Table 5.
Data on the experimental and clinical trials of drugs targeting the tumor microenvironment and OCSC metastatic niche.
| Target | Drug | Mechanism of action | Trial | Reference |
|---|---|---|---|---|
| MSCs | Metformin Letrozole + Ruxolitinib |
Prevention of reprogramming of MSCs into active cancer-associated cells and decrease of tumor Tregs. Clinical utility in early ovarian cancer and pre-treatment in immunotherapy regimens Combined therapy of anti-estrogen drug with inhibitor of JAK enables inhibition of LIF/IL-6–mediated signals from cancer-associated MSCs, which is followed by sensitization of ovarian cancer to anti-estrogen therapy |
Experimental Experimental |
(388) (389) |
| MDSCs | Alemtuzumab | moAb targeting CD52 expressed by vascular leukocytes and Tie2+ monocytes, thus disturbing interactions with SIGLEC10. This moAb induces complement-dependent lysis of CD52-positive cells in ascites and restricts angiogenesis | Experimental | (390) |
| CAMs | Rilotumumab (AMG102) Oregovomab monotherapy Oregovomab + carboplatin + paclitaxel |
Anti-HGF moAb. Although well-tolerated, the treatment showed very limited efficacy Anti-MUC16 moAb. While used in monotherapy, oregovomab did not show any benefit to patients with persistent advanced ovarian cancer moAb combined with first line standard chemotherapy in patients with advanced ovarian cancer showed prolongation of both PFS and OS In patients with optimally resected advanced ovarian cancer, combination of drugs resulted in more than three times longer PFS compared to chemotherapy alone |
Phase II Phase II Phase II Phase II |
(391) (392) (393) (394) |
| REGN4018 monotherapy Anetumab ravtansine + pegylated liposomal doxorubicin |
Bispecific anti-MUC16/CD3 moAb inhibited the growth of murine peritoneal tumors Conjugate of anti-MUC16 moAb with cytotoxic maytansinoid tubulin inhibitor DM4. In recurrent ovarian cancer, this combination showed 28% response rate, mostly in the form of partial response |
Experimental Phase Ib |
(395) (396) |
|
| Intetumumab (CNTO-95) monotherapy Volociximab monotherapy |
moAb targeting αγβ3 and αγβ5 integrins. In patients with solid tumors including ovarian carcinosarcoma, it showed stabilization of the disease moAb against α5β1 integrin. In advanced platinum-resistant ovarian cancer, it failed to demonstrate efficacy |
Phase I Phase II |
(397) (398) |
|
| TAMs | Anti-CD24 moAb Hu5F9-G4 moAb Celecoxib + cyclophosphamide Celecoxib + carboplatin Celecoxib + carboplatin + docetaxel G5-MTX |
CD24 is a “do not eat me” signal for macrophages. Disrupting the signal between CD24 on cancer cells and SIGLEC-10 on TAMs enhanced phagocytosis of cancer cells and could be a novel target for therapy moAb blocking phagocytosis mediated by CD47. Partial remission in two patients COX-2 inhibitor that blocks M2 shift of TAMs mediated by OCSC-derived COX-2 activity. Combination therapy did not show therapeutic benefit in recurrent ovarian cancer The response rate to this combination in recurrent platinum-resistant ovarian cancer was 29% In the group of Ic-IV stage ovarian cancer, addition of celecoxib to first-line standard chemotherapy did not show any benefit G5-methotrexate nanoparticles depleted TAMs in models of ovarian cancer and ascites and were able to reverse anti-angiogenic therapy resistance |
Experimental NCT02216409 Phase I Phase II Phase II DoCaCel study Phase II Experimental |
(399) (400) (401) (402) (403) (404) |
| Clodronate liposomes (biphosphonate) Trabectedin Trabectedin monotherapy Trabectedin + pegylated liposomal doxorubicin Trabectedin + durvalumab Trabectedin + bevacizumab |
