Abstract B031: The PLK1 inhibitor Volasertib as a treatment for HSF1 and MYC coamplified ovarian cancer

Abstract

Abstract Ovarian cancer is a disease that afflicts 1 in 78 women. This disease only has a 5-year relative survival rate of 49% due to the fact that the first line chemotherapy for this disease, platinum-based chemotherapy with taxanes, has an 80% recurrence rate. To improve the treatment for this disease, it would be wise to find biomarkers of sensitivity to other drugs. Using publicly available data from The Cancer Genome Project, our lab has shown that 36% of High Grade Serous Ovarian Cancers (HGSOC) have gene amplifications for both Cellular Myelocytomatosis (MYC) and Heat Shock Factor 1 (HSF1) genes. These genes encode for transcription factors and are known to contribute to malignant disease in multiple cancer types, including ovarian cancer. Evidence indicates that MYC and HSF1 are both essential to HGSOC cells with co-amplification of these genes, that MYC and HSF1 transcriptional activities are highly correlated in patient tumors, and the two transcription factors have a protein-protein interaction, all suggesting these two transcription factors cooperate to drive this subset of HGSOC tumors. Many drugs have been developed to inhibit MYC or HSF1 though they have not shown success in clinical development. We aimed to decrease the activity of these proteins by targeting polo-like kinase 1 (PLK1), a kinase that phosphorylates and regulates both MYC and HSF1 proteins. Active PLK1 levels were highly correlated with MYC and HSF1 protein levels and inhibition of PLK1 with volasertib reduced MYC and HSF1 protein levels and transcriptional activity. Furthermore, volasertib was found to have 155-fold greater potency in HGSOC cells with MYC-HSF1 co-amplification compared to cells without these genes amplified. The increased potency of volasertib in MYC-HSF1 co-amplified cells were also observed in clonogenic growth and spheroid models. Together, these data indicate that MYC and HSF1 cooperate in HGSOC when these genes are amplified and targeting a common kinase between them in PLK1 disrupts this cooperation. Furthermore, MYC and HSF1 co-amplification may serve as a biomarker for volasertib through a personalized medicine approach to treat HGSOC patients. Citation Format: Matthew O'Malley, Imade W. Williams, Bobby Walker, Haimanti Ray, Kenneth P. Nephew, Richard Carpenter. The PLK1 inhibitor Volasertib as a treatment for HSF1 and MYC coamplified ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B031.