Novel Approaches to Clinical Trial Design in Cancer Neuroscience

Abstract

The emerging field of cancer neuroscience has revealed profound bidirectional interactions between the nervous system and cancer cells, identifying novel therapeutic vulnerabilities across diverse malignancies. This review examines the unique challenges and strategies for translating these insights into effective therapies. We propose innovative approaches to overcome these barriers through drug repurposing, enhanced biomarker development, and optimized trial designs. Repurposing neuroactive drugs with established safety profiles offers an accelerated path to clinical impact, particularly for targeting glutamatergic, adrenergic, and neurotrophic signaling pathways. Emphasizing mitigation of neurotoxicity and improved patient quality of life will be paramount moving forward. Repurposed agents that show preliminary potential for ‘dual use’ (i.e., simultaneous toxicity mitigation and synergistic anti-tumor effects) are highlighted for special consideration. Master protocols and window-of-opportunity trials provide platforms to rapidly validate mechanisms while addressing patient-centered outcomes. By systematically addressing these foundational elements across disciplines, cancer neuroscience can translate its profound mechanistic insights into meaningful therapeutic advances for patients with treatment-resistant malignancies.

In Brief

Jones et al. survey new approaches in cancer neuroscience, including repurposing neuropsychiatric drugs and developing predictive biomarkers to guide innovative anti-cancer therapies and clinical trial designs.

I. Introduction

The nervous system plays a central role in modulating cellular activities across developmental stages and organ systems, with emerging evidence highlighting its pivotal role in modulating tumor growth, invasion, metastasis, and treatment resistance.^1–3 Tumor dependance on the most fundamental neural mechanisms —synaptic plasticity, myelin adaptability, electrochemical gradients, axonal guidance, and others—presents both immense challenges and unique therapeutic opportunities for cancer neuroscience.^2–8

Bidirectional communication between neurons and cancer cells facilitates multiple hallmarks of malignancy through distinct yet complementary mechanisms in the central and peripheral nervous systems (for reviews, please see;^3,8–13 Figure 1). Glutamatergic neurons promote glioma growth through neuron-to-glioma synapses^14–16 and through activity-dependent paracrine secretion of signaling molecules such as neuroligin-3 (NLGN3), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1).^5,17–19 Sensory deprivation (visual, olfactory) can prevent glioma formation in the relevant neural circuits of genetically predisposed models,^19,20 and high functional connectivity between the tumor and brain is associated with poorer survival.²¹ Similarly, brain metastases exploit neural circuitry by forming “pseudo-tripartite synapses” where cancer cells receive glutamatergic input through NMDA receptors, facilitating colonization within the neural microenvironment.²² In the peripheral nervous system (PNS), sympathetic signaling drives treatment resistance and immune evasion in multiple cancers through β-adrenergic receptors,^23–26 while sensory nerve-derived CGRP fosters immunosuppression in melanoma and head/neck cancers.^27,28 Similarly, parasympathetic innervation exhibits divergent effects, promoting growth in prostate and gastric cancers while suppressing progression in breast and pancreatic tumors.^8,29–31 From all angles, neurotrophic factors (e.g., NGF, BDNF, GDNF) fuel tumorigenesis and perineural invasion through feedforward loops, increasing neural inputs to the tumor - that accelerate tumor pathogenesis and cancer progression.^25,32 Glial cells, particularly Schwann cells, promote cancer invasion and modulate the tumor microenvironment (TME) by influencing fibroblasts to adopt more pro-tumor subtypes.^33,34 Extracellular matrix (ECM) stiffening itself can facilitate integrin-mediated mechanotransduction to drive the expression of neurotropic factors (BDNF, NGF) and promote tumor hyperinnervation.³⁵ Additionally, immune cells within the TME, such as macrophages and T cells, are influenced by neural signals, with neurotransmitters like acetylcholine and neuropeptides modulating immune responses to either suppress anti-tumor immunity or enhance inflammation, further supporting cancer progression.^11,12 Lastly, cell membrane depolarization and ion channel activity stand as a crucial final point of convergence for both CNS and PNS interactions,^5,14,36–39 highlighting the intricate interplay between neural, immune, and tumor components in driving malignancy (Figure 1).

Figure 1: Central and Peripheral Nervous System Cancer Neuroscience Hallmarks.

(A) Malignant gliomas synapse with glutamatergic neurons through AMPA signaling. (B) Breast-to-brain metastases via NMDA receptors. (C) External visual and olfactory stimuli enhance tumor growth in visual or olfactory circuits. (D) β-adrenergic signaling stimulates cancer cells to produce NGF and BDNF and inhibits CD8+ T cell effector functions. (E) Many tumors (e.g., breast cancer) overexpress ion channels that drive proliferation and metastasis (F) Calcitonin gene-related peptide (CGRP) release drives tumor angiogenesis and promotes immunosuppression.

Despite the compelling biological and preclinical evidence, numerous barriers impede the clinical translation of these insights into effective therapies. The blood-brain barrier and blood-nerve barrier restrict delivery of many drugs to cancers within the nervous system, although this may not be as much of an issue for re-purposed drugs of neurology and psychiatry designed to enter the CNS. Systemic targeting of neural processes important to normal neural cells in the brain and widely distributed PNS risks off-tumor toxicities. Perhaps most critically, the absence of validated biomarkers for neural-tumor interactions further complicates patient selection and response assessment.

To overcome these obstacles, a multifaceted approach is required (Figure 2). First, enhanced collaboration across neuroscience, immunology, and oncology is urgently needed to fully characterize the bidirectional communication between tumors and nerves that creates feedforward loops accelerating malignancy. Second, novel biomarkers that capture the complexity of neuron-tumor interactions must be developed to enable precise stratification of patients likely to benefit from neural-targeted interventions. Third, repurposing existing neuroactive drugs with established safety profiles offers an accelerated path to clinical impact (Figure 2B). Fourth, innovative early-phase trial designs such as expanded window-of-opportunity studies and master protocols—including platform, basket, and umbrella designs—provide platforms to rapidly validate mechanisms while minimizing patient risk (Figure 2C). Most importantly, increased emphasis must be placed on addressing patient-centered outcomes—pain, mental health, cognition, addiction, quality of life, and functionality—to ensure that new interventions not only prolong survival but also preserve the dignity, autonomy, and day-to-day well-being of those navigating the burdens of disease. By systematically addressing these foundational elements across disciplines through integrated biomarker discovery and adaptive trial design strategies, the field of cancer neuroscience can translate its profound mechanistic insights into meaningful therapeutic advances for patients with treatment-resistant malignancies.

Figure 2. Comprehensive Workflow for Biomarker-Driven Clinical Trial Design in Cancer Neuroscience.

(A) Biomarker discovery and validation pipeline showing functional connectivity analysis, population distributions, and tumor-neuron interaction signatures leading to target identification and mechanistic validation. (B) Example adaptive clinical trial design: The CONNECT trial illustrating a two-stage biomarker-stratified approach for testing gabapentin in glioblastoma, featuring interim biomarker analysis, adaptive enrichment strategies, and biomarker refinement in parallel with patient enrollment. (C) Master protocol designs for efficient clinical testing: Platform trials enable continuous addition of new biomarkers and treatments with adaptive randomization; Basket trials test single treatments across multiple tumor types sharing common biomarkers (e.g., anticholinergics for parasympathetic-innervated tumors); Umbrella trials evaluate multiple biomarker-directed treatments within a single disease context (e.g., neural pathway-targeted therapies in glioblastoma). The workflow demonstrates integration of biomarker discovery, therapeutic repurposing, and innovative trial designs to accelerate translation of cancer neuroscience insights into clinical practice. MEG, magnetoencephalography; SOC, standard of care; TSP-1, thrombospondin-1; HFC, high functional connectivity; LFC, low functional connectivity.

