105.Zhang P, Xiao Y, Sun X, Lin X, Koo S, Yaremenko AV, et al. Cancer nanomedicine toward clinical translation: obstacles, opportunities, and future prospects. Med. 2023;4(3):147–67. [DOI] [PubMed] [Google Scholar]
- 106.Dana H, Chalbatani GM, Mahmoodzadeh H, Karimloo R, Rezaiean O, Moradzadeh A, et al. Molecular mechanisms and biological functions of SiRNA. Int J Biomed Sci. 2017;13(2):48–57. [PMC free article] [PubMed] [Google Scholar]
- 107.Tang Q, Khvorova A. RNAi-based drug design: considerations and future directions. Nat Rev Drug Discov. 2024;23(5):341–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Jorge AL, Pereira ER, Oliveira CS, Ferreira EDS, Menon ETN, Diniz SN, et al. MicroRNAs: Understanding their role in gene expression and cancer. Einstein (Sao Paulo). 2021;19:eRB5996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Zou X, Huang Z, Guan C, Shi W, Gao J, Wang J, et al. Exosomal MiRNAs in the microenvironment of pancreatic cancer. Clin Chim Acta. 2023;544:117360. [DOI] [PubMed] [Google Scholar]
- 110.Boisguérin P, Konate K, Josse E, Vivès E, Deshayes S. Peptide-Based nanoparticles for therapeutic nucleic acid delivery. Biomedicines. 2021;9(5).583 [DOI] [PMC free article] [PubMed]
- 111.Loureiro A, da Silva GJ. CRISPR-Cas: converting A bacterial defence mechanism into A State-of-the-Art genetic manipulation tool. Antibiot (Basel). 2019;8(1).18 [DOI] [PMC free article] [PubMed]
- 112.Xu Y, Li Z. CRISPR-Cas systems: overview, innovations and applications in human disease research and gene therapy. Comput Struct Biotechnol J. 2020;18:2401–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113.McAndrews KM, Xiao F, Chronopoulos A, LeBleu VS, Kugeratski FG, Kalluri R. Exosome-mediated delivery of CRISPR/Cas9 for targeting of oncogenic Kras(G12D) in pancreatic cancer. Life Sci Alliance. 2021;4(9).e202000875 [DOI] [PMC free article] [PubMed]
- 114.Won EJ, Park H, Yoon TJ, Cho YS. Gene therapy using nanocarriers for pancreatic ductal adenocarcinoma: applications and challenges in Cancer therapeutics. Pharmaceutics. 2022;14(1).137 [DOI] [PMC free article] [PubMed]
- 115.Uddin F, Rudin CM, Sen T. CRISPR gene therapy: applications, limitations, and implications for the future. Front Oncol. 2020;10:1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116.Liu Mq, Yang X. Patient-derived xenograft models: current status, challenges, and innovations in cancer research. Genes Dis. 2025:101520. [DOI] [PMC free article] [PubMed]
- 117.Braun R, Ungefroren H. Preclinical Patient-Derived culture models for personalized treatment of pancreatic cancer: A dream of the future or useful practice?? Cancers (Basel). 2023;15(11).3027 [DOI] [PMC free article] [PubMed]
- 118.Thorel L, Perréard M, Florent R, Divoux J, Coffy S, Vincent A, et al. Patient-derived tumor organoids: a new avenue for preclinical research and precision medicine in oncology. Exp Mol Med. 2024;56(7):1531–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 119.Kaczmarek M, Poznańska J, Fechner F, Michalska N, Paszkowska S, Napierała A et al. Cancer vaccine therapeutics: limitations and Effectiveness-A literature review. Cells. 2023;12(17).2159 [DOI] [PMC free article] [PubMed]
- 120.Bidram M, Zhao Y, Shebardina NG, Baldin AV, Bazhin AV, Ganjalikhany MR et al. mRNA-Based Cancer vaccines: A therapeutic strategy for the treatment of melanoma patients. Vaccines (Basel). 2021;9(10).1060 [DOI] [PMC free article] [PubMed]
- 121.Rojas LA, Sethna Z, Soares KC, Olcese C, Pang N, Patterson E, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 2023;618(7963):144–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122.El-Tanani M, Rabbani SA, Babiker R, Rangraze I, Kapre S, Palakurthi SS, et al. Unraveling the tumor microenvironment: insights into cancer metastasis and therapeutic strategies. Cancer Lett. 2024;591:216894. [DOI] [PubMed] [Google Scholar]
- 123.Shaashua L, Ben-Shmuel A, Pevsner-Fischer M, Friedman G, Levi-Galibov O, Nandakumar S, et al. BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling. Nat Commun. 2022;13(1):6513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 124.Kindler HL, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Overall survival results from the POLO trial: A phase III study of active maintenance Olaparib versus placebo for germline BRCA-Mutated metastatic pancreatic Cancer. J Clin Oncol. 2022;40(34):3929–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 125.Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance Olaparib for germline BRCA-Mutated metastatic pancreatic Cancer. N Engl J Med. 2019;381(4):317–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Walker EJ, Ko AH. Maintenance treatment for metastatic pancreatic cancer: balancing therapeutic intensity with tolerable toxicity. Cancers (Basel). 2023;15(14).3657. [DOI] [PMC free article] [PubMed]
- 127.Lin Z, Wang L, Xing Z, Wang F, Cheng X. Update on combination strategies of PARP inhibitors. Cancer Control. 2024;31:10732748241298329. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 128.Wang Y, Lei F, Lin Y, Han Y, Yang L, Tan H. Peroxisome proliferator-activated receptors as therapeutic target for cancer. J Cell Mol Med. 2024;28(5):e17931. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 129.Shiravand Y, Khodadadi F, Kashani SMA, Hosseini-Fard SR, Hosseini S, Sadeghirad H, et al. Immune checkpoint inhibitors in Cancer therapy. Curr Oncol. 2022;29(5):3044–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 130.Su X, Li J, Xu X, Ye Y, Wang C, Pang G, et al. Strategies to enhance the therapeutic efficacy of anti-PD-1 antibody, anti-PD-L1 antibody and anti-CTLA-4 antibody in cancer therapy. J Translational Med. 2024;22(1):751. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 131.Gupta M, Sherrow C, Krone ME, Blais EM, Pishvaian MJ, Petricoin EF, et al. Targeting the NTRK fusion gene in pancreatic acinar cell carcinoma: A case report and review of the literature. J Natl Compr Canc Netw. 2021;19(1):10–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 132.Marchetti A, Ferro B, Pasciuto MP, Zampacorta C, Buttitta F, D’Angelo E. NTRK gene fusions in solid tumors: agnostic relevance, prevalence and diagnostic strategies. Pathologica. 2022;114(3):199–216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 133.Solomon JP, Hechtman JF. Detection of NTRK fusions: merits and limitations of current diagnostic platforms. Cancer Res. 2019;79(13):3163–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 134.Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–23. [DOI] [PubMed] [Google Scholar]
- 135.Melisi D, Oh DY, Hollebecque A, Calvo E, Varghese A, Borazanci E et al. Safety and activity of the TGFβ receptor I kinase inhibitor Galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer. J Immunother Cancer. 2021;9(3).e002068 [DOI] [PMC free article] [PubMed]
- 136.Zhang J, Wang S, Zhang D, He X, Wang X, Han H, et al. Nanoparticle-based drug delivery systems to enhance cancer immunotherapy in solid tumors. Front Immunol. 2023;14:1230893. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.