Understanding Molecular Mechanisms of Secondary Resistance in Patients with Metastatic Castrate-Resistant Prostate Cancer
Abstract
Objective and Rationale: One of the fundamental ways to slow down the progression of prostate cancer in men is to reduce the action of androgens, such as testosterone, on prostate cancer tissue. Certain drugs directly reduce androgen levels, while others, such as bicalutamide (Casodex), prevent androgen action on its receptor. However, even with these “androgen-deprivation” therapies, a proportion of cancers escape and progress; this phenomenon is termed “primary resistance.” To counteract this resistance, a second generation of anti-androgen therapies, namely enzalutamide (Xtandi), apalutamide (Erleada), darolutamide (Nubeqa), and abiraterone (Zytiga), has emerged over the last decade. While each drug effectively overcomes primary resistance, all tumors finally escape and progress. Such “secondary resistance” currently poses a major clinical challenge, as patients rapidly follow a downhill course. The paucity of our understanding of mechanisms that underpin resistance has prevented us from developing new therapies. Mouse and cellular models have highlighted molecular pathways; however, not all are applicable to the prostate cancer patient. The focus of this study is therefore to understand the genetic and molecular events that lead to secondary resistance at the level of each individual patient. We will therefore obtain biopsy tissue from 20 patients with lethal prostate cancer using state-of-the-art radiology called molecular imaging. We also know that the cellular composition of biopsy tissue is not homogenous; this requires that we use technologies such as single cell gene sequencing to measure the expression of cancer-associated genes at the level of each single cell. We will then use computational tools to understand which genes are potential drivers of the cancer and, importantly, of secondary resistance. Furthermore, by reconstructing the cellular architecture in three-dimensional cultures termed “organoids,” we will manipulate target genes and study effects on cancer progression. In all, we expect to identify and characterize novel targets that could be interrogated by new drugs to overcome secondary resistance. Applicability and Contributions: The number of deaths due to lethal prostate cancer for 2020 is estimated at 33,330, accounting for 5.5% of all cancer-related deaths. Most of these deaths occur as a result of cancer progression due to secondary resistance, which would also reflect mortality in our older Veteran population where prostate cancer is the most common cancer diagnosis. This proposal will utilize a composite of cutting-edge tools (molecular imaging, single cell gene sequencing, and organoids) to hone in on potential genes and molecules that drive secondary resistance. Our studies will thus provide a solid framework for developing new therapies to fight secondary resistance and its invariably lethal consequences. Furthermore, our collection of well-characterized, patient-specific organoids will serve as a resource for screening future drugs. Finally, and importantly, the robust “imaging–sequencing–organoid” platform that we have established should help inform personalized interventions toward even better outcomes in patients with advanced prostate cancer. Principal Investigator Career Goals: Unlike many other cancers where drug discovery has been relatively stagnant, a remarkably robust portfolio of drugs for prostate cancer has emerged in recent years. It is, however, intriguing that these notable advances have created both clinical and biological challenges, mainly relating to drug resistance. There has thus been reinvigorated interest in probing mechanisms that underpin resistance in prostate cancer, particularly within Dr. Charles Sawyers’ laboratory. My rigorous clinical training and research experience at both the dry and wet bench underscore my ability to use cutting-edge technologies to interrogate resistance mechanisms not only at the individual patient level, bu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110043
Entities
People
- Samir Zaidi
Organizations
- Sloan-Kettering Institute
- United States Army