Understanding Molecular Mechanisms of Secondary Resistance in Patients with Metastatic Castrate-Resistant Prostate Cancer
Abstract
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 antiandrogen 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. During the award period, we have obtained biopsy tissue from 24 patients with lethal prostate cancer using state-of-the-art radiology called molecular imaging. As we know that the cellular composition of biopsy tissue is not homogenous, we have used technologies, such as single cell gene sequencing, to measure the expression of cancer-associated genes at the level of each single cell. We have employed computational tools to understand which genes are potential drivers of the cancer and, importantly, of secondary resistance. We have identified that JAK/STAT and FGFR signaling is critical mediating resistance through a process known as lineage plasticity where cancer cells alter their identity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2023
- Accession Number
- AD1205888
Entities
People
- Samir Zaidi
Organizations
- Memorial Sloan Kettering Cancer Center