Abstract 4233: Ovarian cancer treatments: Using HSF1 and MYC gene amplification as a biomarker

Abstract Ovarian cancer is one of the deadliest gynecological malignancies as approximately 1 in 87 women will die from this disease. One of the reasons for such a dismal prognosis for the disease is due to the limited treatment options and high rate of relapse from the first line treatment of platinum-based chemotherapy and taxanes. Therefore, patients with ovarian cancer would greatly benefit from new treatment options. To find new treatment options for ovarian cancer, we looked for ideal targets by analyzing the biology of high-grade serous ovarian cancer (HGSOC), the most common and most deadly form of ovarian cancer. This type of ovarian cancer is classified by high rates of amplification of oncogenes such as MYC, KRAS, and CCNE1, however this knowledge of oncogene amplification has been understudied as a genetic biomarker for efficacy of various treatments. Approximately 30% of ovarian cancers carry amplifications of both the MYC and Heat-shock Factor 1 (HSF1) oncogenes, which have both been shown to contribute to worse survival in multiple cancer types through mechanisms such as increased proliferation, metastasis, and immune evasion. Many drugs have been developed to directly bind to and inhibit these targets, however none have had success in clinical trials in part due to the difficulty in designing drugs to potently and specifically target transcription factors. To inhibit the activity of the MYC and HSF1 transcription factors in HGSOC, we tested alternative mechanisms of MYC and HSF1 inhibition through targeting a shared activating kinase, Polo-like Kinase 1 (PLK1), with the PLK1 inhibitor Volasertib (BI-6727). Since HSF1 and MYC are both transcription factors, we also aimed to find an epigenetic method of inhibiting their transcriptional activity. We performed a drug screen of epigenetic inhibitors in the background of HGSOC cells that carried the HSF1 and MYC co-amplification and a counter-screen of HGSOC cells that did not carry these amplifications. Results from this screen show that cells that are coamplified for the HSF1 and MYC oncogenes are more sensitive to treatment with class I HDAC inhibitors than HGSOC cells without this amplification. We show that treatment with the class I HDAC inhibitor Entinostat decreases the HSF1 and MYC expression at the mRNA and protein level. We show that loss of HSF1 and MYC decrease proliferation and colony formation ability of ovarian cancer cells using knockdown siRNAs and that the Volasertib and Entinostat inhibitors are more effective in treating ovarian cancers that carry amplifications of HSF1 and MYC than those with other driver amplifications. Work with both Volasertib and Entinostat aim to show that amplifications of oncogenes in high-grade serous ovarian cancer can be used as a biomarker for new treatment strategies in ovarian cancer. Citation Format: Matthew S. O'Malley, Imade Williams, Haddie DeHart, Bobby Walker, Vrushabh Ulhaskumar, Haimanti Ray, Pranav Jothirajah, Joe R. Delaney, Kenneth P. Nephew, Richard Carpenter. Ovarian cancer treatments: Using HSF1 and MYC gene amplification as a biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4233.