Abstract 3801: Reversing chemoresistance in high grade serous ovarian cancer

Abstract

Background: High grade serous ovarian cancer (HGSOC) is the most common ovarian cancer subtype. Although it is initially responsive to platinum-containing chemotherapy, the emergence of chemo-resistant cells is inevitable. Most women with HGSOC die of platinum-resistant cancer, and the five-year overall survival for ovarian cancer has changed little in recent decades. The aim of this project is to identify and validate existing, licensed drugs that selectively target resistant cancer cells in combination with cisplatin or carboplatin. Methods: Established chemo-sensitive HGSOC cell lines Ovcar4, COV318 and OVSAHO were passaged in vitro with increasing doses of either Cisplatin or Carboplatin to achieve a 5-10 fold difference in IC50 in resistant compared to sensitive parental cells, reflecting the chemo-resistance commonly found in patient tumor samples. We screened a library of 1170 FDA-approved drugs in Ovcar4 and carboplatin-resistant Ovcar4 (Ov4Carbo) cell lines and viability was analyzed using Cell Titre Glow (CTG). Ovcar4 or Ov4Carbo cells were injected and intraperitoneal tumor growth was assessed in female CD1 nude mice as in vivo model to assess the effects of drug combinations. Results: Using a high throughput drug screen, we identified Chloroxine as one of the top hits that re-sensitized resistant Ov4Carbo cells to Carboplatin. We have further validated Chloroxine in the platinum sensitive/resistant cell pairs in our novel HGSOC cell line panel (Ovcar4/Ov4Cis; Ov4CarboRFP; Ov4Carbo single cell clone 7 and COV318/Cov318Cis). Previous literature has identified kappa-type opioid receptor, OPRK1 as a potential binding target for Chloroxine. We found that the OPRK1 agonist, U50488 reproduced the synergy with Carboplatin in resistant Ov4Carbo cells, as observed with Chloroxine. Additionally, OPRK1 antagonist, nor- Binaltorphimine (nor-BNI) reduced the combined effects of Chloroxine and Carboplatin in Ov4Carbo cells suggesting that Chloroxine acts via OPRK1 receptor. We have tested Ovcar4, Ov4Carbo and Ov4Cis in vivo and found that all formed tumors in the peritoneum of nude mice and sequential bioluminescent readings correlated with survival. We are currently testing the effects of Chloroxine or OPRK1 agonist, U50488 in combination with Carboplatin in our in-vivo models. Conclusion: We have identified Chloroxine, an FDA-approved clinical drug that combines synergistically with carboplatin or cisplatin to induce cell death in chemo-resistant cell lines. We expect that understanding the mechanism of this synergy will provide novel insights into the pathophysiology of chemotherapy resistance in high grade serous ovarian cancer. In addition, as the pharmacokinetics and toxicity profiles of these FDA-approved drugs have already been established, this ‘repurposing’ of commonly used drugs will allow for a faster bench-to-bedside translation. Citation Format: Jayeta Saxena, Francesco Nicolini, Michelle Lockley. Reversing chemoresistance in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3801.

Labels as a Feature: Network Homophily for Systematically Discovering human GPCR Drug-Target Interactions

“…Some of the observed discrepancies between prior art and the yeast platform can be explained by the comparatively high dynamic ranges on the yeast platform, which may have allowed it to pick up on DTIs that other screens might have missed. Chloroxine is known to bind OPRK1 [42], so based on phylogeny, it is not surprising that it also binds to OPRM1 as shown in our screen, despite the conflicting information from prior art. Activation of MTNR1A by serotonin has already been shown in other publications relying on yeast platforms [26, 43], however, this information is not deposited on either ChEMBL or the IUPHAR/BPS guide to pharmacology, which is why an older, and presumably less sensitive assay, is the only reference on this combination in the dataset[36].…”

Elucidating Novel Targets for Ovarian Cancer Antibody–Drug Conjugate Development: Integrating In Silico Prediction and Surface Plasmon Resonance to Identify Targets with Enhanced Antibody Internalization Capacity

“…Similarly, expression of OPRK1, an opioid receptor that belongs to the superfamily of G protein-coupled opioid receptors, has been reported to be associated with a significantly poorer prognosis and tumour migration in various cancers, such as breast, oesophageal squamous cell carcinoma, metastatic liver cancer, and pancreas neuroendocrine tumours [ 57 , 58 ]. A recent in vitro study conducted with OPRK1 antagonist and agonist identified OPRK1 as mediator of chloroxine therapy, suggesting this target could be further exploited in combination with other chemotherapies [ 59 ]. Although these two targets did not progress in our validation pipeline, this was mostly due to limitations around availability of commercial antibodies against these proteins.…”