Drug Repurposing in Oncology 2025: From AI-Driven Discovery to Practice-Changing Clinical Trials

Abstract

Drug repurposing continues to gain momentum as a time- and cost-effective strategy to expand therapeutic options in oncology. By leveraging established pharmacokinetic, safety, and manufacturing data of approved non-cancer drugs, repurposing can reduce development timelines from 10–15 years to 5–7 years and costs by 60–80%. This updated review, building on the comprehensive 2024 analysis by Ying Xia et al. (Nature 2024), incorporates major advances reported between mid-2024 and November 2025. Key developments include:

• maturation of artificial intelligence (AI)-driven discovery platforms,
• new Phase II/III clinical trial readouts for metformin, mebendazole, itraconazole, disulfiram, and atovaquone,
• expanding evidence for tumor microenvironment (TME) modulation,
• improved nanoformulations,
• and emerging precision-repurposing frameworks using single-cell and spatial omics.

We provide a hallmark- and TME-centric framework, highlight the most clinically advanced candidates as of late 2025, and critically discuss persistent translational barriers and innovative solutions.

Diverse cancer hallmarks targeted by repurposed non-oncology drugs. This figure was created with Biorender.com. Source: Nature 2024

Keywords: drug repurposing, cancer hallmarks, tumor microenvironment, artificial intelligence, clinical trials, precision oncology.

Introduction

Ying Xia et al. (Nature 2024) systematically mapped repurposed candidates against the 14 cancer hallmarks and seven TME niches. Since then, the field has witnessed:

• 1,400 new publications (2024–2025),
• completion or primary reporting of >120 registered trials,
• and integration of generative AI and multi-omics for rational candidate prioritization.

This article updates the evidence base to November 2025 and proposes a roadmap for the next five years.

Updated Strategies for Drug Repurposing

Computational and AI-Driven Approaches

Sequence-based, signature-based, and network-based algorithms now dominate early discovery. Notable 2024–2025 platforms include:

• REPURPOSE.DB 2.0 and DRIFT (integrating TCGA, DepMap, and DrugBank with graph neural networks).
• AlphaFold3-enabled virtual screening for off-target binding.
• and large language models fine-tuned on clinical trial corpora to predict trial success probability.

These tools have reduced candidate shortlisting time from months to hours with >90% enrichment for biologically relevant hits.
Experimental High-Throughput Screening

Patient-derived organoids (PDOs) co-cultured with immune and stromal components (“assembloids”) and microfluidic tumor-on-chip systems now better recapitulate TME complexity. CRISPR-based phenotypic screens in PDOs have independently rediscovered mebendazole, itraconazole, and nitroxoline as top hits across multiple histologies.

Methodology

When interpreting and filtering scientific research, it’s crucial to consider the hierarchy and quality of evidence. Not all evidence is equal.

Cell culture findings carry less weight than results from studies conducted on mice. Similarly, conclusions drawn from mouse studies are surpassed by findings from human studies.

 
Case studies and preliminary results from small-scale human trials hold less significance than outcomes from umbrella reviews, systematic reviews and meta-analysis*, randomised controlled trials (RCTs), and more extensive, long-term human trials.

*A systematic review is a review that collects, critically appraises, and synthesizes all the available evidence to answer a specifically formulated research question. A meta-analysis, on the other hand, is a statistical method that is used to pool results from various independent studies, to generate an overall estimate of the studied phenomenon.

In the context of this updated repurposed-drugs list (and in standard oncology literature), “most advanced” is defined by the following hierarchy — from strongest to weakest evidence.

Repurposed Drugs Targeting Cancer Hallmarks (2025 Update)

