P30 Administrative Supplement for Early-Onset Cancer Research: Repurposing orphan drugs for early-onset endometrial cancer

Wayne State University, Detroit MI

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY/ABSTRACT Endometrial cancer (EC) is the 4th most common cancer in women but has been understudied due to curative hysterectomy being available for patients with early-stage disease. As the incidence for EC rises year over year, the rates of early-onset EC (patients under 50 years of age) have risen more rapidly. Recent studies, including our own, have identified KMT2D as a gene with high mutation rates among early-onset tumors. KMT2D is a histone methyltransferase which regulates enhancer function. Our preliminary findings show that KMT2D-deficiency upregulates the Rb/E2F pathway through histone methylation mis-localized to the promoter. We developed both CRISPR-mediated cell line knockouts of KMT2D and a genetically engineered mouse model of KMT2D-driven EC. In both models, we observe an upregulation of the CDK1 protein. CDK1 has been shown to be sufficient for cell cycle progression in the absence of CDK2, 4 and 6 expression, and CDK can phosphorylate Rb as a non-canonical activity. Currently, there are ongoing clinical trials testing CDK4/6 inhibitors Abemaciclib and Palbociclib for use in endometrial cancer. Here, we propose instead that CDK1 inhibitors, including FDA-approved orphan drugs Alvocidib and Dinaciclib, may be a viable solution for the treatment of KMT2D-deficient early-onset endometrial cancer. Our hypothesis is that KMT2D mutations exist as an alternative pathway for EC which disproportionately affects patients with early-onset disease, contributing to disease progression through upregulation of CDK1 and are susceptible to therapeutic inhibition of CDK1. Our Specific Aims are (1) to characterize the role for CDK1 in driving KMT2D-deficient tumors and (2) to evaluate the efficacy of orphan drugs Alvocidib and Dinaciclib in KMT2D-loss-driven endometrial tumors. Using mouse models, cell models and patient tumors, we will characterize the impact of KMT2D loss on the CDK1 expression and evaluate the therapeutic efficacy of Alvocidib and Dinaciclib in this context. In Aim 1, we will use a panel of high-grade, early-onset EC tumors to measure the expression of CDK1 and correlate with KMT2D mutation. Using RNA-seq data from these tumors, we will evaluate the role for KMT2D in regulation of E2F/Rb among early-onset tumors, and evaluate how this differs from late-onset tumors. We will examine the role for CDK1 protein expression in relation to E2F/Rb signaling amongst this subgroup of tumors. In Aim 2, we will utilize both CRISPR knockout cell lines and our novel genetically engineered mice harboring KMT2D-loss- driven tumors to determine the efficacy of CDK1 inhibitors Alvocidib and Dinaciclib in the context of KMT2D- mediated EC. Our studies will define KMT2D as a biomarker for response to anti-CDK1s and provide clinical rationale for the use of these orphan compounds in the context of early-onset EC. Our lab’s long-term goal is to develop personalized therapies for underserved subgroups of EC patients, including those with early-onset disease.