Abstract B010: A novel systemic methodology for mapping the clonal architectures of human prostate tumors that develop resistance to androgen receptor (AR)-targeted therapy
Authors: Li Chennan , Wilkinson Scott , Trostel Shana Y. , Dahut William L. , Karzai Fatima , Sowalsky Adam G. 
Published: June 2023

Abstract
Developing resistance to therapeutics is a major factor leading to the high mortality rate of metastatic prostate cancer. One critical factor that mediates therapeutic resistance is the diversity of genetic mechanisms used by numerous cancer subpopulations that may be geographically co-mingled in the same physical tumor. Nonetheless, our fundamental knowledge about heterogenous mechanisms that globally contribute to drug resistance is lacking. Preliminary studies conducted by our group have shown that preexisting subclonal heterogeneity in patient tumors prior to treatment can impact clinical and pathologic outcomes. Therefore, we aimed to reconstruct tumor phylogenies and model subclonal evolution using genomic alterations identified in human prostate tumors using samples from a recent clinical trial (NCT02430480), in which patients received six months of intense androgen deprivation (ADT plus enzalutamide) prior to surgery. In this study, MRI/ultrasound-targeted biopsies were acquired at baseline, and whole mount prostatectomies were completely mapped to identify residual disease. To achieve our goal, we are performing laser capture microdissection to obtain samples of histologically distinct tumor from every tumor focus, both at baseline and post-treatment. Whole-exome sequencing (WES) is being used to identify genomic variations and then computationally map tumor subclones to the physical tissue. In addition, bulk whole-genome sequencing is being performed to resolve global subclonal architecture, to be further informed by the ground truth clonal exclusivity determined by WES of geographically distinct tumor foci. From these two complementary datasets, clonal relationships between each patient’s primary disease and its treatment-resistant counterpart will be determined and will reveal the genomic origins of drug resistance and their contribution to disease evolution. Further analyses will distinguish the evolutionary determinants of drug sensitivity (n=15 in this cohort) versus those patients with significant residual disease (n=22). To the best of our knowledge, this is the most comprehensive study mapping tumor subclones both temporally and spatially to understand the genetic origins of therapy resistance in human prostate cancer. Uncovering evolutionary tracks that each tumor utilizes for developing advanced diseases holds an unprecedented potential for effectively preventing disease from progressing. We expect that our analysis will uncover both known (AR variants and TMPRSS2:ERG fusion) and novel resistance mechanisms. Histopathological studies are being conducted in parallel for validating the spatial distribution of uncovered genetic drivers in each case. Establishment of this research framework will be essential to determining bona fide causes of various diseases from an evolutionary standpoint, which will be necessary for future precision medicine that is centered on timely and accurate clinical decision-making. This presentation will primarily be about the proposed research methodology and preliminary data will be discussed.
Citation Format: Chennan Li, Scott Wilkinson, Shana Y. Trostel, William L. Dahut, Fatima Karzai, Adam G. Sowalsky. A novel systemic methodology for mapping the clonal architectures of human prostate tumors that develop resistance to androgen receptor (AR)-targeted therapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B010.