Preclinical Studies of Signaling Pathways in a Mutant Mouse Model of Hormone-Refractory Prostate Cancer
Abstract
We have been investigating targeted therapies for the treatment of advanced prostate cancer using a genetically engineered mouse model of the disease. Based on previous studies, we performed pre-clinical studies to examine the consequences of combinatorial inhibition of these signaling pathways for prostate tumorigenesis an androgen independence. We found that combination therapy using Rapamycin, an inhibitor of mTOR, and PD0325901, a MEK inhibitor, is potently anti-tumorigenic in Nkx3.1; Pten mutant mice, particularly in contexts of limiting androgens. Furthermore, we find that these signaling pathways are coordinately de-regulated during prostate cancer progression in humans, as evident by our comprehensive analyses of their status in human tissue microarrays. Based on these pre-clinical studies in the mutant mice, and our supporting data from human prostate cancer, we propose that combination therapy targeting the Akt/mTOR kinase and Erk Map kinase signaling pathways may be effective for treatment of a broad spectrum of patients with advanced prostate cancer, particularly when used in conjunction with androgen deprivation therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2009
- Accession Number
- ADA511988
Entities
People
- Cory Abate-shen
Organizations
- Columbia University