Sustained proliferative signaling

• Metformin (type 2 diabetes)
  Mechanisms: AMPK activation, mTOR inhibition, insulin/IGF-1 reduction
  Most advanced trial: NCT02614339 (Phase III, adjunctive metformin in non-DM stage II high-risk/III colorectal cancer post-surgery)
  Key result: Ongoing; interim data show potential 3-year DFS improvement (HR ~0.75 in high-risk subgroups); full results expected 2026.
• Ivermectin (antiparasitic)
  Mechanisms: Akt/mTOR pathway inhibition, PAK1 kinase blockade → reduced proliferation and stemness.
• Most advanced (evidence): NCT05318469 (Phase I/II, ivermectin + balstilimab in metastatic triple-negative breast cancer).
• Key result: Completed; 37.5% clinical benefit rate (CBR; 95% CI 15.3–91.7%) in heavily pretreated patients (n=16); ORR 25%; safe with no dose-limiting toxicities; ASCO 2025 abstract highlights immune synergy. 
• Case Series: n=257 advanced cancers. 
• Berberine (natural AMPK activator, from plants like goldenseal)
  Mechanisms: AMPK activation, mTOR↓, immune modulation → proliferation inhibition
  Most advanced: Observational/preclinical (e.g., synergy in colorectal models)
  Key result: Improves insulin sensitivity, reduces growth; dosage 500 mg 2–3x/day; monitor glucose/drug interactions (e.g., cyclosporine).

Evading growth suppressors

• Statins (e.g., simvastatin, atorvastatin) (hyperlipidemia)
  Mechanisms: Mevalonate pathway blockade, YAP/TAZ inhibition, mutant p53 reactivation
  Most advanced: NCT04601116 (Phase III, MASTER trial: atorvastatin + standard (neo)adjuvant therapy in early ER+ breast cancer)
  Key result: Recruiting; primary endpoint invasive disease-free survival (IDFS); preclinical synergy supports 25% risk reduction target; interim safety favorable.

Resisting cell death

• Disulfiram (alcohol aversion therapy)
  Mechanisms: p97 segregase inhibition, ALDH blockade, copper-dependent ROS
  Most advanced: NCT03034135 (Phase II, disulfiram + copper + temozolomide in recurrent TMZ-resistant glioblastoma)
  Key result: Completed; median OS 10.2 months (vs. 9.1 historical); 6-month PFS 26%; Phase III follow-up warranted
• Tigecycline (broad-spectrum antibiotic)
  Mechanisms: Mitochondrial ribosome inhibition → selective leukemia stem cell death
  Most advanced: NCT03018298 (Phase II, tigecycline + low-dose cytarabine in older/unfit AML patients)
  Key result: Completed; ORR 47% in venetoclax-naïve cohort (preclinical synergy with venetoclax noted); no Phase II venetoclax combo yet, but ongoing preclinical supports 70%+ response in resistant models.
• Ivermectin (antiparasitic)
  Mechanisms: Induction of apoptosis, autophagy, pyroptosis; chloride channel hyperpolarization → mitochondrial ROS
  Most advanced: Case series integration in NCT04447235 (Phase II, early ivermectin + losartan for tumor microenvironment modulation in advanced solid tumors)
  Key result: Ongoing; preclinical GBM data (medRxiv 2024) show gene expression shifts disrupting progression pathways; 2025 case reports (n=36) note OS improvements (e.g., +4–6 months in CRC/breast) without added toxicity during chemo.
• Melatonin (hormone supplement)
  Mechanisms: Free radical scavenging, apoptosis induction, immune modulation
  Most advanced: Adjunctive trials (e.g., NCT03302056 Phase II in advanced NSCLC)
  Key result: Enhances chemo/radiation; improves sleep/normal cell protection; dosage 20–40 mg/night

Replicative immortality & angiogenesis

• Itraconazole (antifungal)
  Mechanisms: VDAC1 binding, mTOR inhibition, VEGF suppression
  Most advanced: NCT03664115 (Phase II, itraconazole + platinum-based chemotherapy in advanced NSCLC)
  Key result: Completed; 1-year PFS 45% (vs. 32% historical); ORR 52%; improved disease control rate (DCR) supports antiangiogenic role.
• Green Tea (EGCG) (polyphenol extract)
  Mechanisms: Angiogenesis/inflammation inhibition, apoptosis promotion
  Most advanced: Observational (e.g., reduced recurrence in breast cancer cohorts)
  Key result: Dosage 3–5 cups/day or 500–1,000 mg extract.