II. Biomarker Development and Monitoring Strategies in Cancer Neuroscience

Effective clinical trial design and evaluation of neuroactive cancer therapeutics rely on robust biomarkers for accurate diagnosis and monitoring of therapeutic responses. Currently, research in the identification of biomarkers for nerve-cancer crosstalk is still in its infancy, limiting our ability to meaningfully stratify patients for clinical trials. Increased emphasis on validating and utilizing promising biomarkers in pilot studies is critical. Incorporating multi-omic approaches and cross-validation between tissue, blood, and cerebrospinal fluid (CSF)-based biomarkers could accelerate identification of reliable candidates, enabling more precise patient selection, targeted interventions, and improved therapeutic outcomes.

Central Nervous System Biomarkers and Monitoring Approaches

Despite these challenges, optimized multi-targeted approaches could significantly improve outcomes in brain tumor patients. Synthetic lethality screens can identify combination strategies to overcome intrinsic or acquired resistance, and nanoparticle-based delivery systems allow simultaneous cellular delivery of multiple therapeutic agents.^40,41 Serial tumor sampling and molecular characterization during therapy can reveal adaptive resistance pathways, guiding timely addition of combination therapies to target evolving tumor clones.⁴² Radiolabeled phenoxyacetamide (PEPA) derivatives with high AMPA receptor specificity—such as [¹¹C]K-2—show promise for non-invasive assessment of tumor neuron interactions.⁴³ Ongoing development of longer-lasting ¹⁸F-labeled K-2 derivatives could broaden clinical application in cancer neuroscience.⁴⁴

Markers of neurodegeneration may also help to augment the utility of liquid biopsies for cancer neuroscience studies. For example, Neurofilament light chain (NfL) is released upon axonal injury, with significant elevations demonstrated in CSF and plasma during active central nervous system disease.^45–47 Elevated peripheral NfL has been demonstrated 3 months prior to the diagnosis of brain metastasis (and correlated with shorter OS).⁴⁸ It may also serve as a marker of treatment related toxicities like immune effector cell neurotoxicity syndrome (ICANS) and chemotherapy-induced peripheral neuropathy (CIPN).^49–51 Overall, combining this sensitive (but nonspecific) marker with other targeted assays in the blood and CSF may have significant additive value. Currently however, only a limited number of studies are actively incorporating liquid biopsies as primary or secondary outcomes for CNS tumors (see Table 7 in Soffietti et al.).⁵² Increasing utilization in cancer neuroscience trials can help to serve a dual purpose of optimizing these methodologies while providing enhanced sensitivity to detect clinical response.

Complementary tissue-based studies have identified a neural epigenetic signature in high-grade gliomas, stratifying tumors into low- and high-neural subgroups, with high-neural tumors exhibiting significantly worse outcomes (median OS 14.2 vs. 21.2 months).⁵³ The signature also correlates with elevated serum BDNF levels, offering a potential to be used alongside liquid biopsies for non-invasive monitoring.⁵³ Further supporting these findings, Krishna et al., have demonstrated glioblastoma regions with high functional connectivity driven by synaptogenic factors such as thrombospondin-1 (TSP-1) correlate with poorer patient survival but can be targeted therapeutically (e.g., gabapentin).²¹ Based on this mechanism, retrospective analysis from this same group recently demonstrated approximately 4–6 month survival benefit from the use of gabapentin following surgical resection of newly diagnosed glioblastoma (n = 1,072 across 2 sites), as well as lower serum TSP-1 levels in a small subset gabapentin-treated (n = 9) vs untreated (n = 18) patients.⁵⁴ However, no clear association was made between TSP-1 expression level of the tumor and gabapentin survival response.

Clinical Biomarkers as Vital Secondary Endpoints

The Neurologic Assessment in Neuro-Oncology (NANO) scale is easily performed and demonstrates high inter-observer agreement. It can be readily incorporated with radiologic assessment or other biomarkers for outcomes monitoring in trials.⁵⁸ Seizure control should also be considered as an important secondary endpoint, especially when studying repurposed, neuroactive drugs.⁵⁹ Given the outsized impact of neurological symptoms on functionality and subjective quality of life, trial designs should prioritize capturing and reporting these endpoints alongside survival metrics.

Peripheral Nervous System Indicators and Imaging Advances

While overexpression of neural signaling components like adrenergic receptors in cancer cells could indicate suitability for therapies focused on sympathetic signaling, these biomarkers are not yet routinely implemented in clinical practice. Additionally, receptor expression alone does not reliably predict treatment responses, as receptor activity is modulated by the availability of corresponding nerve-derived ligands.⁶⁰ Transcriptomic and proteomic analyses of tissues from preclinical models or clinical trials, particularly comparing patients who respond to PNS nerve-targeted therapies with non-responders, could aid in identifying a “nerve-activated” molecular footprint in cancers.

Cancer cells are known to secrete exosomes containing metabolites, proteins, and nucleic acids, which facilitate communication with other cells within the TME. These exosomes often contributing to immune suppression, angiogenesis, tumor proliferation, and metastasis.⁶¹ Many miRNAs have been identified from cancer-derived exosomes that exert their effects on intratumoral nerves.⁶² Exosomes derived from human cervical cancer contain both NGF and the axon guidance molecule EphrinB, which promote neurite outgrowth in vitro as well as in murine oropharyngeal squamous cell carcinoma (OPSCC) models.^63,64 Notably, high levels of NGF in circulating exosomes in breast cancer patients undergoing neoadjuvant therapy correlate with poor survival.⁶⁵ Future technological advances in the sensitivity of liquid biopsy techniques for detecting exosomal contents in bodily fluids hold great potential for selecting PNS nerve targets as well as monitoring treatment responses.

Cancer-associated fibroblasts (CAFs) also appear to play a key role in mediating tumor-nerve interactions across multiple cancer types. In colorectal cancer, a bidirectional interplay between sympathetic nerves and NGF-expressing CAFs drives tumorigenesis through a β2-adrenergic nerve growth factor feedforward loop. Sympathetic nerve-derived norepinephrine activates β2-adrenergic receptors on CAFs, promoting NGF secretion that further enhances sympathetic innervation, creating a self-amplifying circuit that accelerates tumor progression.⁶⁶ In gastric cancer, CAFs enhance tumor progression through SLIT2-mediated axonal guidance. SLIT2 secreted by CAFs interacts with ROBO receptors on nerve fibers, directing neural growth toward the tumor and facilitating perineural invasion, a key determinant of poor prognosis.⁶⁷ In pancreatic cancer, CAFs promote perineural invasion through EV transmission of PNI-associated transcript (PIAT). These EVs package PIAT that enhances neural remodeling by mediating m5C modification in the tumor microenvironment. Importantly, clinical data suggests that PIAT expression in serum EVs correlates with the degree of neural invasion and patient prognosis, highlighting its potential as a biomarker for predicting perineural invasion and disease outcomes in pancreatic cancer patients.⁶⁸

While changes in tumor size will be a primary measure of success in treatments targeting the nerve-tumor axis, monitoring alterations in intratumoral nerve distribution may provide additional insights. For PNS tumors, perineural invasion (PNI) status is often not communicated to patients and is significantly underreported, despite its prognostic significance.⁶⁹ In a case series of colorectal cancer patients (n = 269), <0.5% reported PNI on initial pathology versus 22% upon reassessment.⁷⁰ In a study of squamous cell carcinoma of the vulva, 27% of cases inaccurately reported PNI as absent.⁷¹ Lack of concise, objective, and more reproducible criteria for histopathologic assessment of PNI may significantly contribute to this discrepancy.⁷² Detailed visualization of intratumoral PNS nerves is difficult to fully capture by conventional cross-sectional imaging techniques like magnetic resonance imaging. N-acetyl-aspartate, a neuron-specific marker commonly used in magnetic resonance spectroscopy (MRS) to evaluate brain health in various pathological contexts,⁷³ can be modified to detect nerves within the solid tumors. Animal studies have demonstrated the potential of nanoparticles conjugated with the nerve-binding peptide NP41 for imaging peripheral nerves,⁷⁴ with a fluorescent conjugate currently undergoing clinical trials as an intraoperative nerve marker in head and neck cancer (NCT05377554).

