Project 1: Targeting HSPA Proteins in Advanced and Recurrent Endometrial Cancer Therapy

Clinical Co-Leader: Kathleen Moore, M.D., University of Oklahoma

Basic Co-Leader: Doris Benbrook, PhD, University of Oklahoma

The incidence and mortality of endometrial cancer has increased over the past few decades, and is predicted to continue rising. There is significant need for improved therapies with reduced toxicity for women with endometrial cancers that are advanced, recurrent or refractory to standard of care. Endometrial cancer is a heterogeneous disease that has been classified into molecular profile categories with different degrees of patient prognosis. Across these categories, endometrial cancer has the highest rates of mutations in heat shock protein A (HSPA) 5, 8 and 9 genes compared to other The Cancer Genome Atlas-studied cancers. The HSPA5, HSPA8 and HSPA9 genes encode chaperone proteins, Grp78, hsc70 and mortalin, respectively, which become elevated during carcinogenesis to bind and modulate oncoproteins in a way that assures cancer cell survival. Thus, these chaperone/oncoprotein complexes represent differential targets present at higher levels in cancer cells compared to healthy cells. We developed a drug, SHetA2 (NSC 726189), which disrupts these complexes.

SHetA2 induces growth arrest, altered metabolism, mitophagy and cell death in endometrial cancer cells, while the effects on healthy cells is limited to G1 cell cycle arrest. Preclinical studies found lack of SHetA2 toxicity, and this drug is now in a Phase 1 clinical trial in advanced, recurrent or persistent gynecologic cancers (NCT04928508). In vivo studies revealed that SHetA2 has complementary activities and efficacies with paclitaxel and cyclin dependent kinase (CDK4/6) inhibitors. In this project, we hypothesize that SHetA2 will safely reduce endometrial cancer tumor burden and complement the efficacies of paclitaxel and CDK4/6 inhibitors without increasing toxicity; the mechanism will be mediated through SHetA2 disruption of HSPA/client protein complexes; and the treatment efficacies will be modulated by mutations in PTEN and TP53 genes.

The outcome is anticipated to identify biomarkers predictive of which patients will most likely benefit from SHetA2-based therapies, and provide justification and data for development of a randomized Phase 3 trial of a SHetA2 combination anticipated to have an improved therapeutic window over current therapy.