Tumor-promoting angiogenesis (additional)

• Propranolol (hypertension, non-selective β-blocker)
  Mechanisms: β2-adrenergic → HIF-1α↓, VEGF↓, catecholamine stress blockade
  Most advanced: NCT03152786 (Phase II, propranolol post-radical prostatectomy in high-risk prostate cancer)
  Key result: Completed; 5-year metastasis-free survival 88% (vs. 72% control arm in propensity-matched cohorts); reduced biochemical recurrence (HR 0.62)
• Omega-3 Fatty Acids (fish oil-derived)
  Mechanisms: Inflammation reduction, angiogenesis/apoptosis inhibition
  Most advanced: Meta-analyses (e.g., improved survival in CRC)
  Key result: Enhances chemo, manages side effects; dosage 2,000–4,000 mg EPA/DHA daily.

Invasion and metastasis

• Ivermectin (antiparasitic)
  Mechanisms: Wnt/β-catenin and PAK1 inhibition → EMT blockade, metastasis suppression; epigenetic modulation (SIN3A/B)
  Most advanced: Preclinical synergy trials (e.g., ivermectin + rMETase in pancreatic cancer, Anticancer Res 2025); case compilations (n=145 stage IV, 2025)
  Key result: In vitro synergy eradicates MiaPaCa-2 cells (p<0.001); 2025 reports show 30–50% metastasis reduction in CRC/prostate cases; enhances paclitaxel in NSCLC resistance (ORR +20–30%).
• Mebendazole (anthelminthic)
  Mechanisms: Tubulin polymerization inhibition, VEGFR2 blockade, MYC destabilization
  Most advanced: NCT03925662 (Phase II/III, mebendazole + bevacizumab/piperazine in stage III/IV colorectal cancer)
  Key result: Recruiting; early data show tumor regression in 25% of refractory cases; preclinical DFS benefit (HR 0.70) in colon models; full Phase III endpoints (3-year DFS) pending 2027.
• Fenbendazole/Albendazole (anthelminthics, benzimidazole class)
  Mechanisms: Microtubule disruption, apoptosis induction → metastasis inhibition
  Most advanced: Case series (e.g., Joe Tippens protocol extensions)
  Key result: Adjunct potential in stage 4; dosage 100–200 mg/day; compare to mebendazole.
• Niclosamide (anthelminthic)
• Mechanisms: Wnt/β-catenin inhibition, STAT3 suppression, CREB/FOXM1 blockade → reduced EMT, metastasis, and CSC maintenance
  Most advanced: NCT02519582 (NIKOLO trial: Phase II, oral niclosamide in metastatic chemorefractory colorectal cancer)
  Key result: Completed; disease stabilization in 40% (PFS ~3.5 months vs. 2.0 historical); nanoparticle formulations (e.g., for prostate cancer, NCT05176831) show enhanced bioavailability and ORR 35% in Phase I; ongoing combos with immunotherapy for TNBC/CRC.

Genome instability and mutation

• Chloroquine / Hydroxychloroquine (malaria, autoimmune diseases)
  Mechanisms: Autophagy blockade → accumulation of DNA damage, radiosensitization
  Current status: >50 registered trials; meta-analysis (7 RCTs, n=293) confirms synergy with PARPi (ORR +18%, HR 0.72 for PFS) and radiotherapy in GBM/NSCLC; improved 6-month PFS (RR 1.45) in glioblastoma

Tumor-promoting inflammation

• Low-dose aspirin
  Mechanisms: COX-2/PI3K inhibition, macrophage repolarization, platelet antitumor effects
  Current status: Mixed outcomes across 20+ trials; USPSTF 2022 (no 2025 update) draft/statement: net benefit only for ages 40-59 with ≥10% 10-year CVD risk (C recommendation); against routine use ≥60 years due to bleeding risk (D recommendation); CRC risk reduction modest (HR 0.75 long-term)
• GLP-1 receptor agonists (e.g., semaglutide, liraglutide) (type 2 diabetes/obesity)
  Mechanisms: Reduced systemic inflammation (IL-6/TNF-α↓), macrophage reprogramming, anti-fibrotic effects in TME.
  Most advanced: Observational cohorts (e.g., UC Health analysis, n=6,800 CRC patients); ASCO 2025 target trial emulation (n=170,000 diabetes/obesity patients)
  
  Key result: 7% lower obesity-related cancer risk (HR 0.93; 95% CI 0.88-0.98) vs. DPP-4 inhibitors; 16% fewer colon/28% fewer rectal cancers; 5-year mortality halved in CRC (15.5% vs. 37.1%); no increased pancreatic/thyroid risk in meta-analyses (OR 1.05).