The development of neural imaging tracers that are specific to distinct nerve types such as sympathetic, parasympathetic, and sensory nerves coupled with artificial intelligence-powered image analysis will enhance both diagnostic precision, surgical guidance, and treatment evaluation. A sympathetic nerve tracer, iodine-123 Metaiodobenzylguanidine (¹²³I-MIBG), used in single photon emission computed tomography (SPECT) imaging for cardiac conditions and neuroendocrine tumors,⁷⁵ demonstrates the broad potential of such imaging tools in cancer. These possibilities could contribute to more personalized interventions for disrupting the nerve-cancer axis, though further validation and technological progress are required to fully determine their clinical potential.

Translational Model Systems for Biomarker Discovery and Drug Development

Beyond established circulating, neuroimaging, and tissue-based biomarkers, emerging model systems are bridging the gap between preclinical research and personalized biomarker development. Importantly, high-functional connectivity glioma cells integrate extensively into neuronal organoids while low-functional connectivity cells do so minimally.²¹ By combining patient-derived glioma stem cells with cerebral organoids (GBOs), these models enable direct visualization of tumor invasion dynamics, synaptic integration, and functional connectivity patterns and correlate with clinical aggressiveness.^21,55 Patient-derived organoid methodology is becoming sufficiently optimized (2–3 week production times) such that these may transform from in vitro model systems of disease into personalized biomarkers—generated concurrently with or even before patients receive matched treatment.^56,57 For example, recent work by Logun et al. demonstrates promising correlations between patient responses and matched glioblastoma brain organoids (GBOs) in CAR-T cell therapy.⁵⁶

Critically, these same organoid platforms offer unprecedented opportunities to screen and optimize repurposed therapeutic agents targeting tumor-neural interactions in patient-specific contexts. If validated in larger cohorts and expanded to evaluate the repurposed neurotropic agents discussed below, this approach could enable real-time biomarker monitoring while simultaneously accelerating personalized therapeutic strategies to disrupt tumor-neuron interactions.

III. Therapeutic Repurposing Strategies: Targeting Neural Pathways in Cancer

Building on these emerging biomarker and screening platforms, the intricate crosstalk between the nervous system and cancer cells offers a promising frontier for therapeutic innovation. Targeting this axis through drug repurposing—using existing, regulatory-approved pharmaceuticals for new indications—presents a faster, cost-effective alternative to traditional drug discovery, with the added benefit of established safety profiles, known blood brain barrier (BBB) penetration, and reduced developmental risks.⁷⁶ This section explores the transformative potential of repurposing neuromodulatory agents to disrupt tumor-nerve communication, highlighting specific drug classes, mechanisms of action, and emerging clinical opportunities.

Targeting Sympathetic, Parasympathetic, and Sensory Signaling Pathways

Various therapeutic modalities designed to interfere with PNS nerve-tumor interactions are being explored, with particular focus on strategies that block paracrine signaling.⁶² Among these, leveraging the availability of existing FDA-approved drugs with established safety profiles has gained significant interest. For instance, β-blockers, widely prescribed to manage cardiovascular conditions, target the output of sympathetic nerve branch through blunting the effects of its neurotransmitters, catecholamines, such as adrenaline and noradrenaline.⁷⁷ Administering β-blockers in some preclinical models of melanoma, breast, prostate, ovarian, and pancreatic cancers have showed anti-tumor effects.⁷⁸ Notably, some observational studies of prostate, breast, and skin cancer patients have found a correlation between β-blocker use for non-neoplastic indications and reduced cancer-specific mortality.⁷⁹ Ongoing clinical trials are evaluating the safety and efficacy of propranolol, a non-selective β-receptor blocker, in combination with standard-of-care treatments for several solid tumors (NCT05679193, NCT06145074, NCT04682158, NCT05741164, NCT05651594, and NCT04848519). Additionally, β-adrenergic signaling also promotes tumor growth by acting on multiple components of the TME, including inflammation, immune response, and angiogenesis.⁷⁸ In mouse models of melanoma and breast cancer, sympathetic nerve-derived β-adrenergic signaling suppresses CD8⁺ T cell effector functions and drives T cell exhaustion in regions proximal to sympathetic nerves in melanoma-bearing mice. Consequently, a combination of β-blockers and immune checkpoint blockade improve T cell effector functions in these mice.^80,81 These findings highlight the potential for multifaceted benefits of employing β-blockers in cancer therapy across a range of malignancies.

Likewise, the blockade of other neurotransmitters is also being investigated, reflecting growing evidence of other peripheral nerve subtypes (e.g. parasympathetic and sensory) impacting cancer behaviors. Unlike sympathetic innervation, which is predominantly tumor-promoting, parasympathetic innervation exhibits dichotomous roles depending on cancer type, promoting growth in prostate and gastric cancer while suppressing growth in breast and pancreatic neoplasms.⁸ Pharmacological inhibition of parasympathetic cholinergic signaling by muscarinic receptor antagonist prolongs survival in a mouse model of prostate cancer.²⁹ Conversely, systemic muscarinic activation by bethanechol extends survival of mice with PDAC.³¹ Bethanechol is already FDA-approved for treating urinary retention and is now being evaluated in PDAC patients as a neoadjuvant therapy either alone or in combination with gemcitabine and nab-paclitaxel (NCT03572283 and NCT05241249).

Sensory innervation also displays context-dependent roles in cancer behaviors, often accelerating the progression of breast, pancreatic, skin, and prostate cancers.^82–85 In melanoma, CGRP generates an immunosuppressive environment to promote tumorigenesis.²⁷ Of note, sensory nerves are linked to cancer-related pain;⁸ thus, targeting these nerves could also alleviate this element of morbidity in cancer patients. Several CGRP signaling inhibitors have been prescribed for migraines that are available for testing in cancers driven by CGRP activity. Capsaicin is a natural compound derived from chili peppers that inhibits transient receptor potential vanilloid 1 (TRPV1) channels of sensory nerves. It exhibits potent analgesic properties as well as anti-tumor activity in cancers that overexpress TRPV1 or are otherwise influenced by sensory nerves.^83,86 With capsaicin and its analogs currently under investigation in clinical trials for managing cancer-related pain, these studies may soon provide insights into their antineoplastic effects and their ability to reduce tumor-associated pain.