Reduced metastases and ascites formation in HGSOC xenografts Extract from the sea squirt Ecteinascidia turbinata selectively cytotoxic to macrophages and reducing angiogenesis in mouse model of ovarian cancer Sensitizes platinum-resistant tumors for the consecutive platinum treatment Combination showed ORR of 28% in advanced recurrent ovarian cancer Patients with germline BRCA1/2 mutations and platinum-free interval of 6–12 months had survival benefit from this treatment Combination with PD-1/PD-L1 inhibitor resulted in tumor shrinkage and 6-month PFS in 43% of patients with advanced ovarian cancer Combination showed benefit; 75% of patients had PFS of 6 months |
Experimental Experimental Phase II Phase I Phase III TRAMUNE Study Phase Ib Phase II |
(405) (406) (407) (408) (409) (410) (411) |
|
| GW2580 ARRY-382 + pembrolizumab AC708 + anti-VEGF + paclitaxel Mannose receptor (CD206)-targeted nanocarrier of IRF5 and IKKβ mRNA |
CSF1R inhibitor inhibits CSF1/CSF1R pathway responsible for TAMs survival. Reduction of ascites in the mouse model of ovarian cancer Combination with PD-1/PD-L1 inhibitor. One patient with ovarian cancer had partial response Partial restoration of sensitivity to anti-VEGF therapy in mouse xenograft model Reversing TAM phenotype into M1. Reduces tumor growth in mouse model of ovarian cancer |
Experimental NCT02880371 Phase Ib/II Experimental Experimental |
(412) (413) (414) (415) |
|
| CAAs | Metformin | Inhibits adipocyte-mediated cancer cell proliferation, migration, and bio-energetic changes | Experimental | (416) |
| CAFs | A-83-01 LY2109761 + cisplatin Sorafenib monotherapy Sorafenib + bevacizumab |
CAF-derived TGF-β promotes tumor supporting environment. Inhibitor of TGF-β signaling pathway decreased peritoneal metastases and improved survival in mouse model of ovarian cancer Combination of TGF-β type I/type II inhibitor with cisplatin increased significantly cytotoxic activity of chemotherapeutic in chemoresistant cell line In recurrent ovarian cancer and peritoneal carcinomatosis, therapy was effective in two of the 59 patients with partial response and 20 of the 59 patients with disease stabilization but showed substantial toxicity CAFs secrete growth factors stimulating cancer proliferation. Combination of multi-kinase inhibitor against PDGFR, VEGFR, Raf, and CD117 with anti-angiogenic therapy resulted in partial response in 9 of the 35 patients and stabilization in 18 of the 35 of patients |
Experimental Experimental Gynecologic Oncology Group Phase II Phase II |
(417) (418) (419) (420) |
| Sorafenib + topotecan Sorafenib + gemcitabine Sorafenib + paclitaxel + carboplatin |
In recurrent ovarian cancer, therapy was effective in five of the 30 patients with partial response, and 14 of the 30 patients with disease stabilization but showed substantial toxicity Oral sorafenib in combination with topotecan and continued as maintenance monotherapy showed significant prolongation of PFS compared to placebo in recurrent ovarian cancer, with acceptable toxicity The combination was associated with encouraging rates of stable disease and CA-125 response, with manageable toxicity The combination of sorafenib and standard therapy in the first-line treatment of advanced ovarian cancer did not improve efficacy and substantially increased toxicity |
Hoosier Oncology Group Phase II NCT01047891 Phase II Princess Margaret Hospital Phase II Sarah Cannon Research Institute Phase II |
(421) (422) (423) (402, 424) |
|
| Aflibercept monotherapy Cediranib (AZD2171) monotherapy |
This recombinant fusion VEGFR1/2 protein extracellular domain is a decoy receptor that inhibits pro-angiogenic signaling from CAFs. Aflibercept was effective in controlling of malignant ascites in advanced ovarian cancer Receptor tyrosine kinase inhibitor that inhibits VEGFR1/2/3 and PDGFR-α/-β and CD117, thus blocking signals from CAFs; 17% of patients and 13% of patients had partial response and stable disease, respectively In platinum-sensitive group, there was partial response in 26% and stable disease in 51% of patients. In the group of platinum-resistant patients, only stabilization of the disease in 66% was observed |
