Clinical Identification and Targeting of Non-Neuroendocrine Lineage Plasticity in Castration-Resistant Prostate Cancer
Abstract
Untreated prostate cancer is characterized by dependence on a set of proteins called androgen receptors. Hormonal therapy that abrogates testicular testosterone production has been the centerpiece for treatment of advanced prostate cancer for over 75 years. However, most patients progress to a cancer stage that is resistant to hormonal therapy, and many of these patients do not depend on androgen receptors anymore. We have recently identified a group of such tumors that constitute a novel subtype of prostate cancer. Our calculations show that 30% patients with advanced metastatic prostate cancer that is resistant to hormonal therapy belong to this subtype, called stem-cell-like. We have also identified a set of proteins that drive the growth of these tumors. These proteins, FOSL1, TEAD, YAP, and TAZ, become overly active and alter the state of tumor cells to drive their growth. In this proposal, we will test the impact of clinical grade small molecule inhibitors of an important protein in these stem-cell like tumors, TEAD, in in vitro and in vivo studies. We will also develop computational methods to identify prostate cancer patients whose tumors belong to this subtype in a non-invasive manner using their plasma samples. By sequencing the DNA of tumors from this subtype, we will identify the genetic drivers of the growth of such tumors. If successful, the results of this proposal will pave the way for clinical trials of TEAD inhibitors to treat tumors of this subtype. The computational method developed for clinical identification of patients with tumors of this subtype will be validated in larger patient cohorts and, if it shows high sensitivity and specificity, can be translated to the clinic in a relatively short term. If we identify new genetic drivers from this proposal, the next steps would be to perform their functional validation and they may reveal novel proteins for targeted therapy of such tumors, while also helping their clinical identification. This proposal will help men with advanced prostate cancer by revealing the biology of lethal prostate cancer and it will help develop treatments that improve outcomes for men with lethal prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310074
Entities
People
- Ekta Khurana
Organizations
- United States Army
- Weill Cornell Medicine