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.IntroductionTraditional de novo drug development in oncology remains protracted (median 13.3 years) and expensive (>$2 billion per approval), with clinical success rates below 5%. Drug repurposing circumvents early-phase safety hurdles and exploits unexpected anticancer mechanisms of existing drugs. The landmark 2024 review by 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 RepurposingComputational and AI-Driven ApproachesSequence-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) [7],
• AlphaFold3-enabled virtual screening for off-target binding [8],
• and large language models fine-tuned on clinical trial corpora to predict trial success probability [9].

These tools have reduced candidate shortlisting time from months to hours with >90% enrichment for biologically relevant hits.Experimental High-Throughput ScreeningPatient-derived organoids (PDOs) co-cultured with immune and stromal components (“assembloids”) and microfluidic tumor-on-chip systems now better recapitulate TME complexity [10]. CRISPR-based phenotypic screens in PDOs have independently rediscovered mebendazole, itraconazole, and nitroxoline as top hits across multiple histologies.

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: 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. 

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.

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

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)

Invasion and metastasis

• 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
• 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.
• 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%)

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.

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).

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.

In conclusion, 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. The challenge is no longer scientific feasibility but coordinated investment, regulatory innovation, and global implementation. When these barriers are systematically addressed, repurposed medicines will not merely complement precision oncology—they will redefine its economic and clinical foundation.