Neuroendocrine Reprogramming in DSRCT Resistance Mechanisms and Treatment Strategies
Abstract
The proposed research addresses the following Focus Areas of the Rare Cancer Research Program: (1) Biology and Etiology, and (2) Therapy. Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma that kills more than sixty, mostly male children and young adults in the U.S. annually. One-third of these patients receive care at the M.D. Anderson Cancer Center, but no curative therapies exist, and most patients die within five years of diagnosis despite specialized multidisciplinary treatment. The EWS-WT1 fusion protein (FP), a chimeric cancer-causing protein exclusively expressed in every DSRCT patient s tumor, is not targetable. An alternative is to minimize the FP s adverse tumor-promoting effects. To achieve that goal, our lab and others have recently discovered that the androgen receptor (AR), more commonly known for its role in prostate cancer, promotes DSRCT tumor growth and survival by altering how the genetic code is transcribed into proteins that control cell behavior. Despite this exciting discovery, much remains to be determined. The precise epigenetic role of AR in DSRCT, for example, has just begun to be studied, and it remains a mystery how AR coordinates with other transcription factors (and the FP) to dysregulate cell fate. Additionally, since some DSRCTs harbor cells expressing neuroendocrine features often linked to drug resistance, it is unclear how drugs of proven value in prostate cancer will find utility for DSRCT. The current research addresses these seminal questions with three specific aims. Aim 1 uses advanced technologies to assess the individual cells that make up the entire tumor. This single-cell-based approach allows scientists to determine the cell composition of human DSRCT specimens, specifically the presence of AR+ epithelial cells (likely drug-sensitive) and AR- neuroendocrine cells (likely drug-resistant). Aim 2 delves deeply into the interactions between AR and the other proteins that affect AR function. Finally, Aim 3 performs lab experiments designed to predict whether drugs effective in treating prostate cancer might also be used to save the lives of kids diagnosed with DSRCT. Successful completion of this research is expected to lead to exciting new treatment options for adolescents and young adults battling a rare, highly aggressive, incurable cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310888
Entities
People
- Joseph Ludwig
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army