Mechanisms and Therapeutic Targeting of NSD2 in Advanced Prostate Cancer
Abstract
The prostate is a unique organ in its dependency from androgen receptor activity for its growth during development and in almost all stages of prostate cancer progression. That discovery is the basis for the longstanding treatment in prostate cancer targeting the synthesis of testosterone (the hormone binding the receptor) or the receptor itself. These treatments, together with early detection programs, better surgeries, and improved chemotherapies and radiotherapies, have resulted in impressive improvements in the prognosis and survival of prostate cancer patients. However, despite the advances, prostate cancer remains the most diagnosed and the third leading cause of cancer-related mortality among men in the United States. This evidences the fact that standard-of-care treatments are not curative in many cases and that, for a significant number of patients, tumors eventually progress to aggressive forms that are highly metastatic. These aggressive tumors undergo a process of loss of identity and evolution toward an androgen receptor independent state that is inherently treatment-resistant. Fortunately, genome sequencing for personalized medicine is rapidly evolving. Today, we have an accurate picture of the landscape of mutations occurring in prostate cancer, including how they appear and select in the most aggressive forms. The challenge ahead is to distinguish the true driver mutations and the “Achilles heels” that represent cancer vulnerabilities in the acquisition of the androgen-independent state. The ultimate goal is to use those newly identify vulnerabilities as therapeutic targets in combination treatments. Preliminary data from our laboratory have identified a new potential target for prostate cancer therapy. Our proposal aims at utilizing sophisticated genetically engineered mouse models of prostate cancer, computational biology approaches, and genome editing tools to identify and validate new molecular targets in prostate cancer. We will test the therapeutic benefice of the inhibition of these targets in cancer models carrying mutations in well-known drivers of androgen independence. We aim at also understanding the underlying biology that explains how these new targets drive prostate cancer aggressiveness and whether they can be exploited as predictive biomarkers. Our excellent training in cancer biology and translational research at world-class institutions like Columbia University; our close collaboration with patients advocate groups such as The Prostate Net, UsToo, or the Movember Foundation; and the outstanding group of collaborators engaged in this proposal ensure that results and discoveries will be translated to clinical settings shortly after completion. We strongly believe that this project can provide the required preclinical data to immediately move the identified and validated drug targets to clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810193
Entities
People
- Alvaro Aytes
Organizations
- Catalan Institute of Oncology
- United States Army