Molecular Determinants and Therapeutic Sensitivity in Testicular Germ Cell Cancers
Principal Investigator: Robert Weiss
DESCRIPTION (provided by applicant):
Testicular Germ Cell Tumors (TGCTs) are the most common cancers in young men and are composed of cells that share many functional properties with stem cells. Although many TGCTs can be effectively treated, current therapies utilize chemotherapeutics with significant acute and long-term toxicities and which are ineffective in a subset of patients with resistant cancers.
We seek to understand the genetic events that lead to the formation of TGCTs and will also investigate alternative therapies, called differentiation therapies, which may be less toxic and potentially also effective against cancers that are resistant to traditional chemotherapies. We will accomplish these aims using a genetically engineered mouse model of TGCT recently developed in our laboratory. This animal model accurately recapitulates many aspects of the human disease and will allow us to comprehensively map the genes and biological pathways whose alteration contributes to TGCT development. We also will create additional mouse models in which human TGCTs are directly implanted in mice, allowing for the direct analysis of human testicular cancers in a living host. We will use both mouse models to test the effectiveness of alternative therapies designed to target the stem cell nature of these cancers.
The knowledge gained from this work will reveal how to: 1) further improve TGCT treatment while minimizing toxicity, 2) effectively treat the small fraction of therapy-resistant TGCTs an, most importantly, 3) use the understanding of the origins and therapeutic sensitivity of TGCTs to detect and treat other cancers, including stem cell therapy-associated neoplasms as well as cancers that do not respond favorably to conventional chemotherapy.