Modulating Primary CNS Neurotransmitter Systems: Glutamate, GABA, and Beyond

As shown in Figure 1A, high-grade glioma cells receive growth and invasion signals from presynaptic neurons via postsynaptic AMPA receptors, preferentially localized on tumor-associated microtubes (TMs).^5,17,18 Pharmacological inhibition of AMPA receptors with perampanel—a non-competitive AMPA receptor antagonist approved by the EMA and FDA as an add-on epilepsy therapy—has significantly reduced glioma cell proliferation, invasion, and TM formation in patient-derived xenograft mouse models.^14,15,87 A short-acting (3 hour) version (talampanel) has previously demonstrated adjunctive survival benefit in a phase II multicenter trial of patients with newly diagnosed glioblastoma.⁸⁸ Currently a phase IIa, placebo-controlled trial is underway (EUCT 2023–503938-52–00) in patients with progressive or recurrent glioblastoma with an extended window-of-opportunity concept.⁸⁹ Perampanel exemplifies many of the key considerations for drug repurposing in cancer neuroscience. It has high target specificity, potency, oral bioavailability, blood-brain-barrier permeability, a long half-life (terminal t_½ = 105 hours), and minimal susceptibility to efflux (no BCRP nor P-glycoprotein affinity).⁹⁰ Perampanel is primarily metabolized by CYP3A4 and CYP3A5, with metabolites showing negligible contribution to therapeutic effect, imparting a direct correlation between plasma concentration and clinical seizure control.⁹⁰ Furthermore, the drug effectively reduces seizure frequency and has demonstrated promising outcomes for brain tumor-related epilepsy, significantly improving seizure control even at lower daily doses (2–4 mg), with responder rates exceeding 75% and seizure freedom in up to 50% of patients.^91–96 Given its straightforward pharmacology, CNS penetrance, and direct disruption of tumor-neuron signaling, perampanel is an attractive candidate for repurposing in cancer neuroscience. Indirect immune effects have also been observed, for example, perampanel has recently demonstrated TAM polarization toward a less anti-inflammatory state in addition to prolonged survival in GBM mouse models. TSP1 knockout also restored antigen presentation-related genes, promotes the infiltration of pro-inflammatory TAMs and CD8⁺ T-cells in the tumor, and alleviates TAM-mediated T-cell suppression. Notably however, the beneficial effects of perampanel were not observed TSP1 knockout mice, and despite the immunologic shifts, perampanel did not enhance survival with CAR-T therapy.⁹⁷ Conversely, a novel glutamate depleting agent (BHV-4157) has shown synergy with anti-PD1 therapies in mice⁹⁸ and blocking NMDAR with MK801, memantine, or magnesium alters TAM phenotypes, boosting T cell and NK cell-mediated antitumor immunity.⁹⁹ These studies may provide important considerations for designing combination treatments.

GABA, traditionally known as an inhibitory neurotransmitter, plays a complex role in tumor-neuron interactions. In gliomas, GABAergic signaling can have both tumor-promoting and tumor-suppressive effects depending on the disease context. In H3K27M-altered diffuse midline gliomas (DMG), growth-promoting neuron-to-glioma GABAergic synapses form that are depolarizing due to high intracellular chloride concentration in DMG cells, GABAergic interneurons robustly promote the growth of DMG through this mechanism, and benzodiazepines such as lorazepam - positive allosteric modulators of the GABA-A receptor (GABA_A-R) – increase malignant cell proliferation, accelerate growth and decrease survival in preclinical models of H3K27M-altered DMG.¹⁶ Depolarizing GABAergic synaptic signaling was not found in IDH-wildtype hemispheric glioblastoma.¹⁶ On the other hand, GABA_A-R signaling appears to be tumor-suppressive in CNS tumors like certain low-grade gliomas, medulloblastoma, neuroblastoma, and IDH WT glioblastoma, promoting apoptosis and inhibiting cell proliferation.^100,101 For instance, studies have shown that augmenting signaling through GABA_A-Rs with benzodiazepine (and related) compounds can sensitize specific types of cancer cells to radiation, chemotherapeutic agents, and immune checkpoint inhibitors, thereby enhancing treatment efficacy in vitro (medulloblastoma)¹⁰² and in mice (melanoma).¹⁰³ Taken together benzodiazepines can either inhibit or promote growth, as in H3K27M-altered diffuse midline gliomas,¹⁶ underscoring the importance of tailoring medications for disease context.

The effects of GABAergic signaling in anti-cancer immunity is similarly complex. Baclofen is a GABA_B-Receptor (GABA_B-R) agonist which has demonstrated adjunctive efficacy in cancer-related pain, can stabilize PD-L1 and enhance the effects of immunotherapy in mouse breast cancer models.¹⁰⁴ Conversely, Huang et al. found that the accumulation of GABA and its metabolizing enzyme, GAD1, is associated with worse clinical outcomes in lung and colon cancer patients.^105,106 In tumor cells, GAD1 accumulation increases local GABA production, leading to stabilization of β-catenin and activation of its downstream signaling. This occurs through tumor-derived GABA interacting with metabotropic GABA_B receptors, which suppresses glycogen synthase kinase-3B and stabilizes β-catenin. Notably, GABA-mediated β-catenin stabilization suppresses CCL4 and CCL5 cytokine expression, reducing CD8⁺ T cell infiltration and promoting an immunosuppressive tumor environment.¹⁰⁵ In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumor responses.¹⁰⁷ As follows, epidemiologic studies have consistently demonstrated a significant dose-response relationship between benzodiazepine use and overall cancer risk.¹⁰⁸ The complex interplay between GABA and glutamate signaling necessitates a nuanced, context-sensitive approach that carefully delineates their opposing roles in tumor biology. Future efforts must clarify the conditions under which GABA acts as a tumor suppressor versus a tumor promoter, alongside how glutamatergic signaling synergizes or antagonizes these effects (see Pitfalls and Alternatives below).

Neurotrophic Factor Inhibition to Decrease Tumor Functional Connectivity

Trk receptor family inhibitors such as Regorafenib, Entrectinib, and Larotrectinib represent promising cancer neuroscience medications. Trk receptors, activated by neurotrophins, promote neuronal pro-survival and pro-proliferation mechanisms. This is perhaps not surprising, as the neurotrophin NGF was first isolated from cultured sarcoma cells.¹⁰⁹ Activating gene fusion alterations underscore the crucial role neurotrophins play in cancer, first identified in colon cancer patients with NTRK gene fusion causing constitutive pathway activation.¹¹⁰ Such genomic alterations were later described in various solid and hematological tumors (e.g., glioblastomas, thyroid, lung and breast carcinomas), prompting many trials of Trk inhibitors.¹¹¹ Beyond genomic alterations, neurotrophin activation of Trk receptors can mediate tumorigenesis, with pro-tumorigenic capacity extensively demonstrated experimentally.^25,112 Even for gliomas that lack Trk fusion alterations, Trk inhibition may have a therapeutic role. Neuronal activity-regulated secretion of BDNF, signaling to TrkB on glioma cells, promotes glioma proliferation and growth,^5,18 while Trk inhibitor therapy robustly prolongs survival in preclinical glioma models.⁵ BDNF-TrkB signaling not only functions as a growth factor, but also promotes synaptic plasticity of neuron-to-glioma synapses by increasing AMPAR subunit trafficking to the postsynaptic membrane of glioma cells, thereby increasing the strength of these malignant synapses.⁵

Upregulation of TrkB and BDNF has been associated with resistance to multiple antineoplastic agents (cisplatin, etoposide, vinblastine).^113,114 Several humanized NGF neutralizing antibodies are also being clinically tested to manage chronic pain relating to osteoarthritis and bone metastasis.^115,116 These options present opportunities for clinical evaluation of neurotrophic factor antagonists within the context of nerve-cancer crosstalk. Given the immense regenerative capacity of the PNS, the persistence of neutralizing antibodies is particularly attractive. For example, the estimated half-life of tanezumab is approximately 21 days in humans, and BBB penetration is not expected.¹¹⁷ However, NGF-neutralizing antibodies can also risk immune responses and reactivity from glycosylation variants.^118,119

