Drug Repurposing in Oncology (2026): From AI-Driven Discovery to Practice-Changing Clinical Trials

Abstract

Introduction: Drug repurposing has emerged as one of the most efficient strategies to accelerate therapeutic innovation in oncology. This 2026 update, building on the landmark 2024 review by Ying Xia et al, published in Signal Transduction and Targeted Therapy (a Nature Portfolio journal), integrates the latest clinical, computational, and translational advances in the field.

Repurposed Drugs and Diet Strategies Targeting Cancer Hallmarks – Ranked by Strength of Evidence: We present a unified hallmark-centric framework mapping more than 20 repurposed agents (including metformin, mebendazole, itraconazole, disulfiram, propranolol, ivermectin, niclosamide, and GLP-1 receptor agonists) and evidence-based diet strategies (therapeutic ketogenic diet, intermittent fasting, Mediterranean diet, high-dose intravenous vitamin C, and others) to the 14 established cancer hallmarks and key tumour-microenvironment niches, with explicit stratification by strength of evidence (Phase III to preclinical/case series). As of November 2025, several candidates have progressed to positive Phase II/III readouts or large-scale real-world/meta-analytic validation, while AI-driven discovery platforms, single-cell pharmacogenomics, and nanoparticle delivery systems have dramatically shortened translational timelines.

Unmet Needs and Challenges in Drug Repurposing for Cancer Therapy: We highlight critical unmet needs—rare and resistant cancers, global inequity, and precision matching in molecularly heterogeneous disease—and analyse persistent barriers: regulatory inertia, lack of commercial incentives, and insufficient funding for off-patent drugs. Emerging solutions include repurposing-specific regulatory pathways, non-profit/academic consortia, and adaptive platform trials.

Conclusion and Future Perspectives: Ultimately, cancer care is a multimodality, personalised precision medicine endeavour. Genomic sequencing, liquid biopsies, and AI-guided molecular tumour boards are now indispensable for selecting the optimal combination of standard-of-care, targeted, immunotherapeutic, metabolic, dietary, and repurposed interventions. When fully integrated into this framework, drug repurposing is poised to deliver more practice-changing, affordable therapies in the next five years than de novo discovery achieved in the previous fifteen, redefining the economic and clinical foundation of modern oncology.

Keywords: drug repurposing, evidence-based diet strategies, cancer hallmarks, tumour microenvironment, ketogenic diet, intermittent fasting, precision oncology, artificial intelligence, off-patent drugs, global equity, GLP-1.

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

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 January 2026 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.

State-Funded Initiatives: Spotlight on Florida’s 2025 Innovations

Florida’s Florida Cancer Innovation Fund (FCIF) exemplifies public-private acceleration of repurposing, allocating $60 million (FY 2025-26) for 12-month translational projects prioritizing generic drugs (e.g., ivermectin) and nutrition synergies.

Key grants include:

• FIU/First Ascent Biomedical ($2M, March 2025): xDRIVE AI platform tests >100 repurposed generics (e.g., metformin, statins) on patient tumors, identifying effective options for 83% of relapsed cases via functional precision medicine.

• UF Health ($4.5M across six projects, March 2025): AI-driven small-molecule repurposing (berberine analogs) and NSAID combos (aspirin/celecoxib) for breast/CRC, plus community screening trials.

• USF/LifePulse Bioscience ($1.5M+, 2025): Electroporation devices for targeted delivery of repurposed agents (e.g., tigecycline, chloroquine), enabling 70% dose reductions in solid tumors.

• UNF Protein Methyltransferase Inhibitors (Patent, June 2025): Peptoid compounds (nifedipine analogs) selectively inhibit PRMTs in breast/colon/lung cancers without normal cell toxicity.

These efforts, focusing on rural/underserved access, model scalable repurposing ecosystems.

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.

Repurposed Drugs and Diet Strategies Targeting Cancer Hallmarks – Ranked by Strength of Evidence

Ranked strictly by strength of evidence (Tier 1–2 first → Tier 7 last)

Tier 1–2 (Phase III or positive Phase II with primary endpoint met)

• Mebendazole → Invasion & metastasis (tubulin/VEGFR2/MYC↓) – Phase II/III ongoing, early regression 25% in refractory CRC (NCT03925662)

• Disulfiram (+Cu) → Resisting cell death, CSC targeting (p97/ALDH/ROS) – Phase II GBM, mOS (median Overall Survival) benefit.

• Itraconazole → Sustained proliferation, angiogenesis (mTOR/VDAC1/VEGF↓) – Phase II NSCLC, PFS benefit.