Phase II Phase II Princess Margaret, Chicago and California consortium Phase II |
(425) (426) (427) |
|
| Cediranib + olaparib | Combination of two drugs used in the group of patients with progressive HGSOC pre-treated with platinum (both resistant and sensitive) and with acquired PARP inhibitors resistance. Sixteen-week PFS varied from 39% to 55% and was dependent on genomic alterations, being the shortest in the group with reverse BRCA1, BRCA2, and RAD51B mutations and ABCB1 upregulation In platinum-sensitive recurrent ovarian cancer, combination of drugs did not improve PFS, compared to platinum-based chemotherapy. However, in patients with germinal BRCA mutation, it was significantly effective In patients with platinum-resistant recurrent BRCA germline mutation-negative ovarian cancer pre-treated with a median of 4 lines of chemotherapy and bevacizumab, the ORR with this drug combination was 15%, PFS was 5 months, and OS was 13 months |
EVOLVE Phase II NRG-GY004 Phase III CONCERTO Phase III |
(428) (429) (430) |
|
| Nintedanib (BIBF1120) monotherapy Nintedanib (BIBF1120) + carboplatin + paclitaxel Pazopanib (GW786034) + paclitaxel |
Receptor tyrosine kinase inhibitor that inhibits VEGFR1/2/3 and FGFR1/2/3 and PDGFR-α/-β. Maintenance therapy after completed chemotherapy for relapsed ovarian cancer showed improvement of PFS (16% vs. 5%) Combination of drugs compared to standard chemotherapy alone showed modest efficacy (improved PFS) in the group of patients with advanced HGSOC and upfront debulking surgery Receptor tyrosine kinase inhibitor that inhibits VEGFR1/2/3, PDGFR-α/-β, and CD117. Combination of drugs compared to paclitaxel alone showed improvement in PFS (6.3 vs. 3.5 months) and OS (18.7 vs. 14.8 months) in advanced platinum-resistant or platinum-refractory ovarian cancer |
Phase II AGO-OVAR12 Phase III MITO-11 Phase II |
(431) (432) (433) |
|
| Pazopanib (GW786034) + paclitax el Pazopanib (GW786034) + cyclophosphamide Pazopanib (GW786034) + chemotherapy Calcitriol Losartan + platinum + taxol |
In ovarian cancer relapse during maintenance therapy with bevacizumab, combination of drugs compared to paclitaxel alone did not improve efficacy but increased toxicity In the group of recurrent, platinum-resistant and pre-treated ovarian cancer combination of drugs showed promising results (PFS of 8 months and OS of 25 months) Meta-analysis of five studies indicated that pazopanib combined with chemotherapy improved ORR, but without improvement in OS and with increase of toxicity Inhibits SMAD signaling in CAFs. Use of calcitriol improved survival of mice with xenografted HGSOC tumors Angiotensin inhibitor that showed activity against ovarian cancer in combination with standard therapy—prolongation of OS and reduction of ascites |
TAPAZ Phase II PACOVAR Phase I Experimental Observational |
(434) (435) (436) (437) (438) |
|
| Immune cells | Atezolizumab+ platinum + bevacizumab Atezolizumab + bevacizumab Avelumab + carboplatin + paclitaxel |
Immune checkpoint inhibitor anti–PD-L1 moAb in combination with platinum-based chemotherapy and anti-angiogenic therapy in patients with newly diagnosed advanced ovarian cancer with residual disease after primary cytoreduction or in neo-adjuvant setting. No benefit was observed in Atezolizumab therapy compared to placebo In patients with platinum-resistant ovarian cancer, the partial responses were observed in three of 20 and stabilization of the disease in 8 of the 20 patients, respectively Immune checkpoint inhibitor anti–PD-L1 moAb addition to standard chemotherapy in advanced ovarian cancer after primary cytoreduction or in neo-adjuvant setting did not improve PFS |
IMagyn050/GOG3015/ENGOT-OV39 Phase III Phase Ib JAVELIN Ovarian 100 Phase III |