Differential targeting of bedrock pathways for neuronal functioning necessitates careful consideration across the lifespan. Pharmacological inhibition of NLGN3 with ADAM10 inhibitors has shown significant promise in preclinical glioma models.¹⁹ While they appear well-tolerated in clinical trials and show no evidence of overt neurotoxicity in animal studies¹²⁰ – longitudinal neurocognitive evaluation should be a priority moving forward.^121,122 Interestingly, increased ADAM10 plasma levels in older adults have been associated with cognitive decline, and preclinical studies suggest cognitive benefit from ADAM10 inhibition in Huntington’s Disease models.¹²³ However, >50% reduction in ADAM10 activity in post-natal mice causes severe disruption of synaptic architecture, seizures, and increased formation of Aβ peptides—suggesting a potentially narrower therapeutic window in younger patients.¹²⁴ Similarly, BDNF haploinsufficiency or missense mutations in TrkB are associated with hyperphagia, weight gain, and obesity both in human and in mouse models.^125–131 Consistent with these findings, paresthesias, weight gain, cognitive disturbance and dizziness have been reported in patients treated with TRK inhibitors.^132,133 Dose-limiting toxicity of grade 3 cognitive disturbance was noted with entrectinib during the dose-escalation phase of the STARTRK-1 phase I trial. However, these adverse events were reversible in patients for whom dose modification was required.¹³³ Overall, childhood obesity can interfere with normal brain development and has been repeatedly associated with diminished cognitive function later in life, suggesting that careful monitoring and early intervention for weight-related effects is warranted when targeting this axis in pediatric settings.^134–139

Targeting Ion Channel Dysregulation to Disrupt Tumor Excitability and Migration

Ion channels have been extensively studied in the context of pain and other conditions characterized by neural hyperactivity, with sodium channel blockers (e.g. lidocaine, carbamazepine, mexiletine), and calcium channel blockers (e.g. gabapentin, pregabalin) commonly used as therapeutics.¹⁴⁰ Many tumors overexpress ion channels that drive proliferation and metastasis.^37,38 For example, nerve stimulation can trigger action potentials in breast cancer cells.^39,141–149 The applicability of ion channel blockers may vary, given that there is some overlap in expression of ion channel isoforms among peripheral nerve subtypes which have opposing roles in different tumors.¹⁵⁰ Moreover, the ion channel profiles of nerves interacting with neoplastic cells may undergo significant alterations during tumorigenesis, diverging from those observed in nerves interacting with cells from their tissues of origin, a process that remains poorly characterized. Although several ion channel blockers exhibit antitumor activity,¹⁵¹ and peritumoral injection of lidocaine improves overall survival of early breast cancer patients,¹⁵² whether nerve-tumor interactions are perturbed in such interventions have not been formally tested.

Despite this, ion channel blockers hold promise for achieving synergistic effects by targeting both nerve-dependent and nerve-independent mechanisms underlying cancer growth. Retrospective data (n = 54,000 breast, colon and prostate cancer patients) has shown that anti-angina, voltage gated sodium channel blocker ranolazine is associated with significantly reduced mortality (HR = 0.41; p <0.001), even when started (on average) 4 years after the diagnosis (HR = 0.54; p <0.01)¹⁴¹. In vitro and in vivo data across cancer models also support these findings showing ranolazine not only suppresses tumor growth and metastasis^141–146, but also stimulates anti-tumor immunity (i.e., increased infiltration of CD8⁺ T-cells and dendritic cells, decreased tumor CD8⁺ Tim3 content, increased macrophages, and decreased blood myeloid immunosuppressive monocytes)¹⁴³ and prolongs survival in combination with anti-PD-L1 immunotherapy in melanoma models.¹⁵³ Additionally, preliminary studies suggest protective effects against experimental doxorubicin and trastuzumab cardiotoxicity^147,148 and cognitive dysfunction.¹⁴⁹ Despite extensive evidence for the anti-tumor effects of propranolol discussed above, co-treatment with ranolazine has been shown to be significantly (30%) less effective than ranolazine alone,¹⁵⁴ potentially due to competitive binding at neuronal voltage gated sodium channels.¹⁵⁵ Conversely, the potassium (K_ATP) channel opener minoxidil has been shown to significantly potentiate (40%) the effects of ranolazine in breast cancer cell lines at clinically relevant doses.¹⁵⁶

For CNS tumors, other ion channel modulators/anti-epileptics have been evaluated for anti-tumor efficacy, though most in small or retrospective studies (please see the following review).¹⁵⁷ Valproic acid has been associated with improved overall survival in high-grade glioma patients under temozolomide treatment, particularly in younger patients (18–40 years). Levetiracetam has shown survival benefits in glioblastoma patients with methylated MGMT promoters, potentially through inhibition of MGMT expression. Other promising agents include brivaracetam and lacosamide, which have demonstrated anti-migratory effects and dose-dependent cytotoxicity in glioma cell lines through modulation of microRNAs affecting cell cycle and migration.¹⁵⁷ Notably however, drug-drug interactions are common with many anti-epileptics and ion channel modulators (i.e., phenobarbital, carbamazepine, oxcarbazepine and phenytoin, etc.) which may impair their long-term utility for repurposing outside of seizure control. Lastly, dopamine (D2) receptors couple to Go/Gi/Gz proteins to inhibit adenylyl cyclase activity and to also modulate the activities of various ion channels.¹⁵⁸ Dopamine receptor D2 (DRD2), which is overexpressed in many cancers and linked to stemness and treatment resistance for glioblastoma.¹⁵⁹ ONC201 (originally discovered as TRAIL-Inducing Compound #10 or TIC10) is a DRD2/DRD3 antagonist currently undergoing phase 1 and 2 testing in multiple tumor types, including H3K27M gliomas, endometrial cancer, and neuroendocrine cancers.¹⁶⁰

Indirect Cellular Mechanisms: Modulating Metabolic and Immune-Neural Interactions in Cancer

A complete description of cellular elements involved in neuro-immune crosstalk has been elsewhere reviewed in detail.^11,12 Several key mechanisms are highlighted here with proximate potential for clinical drug repurposing. Autophagy plays a critical role in myelin debris clearance by Schwann cells, aiding neural regeneration, but its dysregulation is lethal to neurons.^161–163 In PDAC, where Schwann cells in the TME are linked to poor prognosis, cancer cells trigger autophagy in Schwann cells via the NGF/ATG7 pathway, promoting a “nerve-repair-like” phenotype that enhances nerve outgrowth and guides tumor invasion through perineural invasion (PNI) pathways.¹⁶⁴ This reciprocal autophagy amplifies tumor aggressiveness, but pharmacologic inhibition of NGF (e.g., RO 08–2750) or autophagy (e.g., chloroquine) reduces Schwann cell viability and tumor invasion in PNI models.¹⁶⁵ Chloroquine and hydroxychloroquine show promise as adjunctive therapies across several solid tumors^166–169, including GBM.^170,171

Similarly, calcineurin deletion impairs autophagic flux in Schwann cells.¹⁷²The RCAN1 (regulator of calcineurin 1/Down syndrome (DS) critical region 1) gene is located on chromosome 21 and encodes an endogenous inhibitor of calcineurin, which is overexpressed in DS due to an extra copy, and may contribute to the sevenfold reduced incidence of pancreatic cancer in patients with DS.¹⁷³ RCAN1 expression correlates with reduced PDAC incidence and better prognosis in most solid tumors, though exceptions exist.^172,174,175 As follows, calcineurin inhibitors (CNIs) like tacrolimus or cyclosporin exhibit a dual profile, curbing angiogenesis in some cancers while risking aggressive recurrence in others, necessitating careful scheduling and delivery strategies before repurposing in patients.¹⁷⁵

In low-grade gliomas, neuron-immune interactions critically regulate tumor growth through oligodendrocyte precursor cells (OPCs). Experiments with Nf1 optic glioma mouse models demonstrate that neuronal activity, heightened by Nf1 mutations and light-induced excitability, increases spontaneous action potentials, leading to the release of midkine, a growth factor that activates CD8⁺ T cells to secrete CCL4.¹⁷⁶ This, in turn, prompts microglia to release CCL5, a key mitogen essential for OPC survival and tumor formation.¹⁷⁷ Genetic deletion of Ccl5 in mice prevents OPC-driven tumor formation, underscoring the potential of targeting T cell-microglia interactions as a therapeutic strategy for low-grade gliomas. This neuron-modulated immune axis remains underexplored but offers a promising avenue for intervention.^12,176,177 The brain penetrant HMG-CoA reductase inhibitor lovastatin significantly reduces midkine expression in NF1-mutant neurons, while calcineurin inhibitors suppress midkine-mediated Ccl4 production in T cells, suggesting potentially synergistic (or redundant) effects.¹⁷⁶

