Coordinated Roles of SPOP Mutation and CHD1 Deletion in Prostate Cancer Pathogenesis
Abstract
Objective and Goals: Prostate cancer is a collection of multiple disease variants, each of which is defined by specific genetic alterations. This project is focused on understanding one such variant or subclass, which represents 15% of all primary prostate cancers. This subclass is characterized by alterations in two genes: SPOP and CHD1. Of the estimated 180,890 cases of prostate cancer that will be detected in 2016, roughly 22,000 men will carry these genetic alterations. Although this subclass of the disease was identified in 2012, there have not been tremendous strides in better understanding the disease. Additionally, effective therapeutic strategies (with higher response rates and lower resistance) that patients in this subclass would benefit from are unknown. Expected Results: With the proposed work, we will develop novel genetically engineered mouse models to recapitulate disease characteristics observed in humans. Currently, no models of primary prostate cancer exist that harbor genetic alterations in SPOP and CHD1 genes as they occur in human disease. Therefore, our mouse models are unique to our laboratory and will be valuable tools to the prostate cancer scientific community. In addition, we will also culture mouse prostates in the lab to examine which cellular proteins and pathways are changing most to drive this disease. This can be achieved by performing genome-wide sequencing and subsequent computational analysis. My co-investigator on this proposal, Dr. Sboner, is a computational expert who has made extensive contributions in national and international prostate cancer core groups. Prostate cells depend on steroid hormones, called androgens, for survival and growth. Androgens bind to a protein called androgen receptor (AR), which then activates several genes that enable prostate cell survival and growth. When AR becomes hyperactive, it causes prostate cancer. Therefore, the first line of therapy in prostate cancer is to mediate androgen deprivation to subsequently reduce AR activity. However, in aggressive prostate cancer, the cell is no longer dependent on AR for growth and survival and hence is resistant to androgen deprivation therapy (ADT). From our preliminary data, it appears that the SPOP/CHD1 subclass of prostate cancer is, in fact, highly dependent on AR for growth. Therefore, our studies will investigate whether ADT is an effective line of therapy in these cancers. Should ADT not work in our model systems, the sequencing data will help reveal additional pathways that are driving the disease. This will allow us to focus our efforts on inhibiting alternate pathways to check if we are able to achieve therapeutic efficacy. At the end of the 2 years of the proposed work, therapies that work best in our mice and cell lines can be tested in the clinic. Contributions to Clinical Development and the Field of Prostate Cancer Research: Our lab has developed tests that can detect alterations in the SPOP/CHD1 genes, which can be used for specifically diagnosing this subtype in patients and applying therapeutic approaches identified in this project. This will be highly beneficial to the patient since he will receive treatment with the highest likelihood of improved outcomes and lowest chance of resistance. Trials can be designed to determine whether patients receiving systematic diagnosis and personalized therapeutic approaches have better response rates compared to patients who do not (timeline: 2-3 years). In this way, we will greatly enhance the use of precision medicine in guiding treatment approaches. Data generated from the sequencing studies will help us better understand how one of the largest subclasses of prostate cancer develops in men. Additionally, results from this project will be important to the community as a whole in providing knowledge for the development of mouse models to recapture other prostate cancer subclasses. It will also disseminate knowledge about ho
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710385
Entities
People
- Divya Vasudevan
Organizations
- United States Army
- Weill Cornell Medicine