2022 Recipient Imade Williams, PhD

Imade Williams, PhD

Targeting MYC-HSF1 co-Amplification in High Grade Serous Ovarian Cancer

Project Summary

High grade serous ovarian carcinoma (OC), the most common OC epithelial subtype and fifth leading cause of mortality in women in the U.S., is a highly aggressive disease characterized by genomic instability, rapid tumor growth with a propensity for widespread peritoneal metastasis, and marked chemoresistance. The discovery of novel mechanisms of OC growth, progression and targeting, which is proposed in this research plan will help advance the field and contribute to improving patient care. Although, the MYC proto-oncogene is reported to be frequently amplified in OC and the gene for heat shock factor 1 (HSF1), and its pro-tumor function is emerging in several cancer types, including OC, the role of MYC and HSF1 and their relationship has not yet been investigated in OC. In our preliminary studies using data from The Cancer Genome Atlas (TCGA), we have found that HSF1 is amplified in 32% of OC and that 36% (110/302) of OC patients have both MYC and HSF1 amplifications (p<0.0001). We have also observed that the transcriptional activity of MYC and HSF1 are highly correlated in OC patients, that MYC and active HSF1 protein levels are highly correlated in OC cell lines, and that patients with MYC amplification and high HSF1 activity have worse overall and recurrence-free survival independent of age. Considering there are currently no viable therapeutics targeting MYC or HSF1, we examined potential therapeutic targets in the context of MYC and HSF1 co-amplification (co-AMP). Polo-like kinase 1 (PLK1), which normally regulates mitotic entry, has previously been shown to directly phosphorylate and enhance the activity of both MYC and HSF1. Volasertib (BI-6727) is a highly selective PLK1 inhibitor that has been well-tolerated in clinical trials. Our preliminary results suggest that co-AMP OC cells are highly sensitive to volasertib in vitro and in vivo. In this proposal, we will therefore test the hypothesis that MYC and HSF1 cooperate to promote OC tumor growth and progression and that HSF1-MYC co-amplification sensitizes OC to PLK1 inhibition. To understand the relationship between MYC and HSF1 in OC, we will use co-AMP OC cells engineered to inducibly express MYC or HSF1 knockdown to assess in vitro and in vivo MYC-/HSF1-mediated OC growth kinetics, including metastatic burden. We will also assess for the first time the genome-binding profile of MYC and HSF1 in OC via ChIP-seq, and transcriptional profile changes via RNA-seq. We will then test the hypothesis that OC co-AMP cells are sensitive to PLK1 inhibition in vitro and in vivo in the presence of platinum-based chemotherapeutic carboplatin. These studies interrogate a promising and viable treatment option for the subset of OC patients with MYC-HSF1 co-AMP, and will allow for investigation and novel discovery for a personalized therapy approach for OC in addition to broader understanding of the genome-wide and molecular actions of MYC and HSF1 in OC.