In triple-negative breast cancer (TNBC) brain metastases, estradiol-activated ERα-positive astrocytes release BDNF, stimulating TrkB and EGFR on cancer cells to drive invasion and colonization. Systemic estrogen depletion or CNS-penetrant TrkB blockers (e.g., ANA-12), alongside repurposed Trk (entrectinib, larotrectinib) or EGFR/HER2 inhibitors, disrupt this astrocyte-BDNF/TrkB loop, with additive effects in combination, depending on individual tumor expression patterns.^178,179

Addressing Treatment-Related Neurotoxicity Through Drug Repurposing

Though several non-pharmacologic approaches have demonstrated modest promise (i.e., psychotherapy, qigong and exercise),¹⁸⁰ currently no FDA approved treatments exist for cancer-related cognitive impairment (CRCI) (chemotherapy nor radiation related). Methylphenidate (especially in pediatric survivors), donepezil for post-radiation cognitive deficits, and memantine as a neuroprotective add-on during whole-brain radiotherapy¹⁸¹ show the most reproducible benefits, improving attention or slowing memory decline.¹⁸² In contrast, evidence for modafinil, ginkgo biloba and erythropoietin (EPO) is inconsistent, and no agent has convincingly prevented or reversed chemotherapy-related cognitive impairment in adults. This includes five RCTs¹⁸³ and recent phase 3 randomized placebo-controlled trial of donepezil in breast cancer survivors exposed to chemotherapy.¹⁸⁴ Other neuroprotective agents such as lithium (NCT01486459; NCT00469937), nicotine (NCT02312934),¹⁸⁵ fluoxetine (NCT01615055), and DHA¹⁸⁶ have garnered negative results as well. Ramipril has shown protective effects against radiation induced neuroinflammation through renin-angiotensin system (RAS) inhibition in animal models.¹⁸⁷ A phase II study (n = 75) (NCT03475186) to prevent cognitive decline in glioblastoma patients receiving chemoradiation has recently completed in March 2025 with results still pending. Ibuprofen has also showed improvements in processing speed time and visual memory without increased risk of bleeding or significant AEs in a recent phase 2 study.¹⁸⁸ However, significantly worse verbal memory compared to placebo was also demonstrated requiring further clarification of these findings.

Several licensed drugs display both neuroprotective activity in pre-clinical CRCI models and the ability to enhance anti-tumor therapies. Pioglitazone was safe and well-tolerated in a phase-I radioprotection study in glioblastoma (NCT01151670).¹⁸⁹ It augments the cytotoxicity of multiple chemotherapies in vitro^190,191 and has improved clinical responses when added to (i) taxane ± carboplatin regimens in metastatic breast cancer¹⁹² and (ii) imatinib in chronic myeloid leukemia¹⁹³—making it a potential candidate for further study. Padmanaban et al. showed that sensory neuron–derived substance P drives breast cancer invasion and metastasis by inducing tumour-cell apoptosis and ssRNA release that activates a NK-1R—TLR7–PI3K–AKT pro-metastatic program. Substance P levels in patient tumors correlate with lymph node spread, and substance P blockade suppresses growth and metastasis in vivo.¹⁹⁴ substance P also promotes inflammation via mast-cell interactions and VEGF-mediated angiogenesis.¹⁹⁵ The NK-1R antagonist aprepitant—approved for chemotherapy-induced nausea and vomiting—provides neuroprotection in seizure, ischaemia–reperfusion, Parkinson’s, chemobrain, and carotid-occlusion models.^196,197 Case reports also note improved outcomes when combined with radiotherapy in NSCLC and breast-to-brain metastases.^198,199

The underwhelming results of extant studies for cognitive remediation are perhaps not surprising in the context of approved therapies for primary dementias.^200–202 Almost all phase II/III studies with fail to reach the 4-point change on the de facto standard primary outcome (Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)) at 6 months considered clinically meaningful by most regulatory agencies.²⁰³ Notably, NeuroEPO plus—a hyposialylated, non-erythropoietic EPO analog delivered intranasally—has recently achieved striking, clinically meaningful cognitive benefits in a 48-week, randomized phase II/III trial (ATHENEA).²⁰⁴ Participants (n=170) receiving 0.5 mg or 1.0 mg three times weekly improved their ADAS-Cog scores by a median of −3.0 and −4.0 points, respectively, versus a +4.0-point decline on placebo, more than doubling the clinical differences observed with other agents. Though results are from a single study, the same size is moderately large, and the 4-point improvement achieved in patients with moderate-stage disease in this study is virtually unprecedented.²⁰⁵ Most importantly, across studies intranasal formulation has been well tolerated and no serious related events related to NeuroEPO and no signs of hematologic toxicity.^204,206,207 Together this evidence may suggest that revisiting non-hematologic EPO derivatives may be warranted, particularly if favorable safety profile can be demonstrated in patients with cancer, potentially allowing for higher doses, longer durations, and combinations with other agents.

The NMDA antagonists, ketamine and dextromethorphan (DXM) may hold unique potential as well. Unlike other neuroprotective agents in this class (i.e., memantine), both agents demonstrate very rapid and robust antidepressant efficacy (and FDA approval) in refractory patients (i.e., Auvelity and esketamine).^208,209 Likewise, both agents have demonstrated improvements in cognition in this population.^210–212 Given depression’s frequent comorbidity with—and contribution to—CRCI,^213,214 these agents warrant investigation for cognitive protection during cancer therapy. DXM demonstrates efficacy in both children and adults for the prevention and treatment of subacute methotrexate neurotoxicity, ^215–220 which is predictive of multi-domain, chronic neurocognitive impairment.^210,215 Crucially, metaplasticity-inducing antidepressants like ketamine^221–224 synergize with non-pharmacological interventions such as computerized cognitive training.²²⁵ Developing similar paradigms tailored to personalized deficits for patients with CRCI may provide benefit. Notably higher body mass index (BMI) and greater pain severity—two of the most common adverse effects with TRK inhibitors¹³²—are also positive clinical predictors of antidepressant responses to ketamine,^226–228 suggesting potential applicability for patients receiving these treatments.

Similarly, managing chemotherapy-induced peripheral neuropathy (CIPN) remains challenging as no curative treatments exist and the nerve damage is often irreversible ^229–232. Current approaches focus primarily on symptom management and preventive strategies. Duloxetine is the only pharmacological intervention with modest evidence for treating CIPN-associated pain, though it is frequently ineffective and associated with quality-of-life-limiting side effects. ²³³ Preventive pharmacological agents including amifostine, gabapentin, pregabalin, glutathione, calcium/magnesium, metformin, and venlafaxine have shown limited benefit in clinical trials.^234,235 Topical formulations containing baclofen, amitriptyline, and ketamine have demonstrated minimal efficacy with only slight improvements in motor function in some studies. ²³² Neuromodulatory approaches including TENS devices and neurofeedback have shown promising preliminary results, with neurofeedback demonstrating larger effect sizes than duloxetine in reducing CIPN symptoms, though studies remain underpowered to establish definitive efficacy.^236–238 As with cognitive training, combining it with these neuromodulatory approaches with agents like ketamine may be a promising option, as has been suggested by combining it with transcranial magnetic stimulation in depression.²³⁹ Lastly, clonidine—an alpha 2 adrenergic antagonist approved for refractory cancer pain—can be co-administered to reduce psychotomimetic and sympathomimetic effects of ketamine in patients with depression.^240,241 In line with the established importance of both pain and adrenergic signals to driving tumor formation, both ketamine and clonidine significantly reduce the number of lung metastases in operated animals²⁴² and suppress substance P signaling in glioma cells.²⁴³ Given the well-established opioid sparing and analgesic benefits for both agents,^244–248 assessing ketamine and clonidine combinations for CIPN and CRCI may be warranted, particularly as they negate the major side effects for one another. It may also provide a valuable opportunity to secondarily assess for anti-tumor effects and modulation of the tumor-neuron-immune axis.

