Defining the Role and Therapeutic Potential of Notch Signaling in Aggressive Prostate Cancer
Abstract
Early-stage prostate cancer is typically treated by surgical removal of the prostate or radiation therapy and is enough to treat the majority of patients long term. As prostate cancer advances, however, current treatments are less and less effective. Current treatment for aggressive prostate cancer entails use of hormone deprivation therapy along with anti-androgen therapy. This therapy is effective for a period of 2-3 years, but always results in recurrence of a currently incurable form of prostate cancer, termed “castration-resistant prostate cancer,” which is responsible for the majority of prostate cancer associated deaths. We are interested in learning the mechanisms driving this disease, with the intent of identifying new targets and novel combination therapy strategies for treatment of castration-resistant prostate cancer. Our laboratory studies the Notch signaling pathway, which is important for development and normal cell proliferation and is commonly altered in cancers, including prostate. Notch functions by cell-to-cell signaling, where a ligand from a donor cell activates the Notch receptor on neighboring cells. Activated Notch can then move to the nucleus, where it binds the DNA of its target genes and promotes increased activation of these targets. We have found that Notch expression increases in prostate cancer, corresponding to disease aggressiveness, with the highest levels occurring in castration-resistant patients. Further, Notch, when expressed with other genetic alterations commonly occurring in prostate cancer, results in development of aggressive prostate cancer, which is castration-resistant and able to metastasize to other sites of the body. This suggests that Notch plays an important role in driving the development of aggressive prostate cancer, despite understanding of the topic being currently limited. Castration-resistant prostate cancer patients would benefit from the inclusion of Notch targeting strategies in prostate cancer treatments. The overall goal of this proposal is to further the understanding of mechanisms causing castration-resistant prostate cancer in relation to Notch1 signaling as an oncogenic driver. In this proposal, we are going to study the Notch signaling pathway in prostate cancer to understand the mechanism through which Notch can drive aggressive disease, determine the requirement of Notch for tumor maintenance, and test new treatment strategies involving two types of Notch inhibitors alone and in combination with current standard-of-care treatments for castration-resistant disease. The results of this project will be directly relatable to patients with late-stage, castration-resistant, and metastatic prostate cancers by ultimately leading to new treatment strategies to extend patient life and, ideally, prevent therapeutic resistance. One of the inhibitors being tested here is a new Notch1 antibody that is currently in clinical trials for other cancers, and the application to prostate cancer would be quickly implemented within 1-2 years. Identification of new targets of Notch signaling would be further applicable to treatments down the line; however, in the interim, such identification would help prostate cancer researchers immediately understand the disease. I am excited to use this project to complete my training as a postdoctoral fellow and launch an independent career in prostate cancer research. The interests in my laboratory will revolve around development of new treatment strategies for men with aggressive prostate cancer, for which this project is perfectly designed to prepare me. I am backed by incredible support from my mentor, Tanya Stoyanova, Ph.D., who has experience in signaling mechanisms and preclinical models, and my co-mentor, James Brooks, M.D.., a surgical urologist with over 20 years in fellow mentorship and prostate cancer patient treatment. We have collectively developed a plan involving weekly meetings with each mentor to gui
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810141
Entities
People
- Meghan A Rice
Organizations
- Stanford University
- United States Army