(439) (440) (441) |
| Avelumab + pegylated liposomal doxorubicin Avelumab + Talazoparib Durvalumab + TPIV200 Durvalumab + Olaparib |
In the group of patients with recurrent ovarian cancer pre-treated with at least three cycles for platinum-sensitive disease, combination did not improved either PFS or OS significantly Combination of PD-L1 and PARP inhibitor in solid tumors with BRCA1/2 or ATM mutation (including ovarian cancer) did not reach the presumed PFS Combination of this PD-L1 inhibitor with folate receptor-α vaccine in recurrent advanced platinum-resistant ovarian cancer showed robust immune response but low response rate, however with unexpected prolongation of survival (median OS 21 months) In the group of patients with ovarian cancer with recurrent tumor, this combination showed overall disease control rate of 71% (partial response + stabilization), as well as switch into immunoreactive environment |
JAVELIN Ovarian 200 Phase III JAVELIN BRCA/ATM Phase IIb Phase II Phase II |
(442) (443) (444) (445) |
|
| Durvalumab + Olaparib or Durvalumab + pegylated liposomal doxorubicin/topotecan/paclitaxel or Durvalumab + Tremelimumab (anti-CTLA-4 moAb) + pegylated liposomal doxorubicin/topotecan/paclitaxel Durvalumab + Olaparib + Cediranib Nivolumab + Ipilimumab Nivolumab + Bevacizumab |
Combinations were adjusted to the biosignature of the tumors in the context of PD-L1 and homologous recombination deficiency (HRD) status. In the group of recurrent platinum-resistant ovarian cancer, this therapy showed median ORR of 37% with manageable toxicity Combination of PD-L1 and PARP inhibitors with VEGFR1-3 inhibitor showed disease control rate of 67% in the group of heavily pre-treated patients with gynecologic cancers including seven of the nine ovarian cancers Combined anti–PD-1 and CTLA-4 therapy compared to nivolumab monotherapy indicated better 6-month ORR (31% vs. 12%) and PFS (4 vs. 2 months) in recurrent/persistent ovarian cancer Combined therapy in relapsed ovarian cancer showed ORR of 40% in platinum-sensitive and ORR of 17% in platinum-resistant patients |
AMBITION/KGOG3045 Phase III Phase I NRG Oncology Study Phase II Phase II |
(446) (447) (448) (449) |
|
| Nivolumab monotherapy Nivolumab + Galinpepimut-S Pembrolizumab + Bevacizumab + cyclophosphamid Pembrolizumab monotherapy |
Monotherapy did not improve OS and PFS in patients with recurrent platinum-resistant ovarian cancer, when compared to gemcytabine or pegylated liposomal doxorubicin Combination with tetravalent Wilms’ Tumor 1 (WT1) peptide vaccine in patients with ovarian cancer with second/third remission and tumors showing WT1 expression indicated prolongation of PFS to 1 year in 70% of patients treated with more than two cycles This combination gave clinical benefit in 95% and median PFS of 10 months in the group of patients with mostly platinum-resistant recurrent ovarian cancer In the group of pre-treated with standard chemotherapy patients, monotherapy showed modest clinical efficacy (ORR not exceeding 10%) and better in tumor’s PD-L1 higher positivity |
NINJA Phase III Phase I Phase II KEYNOTE-100 Phase II |
(450) (451) (452) (453) |
|
| Pembrolizumab + cisplatin + gemcytabine Pembrolizumab + Niraparib Pembrolizumab + low-dose carboplatin Pembrolizumab + pegylated liposomal doxorubicin |
In recurrent platinum-resistant ovarian cancer, addition of pembrolizumab to chemotherapy did not result in a benefit of the therapy In recurrent platinum-resistant ovarian cancer, this combination showed disease control rate of 65% In recurrent platinum-resistant ovarian cancer, this combination showed ORR of 62% and better OS in the group of patients with the higher CD8+PD-1+Ki67+ T cells to the tumor burden ratio Combination showed ORR of 26% in the group of patients with recurrent ovarian cancer, and results were better compared to monotherapy using each drug separately |