Delivery Optimization and Barrier Penetration Strategies

Local PNS interventions and targeted denervation can regionally disrupt nerve–tumor crosstalk while minimizing systemic toxicity.^249–256 For example, serial gastric and prostate injections of botulinum toxin A (BTX) impair parasympathetic/sensory neurotransmission to lower tumor incidence²⁵⁷ and burden.²⁵⁸ The broad clinical use of BTX underscores its tractability.²⁵⁹ Nerve-plexus injections (e.g., celiac plexus analgesics) used in pancreatitis and pancreatic cancer²⁶⁰ could be repurposed for delivering nerve-targeting agents. Alternatively, surgical, chemical, or radiofrequency ablation of sympathetic and sensory fibers improves chemotherapeutic responses in mouse models of triple-negative breast cancer and PDAC,^25,261 attenuates prostate cancer progression,²⁹ and, by vagotomy or distal gastrectomy, correlates with reduced gastric cancer risk.²⁵⁸ Even if more invasive, permanent denervation offers regional specificity and avoids chronic drug toxicity.

Enhancing CNS and tumor penetration further augments these approaches. Transient BBB and blood-tumor barrier (BTB) disruption via magnetic-resonance- guided focused ultrasound (MRgFUS) (immediate, resolves ~20 h) or laser interstitial thermal therapy (LITT) (peaks 1–2 weeks, resolves 4–6 weeks) increases intratumoral drug uptake on complementary timescales.^262–264 Non-invasive tumor treating fields disrupt glioma mitotic networks and neuron–tumor microtubes, activating antitumor immunity,^265,266 and improving survival when combined with temozolomide.^267,268 Super-selective intra-arterial delivery achieves 15-fold greater PSMA-radioligand uptake.²⁶⁹ Peptides and nanoparticles exploiting LDL-RP1–mediated transcytosis (e.g., ANG1005) have shown promise for leptomeningeal disease and recurrent brain metastasis.²⁷⁰ Finally, engineered cellular therapies—chimeric antigen receptor (CAR) constructs can persistently target cancer-associated antigens despite clonal evolution and expressive heterogeneity.^271,272 However toxicities remain a major concern.²⁷³ CAR-NK cells lack an antigen-specific T-cell receptor and can therefore be applied off-the-shelf for adoptive without CAR-T associated complications such as neurotoxicity (ICANS) and cytokine release syndrome (CRS).²⁷⁴ They have been shown to target glioma stem cells and have been implemented safely in phase I human studies.^275,276 This is particularly important as even very promising CAR-T cell therapies have demonstrated low persistence after infusion in patients.²⁷² Direct delivery of these cellular therapies via an Ommaya reservoir combined with minimal toxicity in early studies holds great potential for augmenting standard treatments.

IV. Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Drug Repurposing in Cancer Neuroscience

The implementation of master protocols (i.e., umbrella, platform, basket trials) could eventually revolutionize our approach to cancer neuroscience trials by enabling more efficient patient stratification and rapid evaluation of repurposed treatments. That potential has been demonstrated by GBM AGILE (platform trial), which has screened over 1,300 patients and achieved enrollment rates three to four times higher than conventional GBM trials.²⁷⁷ With repurposed, low-toxicity drugs, that multiplier could be even greater, for example, in gliomas with validated neural connectivity and/or epigenetic signatures.^5,21,53 A hypothetical adaptive platform trial could evaluate potential neuroprotective agents such as perampanel, memantine, and gabapentin, initially as monotherapies and subsequently in combinations. Following the INSIGhT model (platform trial), Bayesian estimation of treatment impact on progression-free survival (PFS) could dynamically guide the addition of agents or the transition from monotherapy to combination arms, maximizing trial efficiency.²⁷⁸ Given the current lack of validated biomarkers and anticipated low toxicity of the agents, enrolling all patients but analyzing by biomarker status seems most prudent. [11C]K-2 PET imaging to quantify AMPA receptor occupancy for perampanel or MEG/EEG to measure changes in neural network activity may provide crucial mechanistic validation and inform adaptive decision-making within the trial. Whether existing preclinical/observation data support a plausible benefit for the repurposed agent as a neuroprotectant, a radio/immune sensitizer, or an adjuvant therapy must also be considered in terms of timing for drug administration. Bayesian adaptive designs can flexibly accommodate such differences, for example, CC-115 replaced temozolomide during RT based upon the potential for radiosensitization in the INSIGhT study.²⁷⁸ In that regard, grouping agents together which have shown preclinical promise in potentiating immunotherapies may facilitate a more standardized pattern of response to simplify Bayesian adaptive designs.

Additionally, targeting multiple points in the same pathway, rather than non-overlapping effects, may or may not be warranted. For example, alprazolam has been shown to reduce, to slow down tumor progression in breast cancer mouse models by inhibiting corticotropin-releasing hormone (CRH) neurons in the central medial amygdala (and thus downstream peripheral nerve–derived NE).^279,280 Combining this agent with beta blockers may provide synergy for adrenergic-driven tumors, allowing for lower doses of both medications in the periphery. It may also be redundant and increase risk for adverse effects. Sequential testing (i.e., propranolol followed by the addition of alprazolam in non-responders) could help make that determination and enrich for refractory patients.

Repurposed “dual use” agents (i.e., potential anti-tumor effects plus efficacy for seizures, pain, nausea, etc.) present a key opportunity to utilize extended window-of-opportunity concepts in cancer neuroscience.⁸⁹ Rapidly addressing these symptoms is paramount, as only 24% of new cancer medicines demonstrate quality of life improvements despite disease control.²⁸¹ Moreover, these extended windows provide valuable opportunities to identify and validate neural biomarkers that can: (i) demonstrate robust target engagement, (ii) stratify patients at baseline, (iii) track with short term outcomes that might be used to guide adaptive randomization in larger studies. Because the full potential of neuroactive drug repurposing will likely be realized via multi-drug designs, window of opportunity studies can optimize dosing and timing for proposed combinations with complex pharmacology. For example, both lovastatin and tacrolimus show potential as dual-purpose agents, reducing immunosuppressive midkine expression and midkine-mediated Ccl4 production respectively.¹⁷⁶ Lovastatin has also demonstrated efficacy in reversing learning and attention deficits in Nf1 mouse models ²⁸² and in children (n = 24) with Nf1²⁸³. Low-dose tacrolimus has shown extremely potent neuroregenerative/protective effects—even at sub-nanomolar concentrations²⁸⁴—across many different models.^285–289 Significant efforts have been dedicated to optimize localized delivery of tacrolimus, in order to harness its potent neuroplastic effects while mitigating off-target toxicities.^290–293 Because tacrolimus has a narrow therapeutic window and is a known substrate for the P-glycoprotein (P-gp) efflux pump, this limits its neuroprotective potential at safe systemic doses. Lovastatin is a P-gp inhibitor, and increases doxorubicin accumulation in multidrug-resistant (MDR) tumor cells, potentiating DNA damage, growth arrest and apoptosis.²⁹⁴ With careful monitoring, it may be possible to preferentially increase tacrolimus concentrations in the CNS at lower systemic doses. A multi-arm study comparing tacrolimus, lovastatin, and their combination leading up to surgical resection would be a hypothetical starting point. Such a design could also provide preliminary evidence of synergy, measuring not only pharmacokinetics (intertumoral and systemic drug concentrations alongside BBB permeability metrics), but also its impact on neuroprotection via, for example neurofilament light chain and BDNF.