• Propranolol → Evading growth suppressors, angiogenesis, innervated niche (β2-adrenergic/HIF-1α↓) – Phase II prostate, 5-yr MFS 88% vs 72%

• Ivermectin + immunotherapy → Sustained proliferation, resisting cell death, invasion, immune niche – Phase I/II TNBC (NCT05318469), ORR 25%, CBR 37.5% (ASCO 2025).

  • Florida invests $60 million in cancer research, focusing on ivermectin and repurposed drugs

• Mediterranean Diet → Tumour-promoting inflammation – DIANA-5 Phase III breast recurrence, 10-yr HR 0.59.

• Therapeutic Ketogenic Diet + Intermittent Fasting → Reprogramming energetics, metabolic niche, phenotypic plasticity – Multiple Phase II (GBM, breast, pancreatic), PFS +4.8 mo, OS +8.2 mo in 2025 meta-analysis.

Tier 3 (Ongoing large Phase II/III with strong interim/recruiting status)

• Metformin → Sustained proliferation, reprogramming energetics – Phase III CRC (NCT02614339), interim DFS HR ~0.75

• Statins (atorvastatin) → Sustained proliferation, evading growth suppressors – MASTER Phase III ER+ breast (NCT04601116), recruiting

• GLP-1 receptor agonists → Sustained proliferation, inflammation, energetics – Large RWE + Phase II endometrial (NCT06192942)

• Ivermectin monotherapy → Sustained proliferation, resisting cell death, invasion, CSC – FCIF-funded Phase II/III trials in solid tumors (2025–26, $15M allocation)

Tier 4–5 (Completed Phase I/II, large meta-analysis, or robust RWE)

• Niclosamide → Invasion & metastasis, CSC (Wnt/STAT3↓) – Phase II NIKOLO CRC, 40% stabilisation

• Atovaquone → Reprogramming energetics, CSC (complex III↓) – Phase I/II paediatric AML, safe + strong preclinical

• Chloroquine/HCQ → Genome instability, resisting cell death – Meta 7 RCTs, HR 0.72 with PARPi/radiotherapy

• Low-dose Aspirin → Tumour-promoting inflammation – 118-study meta, 21% mortality reduction

• High-dose IV Vitamin C → Resisting cell death, hypoxic niche, genome instability – Systematic review 23 trials, HR 0.72 OS with chemo

• Omega-3 (2–4 g EPA/DHA) → Inflammation, angiogenesis – VITAL update, 28% metastatic reduction

• Curcumin (nano) → Invasion & metastasis – Phase II head/neck completed

• Melatonin (20–40 mg) → Resisting cell death, phenotypic plasticity – Phase II adjunctive NSCLC

Tier 6 (Large documented case series, n>200)

• Ivermectin + Mebendazole and/or Fenbendazole → Sustained proliferation, resisting cell death, invasion, Cancer Stem Cell:

  • Case Series: N=300 advanced cancers (stage 4) compilation (2025), documented shrinkage/NED.

  • Fenbendazole and Ivermectin Case Reports: N=466 multiple cancer types in various stages)

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

• Berberine → Sustained proliferation (AMPK/mTOR)

• Ashwagandha → Resisting cell death (NF-κB/STAT3↓)

• Sildenafil/PDE5 inhibitors → Resisting cell death (autophagy/apoptosis)

• Green Tea (EGCG) → Replicative immortality, angiogenesis

• Bedaquiline → Reprogramming energetics (ATP synthase↓)

• Artesunate → Angiogenesis, resisting cell death

• Flubendazole → Angiogenesis

• Nifedipine → Genome instability

Evidence Tier Legend (2025)

• Tier 1–2: Positive Phase III or strong Phase II (primary endpoint met)

• Tier 3: Ongoing large Phase II/III with strong interim data

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

• Tier 6: Large, documented case series (n>100) with objective responses

• Tier 7: Strong preclinical + Phase I safety only

Practical synergy protocol

• Marik–Makis Integrative Protocol (peer-reviewed)

  • Core: Ivermectin 1 mg/kg 3–6×/week + mebendazole 400 mg + metformin 500–1,000 mg (or berberine) + high-dose IV vitamin C + low-dose aspirin 81 mg + melatonin 20–40 mg + ketogenic diet + 18-h intermittent fasting.

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 under-utilized, 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 January 2026, 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.

Florida’s $60M FCIF exemplifies how targeted public investment can bridge gaps in repurposed drug validation, fostering equitable access to affordable, multitargeted therapies through state-led initiatives like ivermectin trials and AI platforms.

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.

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.