Effect of PTEN Loss on Combination PI3K Inhibition, Castration, and Radiation in Clinically Localized, Aggressive Castration-Sensitive Prostate Cancer
Abstract
Prostate cancer is the most common epithelial malignancy in men, representing a growing global health burden. It is a disease of aging, primarily diagnosed in older males, and effectively treated with either surgery or radiation therapy. However, a subset of men will go on to develop lethal, metastatic disease. Identifying indolent prostate cancers, which may be easily cured or not require treatment, from more aggressive disease remains challenging. In nearly half of all prostate cancers, a key gene, PTEN, is either mutated or deleted and is associated with higher Gleason scores and more advanced disease. A well-known function of the PTEN protein is to inhibit the signaling pathway activated by the enzyme, phosphoinositide 3-kinase. In the absence of PTEN, phosphoinositide 3-kinase is overactive and unregulated. We propose to investigate the effect of a phosphoinositide 3-kinase inhibitor in combination with conventional prostate cancer therapy. In particular, we are interested in patients with tumors that do not express the PTEN protein to take advantage of the resulting phosphoinositide 3-kinase activation. Phosphoinositide 3-kinase inhibitors are currently being tested against several malignancies, including prostate cancer. However, the majority of open clinical trials are assessing the effect of these agents against metastatic disease, which is largely incurable. We propose to treat localized prostate cancer to further improve survival in patients with more aggressive, yet potentially curable, disease. My personal interest is in drug development and early phase, clinical trial design. This research proposal uses novel compounds to target a well-characterized cancer pathway. We will explore the efficacy of these agents in prostate cancer cell lines and examine the effects on molecular signaling. These experiments are an excellent opportunity to better understand the tumor biology of prostate cancer. As chemotherapy becomes more targeted to specific dysregulated pathways, creating a solid foundation of knowledge about the molecular pathogenesis of prostate cancer will yield additional hypotheses for future, potential treatments. Moreover, Dr. De Marzo and our collaborator, Dr. Charles Bieberich, have pioneered the development of innovative mouse prostate cancer models, which are vital to identifying efficacious new cancer treatments. Learning how to design and analyze experiments with cohorts of animal models will complement my understanding of Phase I clinical trials in humans. If successful, our research will identify PTEN as an important biomarker that predicts response to phosphoinositide 3-kinase inhibitors when combined with hormonal therapy and radiation. This therapy will be of particular benefit to patients with localized, aggressive prostate cancers who cannot undergo surgery. The basic science of the proposal will serve as ideal training for a career as a clinician and scientist in the prostate cancer field.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510432
Entities
People
- Mark C Markowski
Organizations
- Johns Hopkins University
- United States Army