V. Potential Pitfalls and Alternatives

Much like targeting the CNS, targeting the PNS for cancer therapies presents distinct challenges. The dispersed distribution of PNS nerves throughout the body coupled with their vital roles in regulating other systems such as the cardiovascular and gastrointestinal systems,^249–251 increase risks of systemic toxicity from interventions aimed at disrupting nerve-tumor crosstalk. Potential side effects, including pain, neuropathy, and autonomic dysfunction, necessitate careful evaluation to balance therapeutic safety and efficacy. Nevertheless, the higher accessibility of the PNS for drug delivery compared to the CNS is the major advantage in targeting the neural components of cancer biology.

Systemic pharmacological interventions targeting neural pathways face significant challenges due to the widespread expression of many candidate targets across organ systems. Well-documented adverse side effects of β-adrenergic antagonists include bradycardia, shortness of breath, fatigue, hypoglycemia, along with neurological symptoms such as sleep disturbance and depression.^252,253 Blocking neurotrophic factor signaling with TRK inhibitors can lead to subsequent withdrawal pain, including full-body aches, muscle pain, and exacerbation of pre-existing cancer-related pain.²⁵⁴ Even when designed with greater specificity, a variety of gastrointestinal, cardiovascular, and metabolic symptoms have been reported for CGRP inhibitors and cholinergic modulators.^254–256

While repurposing FDA-approved drugs with established safety profiles to address PNS-cancer interactions is promising, achieving an adequate therapeutic window is often challenging. With antibody-based approaches (e.g., NGF-neutralizing antibodies), patients may also develop immune responses to them after repeated exposure, despite the humanized nature of these antibodies.¹¹⁸ Although antibodies can be produced in human cell lines like HEK293 and HT-1080, small variations in post-translational modifications, such as glycosylation, in the non-native cells could still trigger immune reactivity.¹¹⁹ Future advances in generating B cells or cells capable of producing native proteins of interest from human pluripotent stem cells could help circumvent the immunogenicity issues of protein-based therapies.

Strategies for localized drug administration, nerve stimulation, and nerve ablation discussed in this review aim to minimize toxicity to non-target tissues. Nevertheless, neurological side effects, including neuropathic pain, sensory deficits, and motor dysfunction may arise. In cases of denervation therapy or drug delivery to nerve bundles outside of the tumor mass, pathogenic and healthy nerves cannot be easily distinguished, which renders off-target effects nearly inevitable. Additionally, adjacent non-cancerous tissues that are innervated by similar nerve types may be affected. Depending on the specific nerve types and the anatomical locations of nerve bundles, ablation techniques may not always be ideal but could be particularly suitable for managing unresectable tumors where the potential benefits outweigh the associated risks. Some nerve modulators with known impact on endothelial cells may compromise the vascular integrity, a factor that must be considered when delivering therapies to nerve plexuses due to their proximity to major blood vessels. Off-target neurotoxic effects can compromise patients’ quality of life, often lingering well beyond the completion of primary treatment. Proper management of neurological symptoms should be investigated early in pretreatment evaluation to optimize care for cancer patients undergoing and recovering from PNS nerve therapies. These risks undoubtedly grow with the burden of repeated administration required to overcome PNS regenerative capacity.²⁹⁵ One conceivable strategy may be to combine other localized targets with long-lasting neurotrophic antagonists such as tanezumab to sustainably disrupt the feedforward loops enhancing tumor innervation and neuronal regeneration.^{25,30,32,296,297}

For CNS tumors, glutamatergic/GABA-ergic signaling (>90% of neurons) are undoubtedly attractive targets for cancer neuroscience.²⁹⁸ However, careful consideration of off target effects must be individualized to specific tumors. For example, with GABA augmenting therapies, the diazepam-binding inhibitor (DBI), overexpressed in gliomas, has been shown to inhibit GABA_A-R-mediated currents ²⁹⁹ and promotes tumor growth through a GABA-independent lipid metabolism pathway. ³⁰⁰ Notably, high-grade glioblastoma cells exhibit significant downregulation of the GABA_A-R signaling pathway, with receptor expression inversely correlated with tumor grade, and being nearly absent in high-grade glioblastomas.³⁰⁰ The gabapentin receptor α2δ−1 is a neuronal TSP-1 receptor responsible for excitatory CNS synaptogenesis.³⁰¹ Multiple groups have shown that TSP-1 inhibition has anti-tumor effects in glioma via immunomodulatory (TGFβ1-SMAD3) signaling and disruption of TMs.^21,302 In the periphery however, this mechanism appears to be inverted: TSP-1 signaling itself has demonstrated anti-tumor effects in breast, lung, colorectal, cervical and melanoma models.^302–306 Thus, it is conceivable that an agent modulating this axis—though effective at disrupting tumor-neuron interactions for some tumors—may inadvertently promote immunosuppression and metastasis in others.

Furthermore, metastatic tumors may differentially adapt to the CNS. For example, contrasting AMPA-mediated synaptic integration with gliomas, breast to brain metastases have been shown to form “pseudo tripartite synapses” with excitatory neurons. Breast cancer cells activate N-methyl-d-aspartate receptor (NMDARs) by the autocrine secretion of glutamate to promote cell proliferation and migration.³⁰⁷ These divergent effects are vital to consider for drug repurposing because NMDA receptors are not only co-expressed with AMPA-Rs and coactivated by glutamate,³⁰⁸ but also actively maintain a constant receptor ratio across a neuron’s synapses.^309,310 Partly for this reason, pharmacologic antagonism of either can have unexpected consequences. For example, NMDA blockade on GABAergic interneurons can lead to increased extracellular glutamate release.³¹¹ Furthermore, in settings of abundant extracellular glutamate, post-synaptic NMDA antagonism can result in preferential activation of AMPA receptors (i.e., enhanced NMDA-to-AMPA throughput), which in turn activates downstream synaptogenic signaling pathways (e.g., BDNF, mTOR).³¹² As follows the anticonvulsant effect of the AMPA receptor antagonist NBQX can be potentiated by extremely low doses (0.0001–0.1 mg/kg) of the NMDA receptor antagonist MK-801 (dizocilpine) or by memantine.^313,314 To that end, low dose polytherapy to leverage the synergic effects of antiepileptic drugs—particularly GABA agonists with NMDA and AMPA antagonists—may not only lower toxicity but help to overcome the compensatory mechanisms of resistance that vary widely between individual CNS tumors. However, lack of survival benefit from parampanel in TSP-1 knockout mice suggests that further elucidation of mechanistic overlap for these agents is needed to inform combinations of repurposed therapies for patients.⁹⁸

VI. Conclusion

The emerging field of cancer neuroscience has revealed profound bidirectional interactions between the nervous system and malignant cells, identifying novel therapeutic vulnerabilities across diverse cancer types. As outlined in this review, these insights create exciting opportunities to improve outcomes for patients with treatment-resistant malignancies. However, significant challenges remain in translating these biological discoveries into clinical benefit. Addressing these hurdles demands concerted, multidisciplinary efforts to harmonize expertise from neurology, oncology, immunology, and other allied fields. Only through such broad-based collaboration—coupled with innovative trial designs, targeted biomarker development, and a steadfast commitment to patient-centered outcomes—can the full potential of cancer neuroscience be realized, transforming mechanistic insight into tangible therapeutic progress for patients who urgently need it.