Drug repurposing strategies for ovarian cancer
This comprehensive review examines drug repurposing strategies for ovarian cancer treatment, focusing on non-oncological drugs that could offer cost-effective alternatives to expensive targeted therapies.
Background and Rationale
Ovarian cancer remains the leading cause of gynecological cancer mortality worldwide, with approximately 75% of patients developing incurable recurrences despite initial treatment responses. While targeted therapies like PARP inhibitors and bevacizumab have improved outcomes, progression-free survival remains limited to around 21 months even in best-case scenarios. Drug repurposing offers a promising alternative approach, leveraging existing safety profiles and known pharmacokinetics to accelerate clinical development while reducing costs.
Key Repurposed Drug Candidates
Statins inhibit cholesterol biosynthesis through HMGCR blockade, disrupting multiple cellular processes including proliferation, migration, and metastasis. Clinical studies demonstrate significant survival benefits, with ovarian cancer patients showing hazard ratios of 0.63-0.87 for overall survival compared to non-users. Pitavastatin shows particular promise for chemoresistant tumors, especially given the near-universal TP53 dysregulation in high-grade serous carcinoma.
Metformin, primarily used for diabetes management, exhibits anti-cancer properties through AMPK activation and mTOR inhibition. It preferentially targets cancer stem cells and reverses chemoresistance. Clinical data shows impressive results, with 5-year survival rates of 67% in metformin users versus 47% in non-users. Recent phase II trials demonstrate median progression-free survival of 18 months in non-diabetic ovarian cancer patients.
Bisphosphonates block farnesyl pyrophosphate synthase in the mevalonate pathway, inhibiting tumor proliferation and metastasis. These osteoporosis medications show anti-tumoral effects with odds ratios of 0.49 for ovarian cancer risk reduction. They demonstrate particular efficacy in delaying recurrences and reducing tumor burden in preclinical models.
Ivermectin, an antiparasitic agent, targets multiple pathways including MDR proteins, Akt/mTOR signaling, and cancer stem cell populations. It shows synergistic effects with conventional chemotherapy, particularly cisplatin and paclitaxel, and can completely reverse tumor growth in xenograft models when used in combination.
Itraconazole inhibits multiple oncogenic pathways including Hedgehog, mTOR, and Wnt signaling while demonstrating anti-angiogenic properties. Clinical studies in platinum-resistant ovarian cancer patients show significant improvements in progression-free survival (HR = 0.24) and overall survival (HR = 0.27) when combined with taxane-based chemotherapy.
Ritonavir, an HIV protease inhibitor, induces apoptosis through PI3K/Akt pathway inhibition. While evidence is more limited, it shows promise for combination therapy with conventional chemotherapy in ovarian cancer treatment.
Personalized Testing Approach
The review proposes using ex vivo models derived from patient ascitic fluid to test drug repurposing efficacy. This personalized approach could validate existing evidence and guide individualized treatment decisions. Ascites provides an accessible source of viable tumor cells that maintain patient-specific characteristics, making it ideal for high-throughput drug sensitivity screening.
The proposed model involves establishing cancer cell cultures from ascitic fluid and testing combination therapies pairing repurposed drugs with conventional chemotherapy. This approach could identify synergistic effects and overcome the limitation of low potency often associated with repurposed drugs when used as monotherapy.
Clinical Implications
Drug repurposing offers several advantages: reduced development costs, known safety profiles, immediate availability, and potential for combination with existing therapies. Multiple ongoing clinical trials are evaluating these strategies, with several showing promising preliminary results.
Conclusion
Drug repurposing represents a viable strategy for improving ovarian cancer outcomes, particularly in resource-limited settings. The combination of established safety profiles, promising preclinical and clinical data, and the potential for personalized testing through ex vivo models makes this approach highly attractive. However, sustained research investment and fair comparison with newer therapies remain essential for validating and implementing these cost-effective treatment strategies.
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