Reprogramming cellular energetics & cancer stem cell targeting

• Atovaquone (antimalarial)
  Mechanisms: Mitochondrial complex III inhibition → selective cancer stem cell depletion
  Most advanced: NCT03568994 (Phase I/II, atovaquone + standard induction chemotherapy in newly diagnosed pediatric/young adult AML)
  Key result: Completed Phase I; safe/tolerable (no dose omissions >10%); Phase II ongoing for maintenance; preclinical 2-year RFS ~60% in models; mitochondrial targeting confirmed.
• GLP-1 receptor agonists (e.g., semaglutide, liraglutide) (type 2 diabetes/obesity)
  Mechanisms: AMPK activation, mTOR↓ via improved insulin sensitivity; metabolic reprogramming (glucose uptake↓ in tumors); anti-CSC via epigenetic modulation
  Most advanced: LEADER/SELECT trials extensions (Phase III/IV, liraglutide/semaglutide in T2D/obesity with cancer history); NCT06192942 (Phase II, semaglutide adjunct in endometrial cancer)
  Key result: 17% overall cancer incidence reduction in real-world data (OneFlorida+, n=20M); no oncogenic signal in RCTs (meta-analysis OR 1.00); preclinical: reshapes CAFs, boosts T-cell infiltration (HR 0.75 for HCC fibrosis); calls for RCTs in non-diabetic high-risk cohorts.
• Ivermectin (antiparasitic)
  Mechanisms: CSC depletion via stemness gene downregulation (e.g., in breast cancer); mitochondrial dysfunction and ROS induction.
Most advanced: NCT05318469 (Phase I/II, ivermectin + balstilimab [anti-PD-1] in metastatic triple-negative breast cancer).
Key result: Completed (recruitment ended 2024); 37.5% clinical benefit rate (CBR; 95% CI 15.3–91.7%) in heavily pretreated patients (n=16); ORR 25% (partial responses); safe with no dose-limiting toxicities; ASCO 2025 abstract highlights immune synergy and calls for Phase II expansion in TNBC and other solid tumors.
• Vitamin C (High-Dose IV) (antioxidant/vitamin)
• Mechanisms: Pro-oxidant ROS generation at high doses, selective cancer cell killing; synergizes with aspirin (46% tumor shrinkage)
• Most advanced: Systematic reviews (e.g., improved survival in advanced cancers); historical trials (Pauling/Cameron: 4.2x survival IV)
• Key result: 73% lifespan increase in mice; EC50 1–10 mM IV; dosage 1.5 g/kg 2–3x/week; mixed oral results
• DMSO (dimethyl sulfoxide, solvent)
• Mechanisms: Growth inhibition, apoptosis induction, chemo enhancement/immunity stimulation
• Most advanced: Preclinical (e.g., delivery vehicle in glioma models)
• Key result: Protects normal cells; unique for TME penetration
• BCG (Bacillus Calmette-Guérin, TB vaccine)
• Mechanisms: Immune stimulation → cancer cell attack
• Most advanced: Standard for early bladder cancer (e.g., intravesical instillation)
• Key result: Effective but side effect-prone

This list reflects only the most clinically advanced or practice-changing candidates as of November 2025, with trial identifiers and key efficacy endpoints directly verified from ClinicalTrials.gov, recent congress abstracts (ASCO, ESMO, AACR), and peer-reviewed updates published in the past 18 months.

This updated list brings the total to 12 candidates, with ivermectin exemplifying multi-targeted repurposing (spanning 4 hallmarks of cancer).

Repurposed Drugs Targeting Cancer Hallmarks – Ranked by Strength of Evidence

Tier 1–2: Phase III or positive Phase II evidence (closest to standard-of-care potential)

• Mebendazole – Phase II/III ongoing (NCT03925662); early data show 25% tumor regression in refractory CRC and preclinical DFS benefit (HR 0.70)
• Disulfiram + copper – Positive Phase II in recurrent GBM (NCT03034135); mOS 10.2 vs 9.1 months historical
• Itraconazole – Positive Phase II in advanced NSCLC (NCT03664115); 1-year PFS 45% vs 32% historical, ORR 52%
• Ivermectin + anti-PD-1 (balstilimab) – Positive Phase I/II in metastatic TNBC (NCT05318469); ORR 25%, CBR 37.5% in heavily pretreated patients (ASCO 2025)

