Platinum-resistant High-grade Serous Cancer Research Articles

Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer

High-grade serous cancer (HGSC) accounts for ~67% of all ovarian cancer deaths. Although initially sensitive to platinum chemotherapy, resistance is inevitable and there is an unmet clinical need for novel therapies that can circumvent this event. We performed a drug screen with 1177 FDA-approved drugs and identified the hydroxyquinoline drug, chloroxine. In extensive validation experiments, chloroxine restored sensitivity to both cisplatin and carboplatin, demonstrating broad synergy in our range of experimental models of platinum-resistant HGSC. Synergy was independent of chloroxine’s predicted ionophore activity and did not relate to platinum uptake as measured by atomic absorption spectroscopy. Further mechanistic investigation revealed that chloroxine overrides DNA damage tolerance in platinum-resistant HGSC. Co-treatment with carboplatin and chloroxine (but not either drug alone) caused an increase in γH2AX expression, followed by a reduction in platinum-induced RAD51 foci. Moreover, this unrepaired DNA damage was associated with p53 stabilisation, cell cycle re-entry and triggering of caspase 3/7-mediated cell death. Finally, in our platinum-resistant, intraperitoneal in vivo model, treatment with carboplatin alone resulted in a transient tumour response followed by tumour regrowth. In contrast, treatment with chloroxine and carboplatin combined, was able to maintain tumour volume at baseline for over 4 months. In conclusion, our novel results show that chloroxine facilitates platinum-induced DNA damage to restore platinum sensitivity in HGSC. Since chloroxine is already licensed, this exciting combination therapy could now be rapidly translated for patient benefit.

Abstract A64: β-catenin as a TIC therapeutic target in epithelial ovarian cancer.

Abstract Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and is the fifth leading cause of cancer deaths in women. The most common and lethal form of EOC which makes up greater than 75% of cases is high-grade serous cancer (HGSOC). Platinum-based drugs are used as first-line chemotherapeutics for all women diagnosed with HGSOC. Unfortunately, ~20% do not respond to this treatment and up to 80% of those patients which do respond recur within 5 years at which point the cancer is particularly difficult to eradicate. Emerging evidence supports the concept that platinum based therapies are able to eliminate the bulk of differentiated cancer cells but are unable to eliminate tumor-initiating cells (TICs) which are rare populations of tumor cells characterized by their ability to self-renew indefinitely and thus drive the expansion of drug-resistant tumors. Hence, there is immediate need of novel TIC targeted therapeutic approaches that can overcome chemo-resistance in EOC. Thus, identifying critical drivers of the stem-like phenotype that can be pharmacologically modulated in ovarian TICs is required. To date, no TIC targeting drugs have successfully completed clinical trials in EOC. Using primary HGSOC cells derived from HGSOC patient derived xenograft (PDX) models, we have recently identified β-catenin as a critical driver of HGSOC TIC phenotype in-vitro. β-catenin knockdown decreased stem-cell frequency and induced chemo-sensitivity in-vitro in platinum resistant HGSOC PDX derived primary cells. ALDH positive Ovarian TIC subpopulation with high Wnt reporter activity was platinum resistant and exhibited increased expression of β-catenin regulated stem-cell markers clearly identifying β-catenin regulated stem-cell transcriptional axis as a driver of chemo-resistance in Ovarian TICs. Accordingly, the β-catenin stem-cell transcriptional axis specific inhibitor iCG-001 (PRI-724) decreased stem-cell frequency and induced chemo-sensitivity in platinum resistant ovarian TICs, suggesting that pharmacologic inhibition of β-catenin could be a potential novel approach aimed at eradicating TICs in EOC. Furthermore, in-vivo tumor-initiation assays showed a robust decrease in tumor-initiation capacity upon β-catenin knockdown in platinum resistant HGSOC cells, thus establishing β-catenin as a driver of TIC phenotype in HGSOC. In sum, we have identified that pharmacologic inhibition of β-catenin can be a novel TIC targeted therapy approach to overcome chemo-resistance and improve patient outcome in in EOC. Our results suggest that the β-catenin specific inhibitor PRI-724, that has shown promising results in phase I clinical trials in solid tumors, can be a potential TIC targeting drug in EOC. These results will form a solid foundation for clinical trials with PRI-724 in patients with chemo-recurrent EOC. Citation Format: Anil Belur Nagaraj, Peronne Joseph, Olga Kovalenko, Sareena Singh, Amy Armstrong, Analisa DiFeo. β-catenin as a TIC therapeutic target in epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A64.