Phase II Phase II Phase II Phase II |
(454) (455) (456) (457) |
|
| Exosomes | Peptide-engineered exosomes Tumor suppressor miRNA Exosomes with Triptolide Exosome-liposome hybrid nanoparticle delivery system α-Mangostin + cisplatin |
Artificially generated exosomes with overexpression of miR-92b-3p could be used as an anti-angiogenic therapy MiR-199a-3p loaded to exosomes inhibited ovarian cancer proliferation and invasion and, in xenograft mouse model, inhibited peritoneal dissemination of cancer Diterpenoid epoxide packed into exosomes showed anti-proliferative effect on ovarian cancer cell lines and xenografted tumors, however with considerable hepatic and splenic toxicity Hybrid transport system packed with Triptolide and miR-497 showed apoptotic effects and enabled to overcome platinum resistance Combination of natural plant derivative with cisplatin changed the number and activity of CAF-derived exosomes |
Experimental Experimental Experimental Experimental Experimental |
(458) (459) (460) (461) (374) |
| RNAs-targeted therapy | Circ_EXOC6B RNA miR-671-5p Icariside II Circ_TYMP1 RNA circ_0026123 RNA |
Circ_EXOC6B RNA suppressed the progression and paclitaxel resistance of ovarian cancer cells through sequestering miR-376c-3p miR-671-5p reduces tumorigenicity of ovarian cancer through suppressing histone deacetylase 5 (HDAC5) and HIF-1α expression Herbal component from Epimedium brevicornum. Suppresses the tumorigenesis of ovarian cancer by promoting autophagy by miR-144-3p/IGF2R axis Downregulation of circ_TYMP1 decreased ovarian cell proliferation and invasion by miR-182A-3p/TGF-β pathway Downregulation of this circRNA inhibited proliferation and metastases of ovarian cancer through miR-124-3p/enhancer of zeste homolog 2 (EZH2) pathway |
Experimental Experimental Experimental Experimental Experimental |
(462) (463) (464) (465) (466) |
| miR-146a Follistatin mRNA anti-PLXDC1 siRNA miR-20c |
MiR-146a secreted by MSCs increased the chemosensitivity of ovarian cancer resistant cell lines to docetaxel Lipid nanoparticles containing mRNA for follistatin injected intraperitonealy inhibited cancer dissemination and prevented the onset of cachexia in the mouse model of ovarian cancer Chitosan nanoparticles containing anti-PLXDC1 siRNA decreased tumor proliferation and microvessel density and increased apoptosis in murine model of ovarian cancer MiR-200c was used as an inhibitor of NRP1 transmembrane receptor highly expressed by ovarian cancer and connected to multi-drug resistance. Combination of miRNA with olaparib enhanced its cytotoxicity |
Experimental Experimental Experimental Experimental |
(220) (467) (468) (469) |
MSCs, mesenchymal stem cells; MDSCs, myeloid-derived stem cells; HGF, hepatocyte growth factor; MUC16, mesothelin; CD52, CAMPATH-1 antigen; SIGLEC-10, silica acid binding Ig–like lectin-10; Tregs, T regulatory cells; CAAs, cancer-associated adipocytes; DNMT1, DNA-(cytosine-5)-methyltransferase-1; TAMs, tumor-associated macrophages; COX-2, cyclooxygenase-2; ORR, overall response rate; CSF1, colony-stimulating factor-1; CSF1R, colony-stimulating factor-1 receptor; IFR5, Interferon regulatory factor; IKKβ, IkappaB kinase beta; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor; Raf, RAF proto-oncogene serine/threonine-protein kinase; PFS, progression-free survival; BRCA, breast cancer type 1 susceptibility protein; RAD51B, RAD51 paralog B; ABCB1, ATP-binding cassette sub-family B member 1; FGFR, fibroblast growth factor receptor; ORR, overall response rate; PARP, poly-(ADP-rybose) polymerase; CTLA-4, cytotoxic T-cell antigen 4; IGF2R, insulin-like growth factor-2 receptor; mRNA, messenger RNA; siRNA, small interfering RNA; PLXDC1, plexin domain containing 1; NRP1, neuropilin-1.