Abstract 4143819: The Cardiotoxic Effect of Androgen Deprivation Therapy on the Genome of Men Diagnosed with Prostate Cancer

Background: Prostate cancer (PC) is the second leading cause of cancer-associated mortality among men. In addition, cardiovascular disease (CVD) is the most common cause of death in men with prostate cancer who survive chemotherapy. Conventional chemotherapy is often paired with androgen deprivation therapy (ADT) to prevent metastasis. Although ADT has increased cancer survival rates, the presence of CVD has increased substantially. From an epidemiological perspective, genetic diversity is related to disease predisposition; however, the causal factors remain unknown. Thus, this study sought to (1) evaluate the cardiotoxic effect of ADT using drug screening on differentiated cardiac stem cells, and (2) determine whether affected genes identified in the cell experiment were present in samples collected from men with PC before and following ADT. Methods: First, induced pluripotent stem cells (iPSCs) from 4 men were differentiated into endothelial cells and cardiotoxicity screening was conducted by comparing the gene response of ADT treated and untreated cells using RNA seq and gene ontology. Next, 19 men with PC were enrolled for the human experiment, and blood samples were collected at baseline, and 4 and 12 weeks following ADT. O-link proteomics was performed at all time points to determine overlap between biomarkers associated with increased CVD risk during ADT identified in the cell experiment. Results: The iPSC RNA seq data identified 301 genes that were significantly altered by ADT. Specifically, in the ADT treated cell lines, there was overexpression ( p <0.001) among members of the cyclin-dependent kinase (CDK) and transforming growth factor (TGF) families when compared to the untreated cells. In the human samples, there was an increase in the normalized plasma expression of CDK1 (0.428±0.9 to 1.036±1.0; p =0.133) and TGFBR2 (0.789±0.6 to 1.128±0.6; p =0.058) from baseline to 12 weeks, respectively. Discussion: CDK and TGF, genes known to play a role in CVD, were upregulated following ADT in both cell and human experiments. Different CDKs have been linked to various aspects of heart disease. Similarly, TGFβ isoforms are known to be upregulated and activated in myocardial diseases, playing an important role in regulating the heart phenotype and function. Therapies to reduce CDK and TGF isoforms represent a novel approach to decrease the CVD risk associated with ADT in men with prostate cancer; however, future studies are certainly warranted.