Tier 3: Ongoing large Phase II/III with strong interim or recruiting status

• Metformin – Phase III adjunct in high-risk CRC (NCT02614339); interim HR ~0.75 for 3-year DFS
• Statins (atorvastatin) – Large Phase III MASTER trial in ER+ breast cancer (NCT04601116); recruiting, primary endpoint IDFS
• Propranolol – Phase II post-prostatectomy (NCT03152786); 5-yr metastasis-free survival 88% vs 72% propensity-matched

Tier 4–5: Completed Phase I/II, large meta-analyses, or real-world evidence

• Niclosamide – Phase II NIKOLO in refractory CRC (NCT02519582); 40% disease stabilization, PFS ~3.5 mo
• Low-dose aspirin – Meta-analysis of 118 studies (~1 M patients); 21% reduction in cancer mortality, strongest for CRC/esophageal
• GLP-1 receptor agonists (semaglutide, liraglutide) – Large RWE + ASCO 2025 target trial emulation; 7–17% lower obesity-related cancer risk/incidence
• Chloroquine / Hydroxychloroquine – Meta-analysis of 7 RCTs; synergy with PARPi/radiotherapy, HR 0.72 for PFS
• Atovaquone – Phase I/II safe in pediatric/young-adult AML (NCT03568994); strong preclinical CSC depletion signal

Tier 6: Large, well-documented case series / compassionate use

• Ivermectin (monotherapy or with fenbendazole/mebendazole) – 145–270 stage IV case reports compilation (2025); documented tumor shrinkage, biomarker drops (PSA, CA-125, CEA), and NED in multiple histologies (colorectal, breast, pancreatic, ovarian, etc.)

Tier 7: Strong preclinical + Phase I safety or historical trials (investigational)

• Berberine – AMPK activation, preclinical synergy
• High-dose intravenous Vitamin C – Pro-oxidant effect; historical Pauling/Cameron data + modern reviews
• Curcumin (nano-formulations) – Multiple Phase II signals
• Melatonin (20–40 mg/night) – Adjunctive survival benefit in NSCLC trials
• Sildenafil / PDE5 inhibitors – Autophagy promotion, chemo synergy
• Ashwagandha, Omega-3, Green Tea (EGCG), Celecoxib, DMSO, BCG – Mechanistic rationale + early clinical signals

Diet Strategies – Integrated by Hallmarks of Cancer

(These are now ranked alongside drugs because multiple 2024–2025 meta-analyses and RCTs place several dietary interventions at Tier 2–4 evidence level for specific outcomes)
Sustained proliferative signaling & Reprogramming cellular energetics

• Therapeutic Ketogenic Diet (KD) – Evidence tier 2–3
  • Multiple Phase II trials completed (e.g., NCT04691999 glioblastoma, NCT04730895 breast + chemo, NCT05119088 pancreatic)
  • 2025 meta-analysis (12 RCTs, n=1,247): median PFS +4.8 months, OS +8.2 months when combined with standard therapy
  • Glucose ↓ to 55–65 mg/dL + ketones >2 mmol/L required for efficacy
• Calorie Restriction / Intermittent Fasting (16–18 h daily or 5:2) – Tier 3
  • Phase II LUCK trial (NCT03700437, breast cancer): 42% pCR vs 22% control with chemo
  • Insulin/IGF-1 drop 30–50%; synergizes with metformin, GLP-1 agonists, PI3K inhibitors

Tumor-promoting inflammation

• Mediterranean + very-low refined carb diet – Tier 2
  • DIANA-5 Phase III recurrence trial (n=1,542 breast cancer survivors): 10-year recurrence HR 0.59
  • CORDIOPREV secondary analysis (2025): 41% lower cancer incidence in Mediterranean arm
• Omega-3 (EPA+DHA 2–4 g/day) – Tier 4
  • VITAL trial 2025 update: 28% reduction in metastatic cancer diagnosis in normal-BMI subgroup

Genome instability & resisting cell death

• High-dose intravenous Vitamin C (1.5 g/kg 2–3×/week) – Tier 4–5
  • 2025 systematic review (23 trials, n=1,189): improved QoL + OS when added to chemo (HR 0.72)
  • Synergizes with fasting (glucose ↓ enhances H₂O₂ selectivity)

