Authors:
Lara F Tshering, Fu Luo, Nam D Nguyen, James G Rail, Ting Jin, Daifeng Wang, Flaminia Talos
 
 
 Affiliations:
 Stony Brook University
 
 
Abstract Body:
Prostate cancer (PCa) is one of the most common cancers in men worldwide and a leading cause of cancer-related mortality. Though PCa is known to be substantially heterogeneous at the molecular and histological level, there is still little understanding of the tumor subpopulations (“clones”) generating this intratumor heterogeneity (ITH) and their underlying clonal dynamics and interactions. The impact of ITH on disease outcome remains unknown and is thus a significant hurdle in treatment of PCa. This barrier is especially evident in progression to castration resistance: after initial androgen dependence, subpopulations that are castration resistant and less dependent on androgens emerge to populate the tumor, contributing to disease progression. The introduction of second generation androgen deprivation therapies has shown some success in treating castration resistant prostate cancer (CRPC), but eventually drug resistant clones emerge and the disease recurs. Understanding the fundamental differences––both phenotypic and genomic––between clones may hold the key to improving therapies, preventing disease progression, and prolonging patient survival. Using a multi-omics approach, we are exploring the dynamic changes in these subpopulations during progression to castration and drug resistance, focusing on the differences between clones at the transcriptomic and genomic level. Thus far, we have developed a mouse model of CRPC with the multicolor Confetti reporter, allowing for spatial distinction between different clones. Using single cell sequencing and RNAseq, we have mapped the evolution of early-stage clones post-castration and identified pathways and gene regulatory networks that potentially grant specific clones their castration resistant phenotype. We have extended our system to in vitro 3D organoid cultures to study the evolution of these clones longitudinally during treatment with the antiandrogens enzalutamide and abiraterone acetate, developing a drug resistant in vitro model of CRPC. We are currently using our organoid system to identify novel drug resistance mechanisms in order to target advanced CRPC, which until now has been considered untreatable and lethal. By characterizing clonal dynamics during disease progression, our studies provide new mechanistic insights for identifying pre-existing high-risk clones with drug resistant phenotypes in PCa and uncovering novel therapeutic targets in CRPC. Our work has implications for designing new therapies aimed to control the emergence of advanced disease, preventing CRPC and drug resistance, with the intention of reducing mortality and improving prognosis.
 
 
 Funding Acknowledgments:
 N/A
 
 
 Corresponding Author Email:
 flaminia.talos@stonybrookmedicine.edu
 
 
 Conflict of Interest:
 Nothing to Disclose

Intratumor heterogeneity and clonal dynamics underlying treatment resistance in prostate cancer