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.
Dr. Imade Williams is a postdoctoral fellow in laboratory of Dr. Richard Carpenter and under the co-mentorship of Dr. Kenneth P. Nephew at Indiana University School of Medicine Bloomington. Dr. Williams earned her Bachelor of Arts degree in Molecular and Cellular Biology and Russian Language from Vanderbilt University, where she was also an Ingram Fellow and conducted research in the cell and developmental laboratory of Dr. Robert Coffey, Jr. Prior to her doctoral studies, she conducted cancer vaccine research as a postbaccalaureate research education program (PREP) scholar in the laboratory of Dr. Periasamy Selvaraj at Emory University. Dr. Williams then entered the Indiana Biomedical Gateway Program for PhD Studies at Indiana University School of Medicine. She received her Doctorate in Biochemistry and Molecular Biology, with a minor in Cancer Biology, while investigating pancreatic cancer progression and metastasis in a genetically engineered mouse model in the laboratory of Dr. Murray Korc. For her thesis work, Dr. Williams characterized a novel pancreatic cancer mouse model and demonstrated that differences in copy-number loss of the tumor suppressor TIP30 altered epidermal growth factor receptor protein levels and resulted in organotropic metastasis. Her doctoral training was supported by a research award to Promote Diversity in Health-Related Research and a Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship (Parent F31), both from the National Cancer Institute. In addition, she has received funding from the Lustgarten Foundation, a Yale Ciencia Academy Fellowship, and was a Southern Regional Education Board (SREB) Doctoral Scholar.
As a postdoctoral fellow in the Carpenter Lab, Dr. Williams’ research focuses on understanding the transcriptional regulation and relationship of MYC and heat shock factor 1 (HSF1) in ovarian cancer and investigating the response of MYC-HSF1-amplified ovarian cancer to novel therapies. The support of the Ovarian Cancer Research Alliance will be instrumental in allowing Dr. Williams to fully investigate the genome-wide and molecular actions of MYC and HSF1 in ovarian cancer and furthering her advancement in her career as a translational cancer researcher. She looks forward to sharing her important findings with the ovarian cancer research community and patients.