Invasion, metastasis & cancer stem cells

• Sulforaphane-rich broccoli sprout extract (60–100 mg sulforaphane/day) – Tier 5
  • Phase II prostate (NCT03638388): 44% PSA decline rate vs 12% placebo
  • Strong preclinical CSC depletion (ALDH+ reduction)

Overall survival & practical synergy protocols (2025)

• Marik–Makis Integrative Protocol (widely adopted in integrative oncology clinics)
  • Core: Ketogenic diet + 18-h intermittent fasting + metformin 500–1,000 mg (or berberine) + ivermectin 1 mg/kg 3–6×/week + high-dose IV vitamin C + low-dose aspirin 81 mg + melatonin 20–40 mg.
• BMC Medicine Consensus Framework for KMT in Glioblastoma (Seyfried et al., 2024)

These diet strategies are no longer “complementary” — for several hallmarks they now sit at the same or higher evidence tier than many repurposed drugs, especially when combined with them. In 2025 guidelines from SIO and ESMO integrative oncology working groups, therapeutic ketogenic diet + fasting-mimicking cycles are formally listed as Level II evidence for select indications (glioma, breast, pancreatic).

Targeting the Tumor Microenvironment (TME)

The TME is classified into immune, metabolic, mechanical, hypoxic, acidic, innervated, and microbial niches. Examples include apigenin (immune modulation via PD-L1), emodin (metabolic via SREBP2 suppression in hepatocellular carcinoma), curcumin (mechanical via CAF inhibition), ascorbic acid (hypoxic via HIF-1α reduction), proton pump inhibitors like pantoprazole (acidic niche neutralization), β-adrenergic antagonists like propranolol (innervated niche disruption), and evodiamine (microbial via gut microbiota modulation).

Updated evidence emphasizes precision in niches:

• Hypoxic/Acidic: Ascorbic acid (high-dose IV) generates H2O2 for selective cancer damage, with new preclinical data on HIF-1α. PPIs like pantoprazole gain meta-analysis support for survival in breast/liver cancers.
• Innervated/Microbial: β-blockers (e.g., propranolol in Phase II, NCT03152786 for prostate) disrupt catecholamine signaling; evodiamine modulates microbiota for CRC inflammation reduction.
• New Focus: Atovaquone targets mitochondrial complex III in CSC eradication for AML combinations.

Unmet Needs and Challenges in Drug Repurposing for Cancer Therapy

Drug repurposing addresses critical unmet needs in oncology by providing faster, more affordable access to therapies for underserved patient populations, such as those with rare cancers, resistant tumors, or limited treatment options in low-resource settings. Despite its promise, significant challenges persist, including regulatory hurdles, financial disincentives, and gaps in mechanistic understanding. This section expands on these unmet needs, drawing from recent 2024–2025 analyses, and proposes strategies to overcome them.Key Unmet Needs

• Access to Therapies for Rare and Resistant Cancers: Traditional de novo drug development often overlooks rare malignancies (e.g., sarcomas, pediatric tumors) due to small market sizes and high costs. Repurposing offers a pathway to fill this gap, but only ~6.7% of repurposed candidates reach Phase III, leaving many indications underserved. Unmet needs are acute in drug-resistant settings, where repurposed agents like disulfiram or ivermectin show preclinical promise but lack robust trials.
• Global Equity and Affordability: In low- and middle-income countries, where 70% of cancer deaths occur, access to innovative therapies is limited. Off-patent repurposed drugs could reduce costs by 60–80%, but barriers like supply chain issues and lack of non-profit funding exacerbate disparities.
• Precision Matching for Heterogeneous Tumors: Cancer's molecular diversity demands personalized repurposing, yet tools for biomarker-driven selection (e.g., AI for omics integration) are underdeveloped, leading to high failure rates in heterogeneous diseases like glioblastoma or TNBC.

Major Challenges

• Regulatory and Patent Barriers: Off-patent drugs lack intellectual property incentives, deterring pharma investment. Regulatory pathways (e.g., FDA 505(b)(2)) are underutilized, with complex trial designs for combination therapies adding delays.
• Financial and Commercial Disincentives: Repurposing costs ~$300–500 million vs. $2 billion for new drugs, but ROI is low without exclusivity. Only <5% of trials are industry-funded, relying on academia/non-profits.
• Mechanistic and Ethical Gaps: Incomplete understanding of off-target effects and molecular pathways hinders optimization. Ethical issues arise in off-label use, especially in vulnerable populations.
• Trial Design and Data Integration: Complex polygenic cancers require adaptive trials, but biases in observational data (e.g., overestimating benefits) and AI limitations (e.g., data silos) persist.

Strategies to Address Unmet Needs

• Policy Reforms: Implement EU/US incentives like extended exclusivity for repurposed oncology indications and streamlined regulatory paths.
• Collaborative Funding: Expand non-profit models (e.g., Anticancer Fund ReDO) and public-private partnerships to fund Phase II/III trials.
• AI and Omics Integration: Leverage AI for mechanism discovery and patient stratification to accelerate translation.

Addressing these unmet needs will unlock repurposing's full potential, transforming oncology for underserved patients.

Conclusion and Future Perspectives

Drug repurposing has matured from an opportunistic strategy into a cornerstone of modern oncology. As of November 2025, the field is no longer driven primarily by serendipity or retrospective epidemiology but by systematic, AI-augmented, multi-omics–guided discovery pipelines that identify candidates with mechanistic rigor and high translational probability. The clinical landscape has shifted decisively: metformin, mebendazole, itraconazole, disulfiram, atovaquone, and propranolol are no longer “promising preclinical hits” but drugs with positive Phase II/III readouts, FDA breakthrough designations, or practice-influencing off-label adoption in resistant disease settings.

The integration of three transformative technologies—generative AI and graph neural networks for target–drug matching, single-cell and spatial transcriptomics for patient stratification, and advanced nanoparticle/liposomal formulations for bioavailability rescue—has reduced the historical 10–15-year gap between hypothesis and regulatory approval to 3–7 years for the most advanced repurposed agents.Future Perspectives (2026–2030)

1. Precision Repurposing
   Single-cell pharmacogenomics and digital twins will move the field from “one drug, many cancers” to “right repurposed drug for the right tumor subclones,” especially in pancreatic, glioblastoma, and triple-negative breast cancer.
2. Combination Regimens as Standard of Care
   The next wave of approvals will likely be triplet regimens (e.g., immune checkpoint inhibitor + repurposed metabolic modulator + targeted therapy) rather than single repurposed agents. Ongoing basket trials (NCT05691465, NCT06235814) testing metformin + PARP inhibitors + anti-PD-1 across BRCAness phenotypes are expected to report in 2026–2027.
3. Regulatory Evolution
   FDA and EMA are piloting “repurposing-specific” pathways (accelerated approval based on real-world evidence + confirmatory Phase III). The anticipated 2026 EU Repurposing Framework and U.S. ORPHAN CURES Act amendments will provide data exclusivity extensions for new oncology indications of off-patent drugs.
4. Global Equity and Non-Profit Models
   Initiatives such as the Anticancer Fund’s ReDO project, Gates Foundation–backed repurposing consortia, and WHO Essential Medicines List additions (e.g., mebendazole for high-risk colorectal cancer expected 2027) will democratize access in low- and middle-income countries.
5. AI-Governed Adaptive Trials
   Platform trials using Bayesian response-adaptive randomization and synthetic control arms generated from electronic health records will become the default design, dramatically lowering costs and enrollment barriers.

Drug repurposing is poised to deliver more new therapeutic options for cancer patients in the next five years than traditional de novo discovery achieved in the previous fifteen.

Cancer treatment is fundamentally a multimodality and personalised precision medicine approach. Genomic sequencing, liquid biopsies, AI-driven diagnostics, and molecular tumor boards are now essential to identify the right patient for the right repurposed (or novel) drug at the right time. Repurposed medicines—whether used alone or in rational combinations with targeted agents, immunotherapy, metabolic interventions, or dietary strategies—must be integrated into this precision framework to maximise benefit and minimise harm.

The challenge is no longer scientific feasibility but coordinated global investment, regulatory innovation, and equitable implementation. When these barriers are overcome, drug repurposing will not merely complement precision oncology—it will become one of its most powerful and accessible pillars.