Role of Rac-GEFs in Prostate Cancer Metastasis
Abstract
Despite improvements in the treatment for prostate cancer, it still remains one of the leading causes of cancer-related deaths in men worldwide. This is largely due to the progression of the disease to a “hormone refractory” or “castration-resistant” state. The work I am proposing focuses on prostate cancers that are in this aggressive and hard-to-treat state, with a goal of identifying new therapeutic targets and/or diagnostic markers. The proposed work centers on the protein, Rac1, and its hyperactivation in aggressive prostate cancer. This protein is a binary switch that exists in either an active “on” state or inactive “off” state. In its active state, Rac1 is bound to GTP and regulates the rearrangement of the cell cytoskeleton to drive cell movement. It is, therefore, an essential component required for cells to migrate, invade, and ultimately metastasize. Interestingly, my preliminary results have revealed that, in aggressive androgen-independent prostate cancer cells, Rac1 is markedly hyperactivated, whereas normal prostate cells or less aggressive prostate cancer cells have low levels of active Rac1. Therefore, based on these attractive results, I hypothesize that Rac1 hyperactivation in aggressive prostate cancer is due to enhanced “inputs” from Rac-Guanine nucleotide Exchange Factors (Rac-GEFs), which are proteins that are responsible for facilitating the activation of Rac1. It is possible that one or more of these Rac-GEFs is/are expressed at abnormally high levels or is/are unusually active (e.g., mutated) in aggressive prostate cancer. In order to tackle this problem and address this very important aspect of prostate cancer progression, I am proposing a screen using stable knockdown of these genes, in conjunction with an assay that measures the amount of active Rac1, to identify the Rac-GEF responsible for this hyperactivation. This is necessary because there are many Rac-GEFs in the genome, and the expression of these proteins in prostate cancer is only partially known. Once I have identified the Rac-GEFs responsible for the Rac1 hyperactivation status, I will investigate how these proteins control prostate cancer cell migration, invasion, and metastasis, particularly to the bone, which is a main site of prostate cancer cell metastasis. Our hypothesis is that at least one Rac-GEF is responsible for Rac1 hyperactivation and therefore drives the metastatic potential of these aggressive prostate cells. The identification of this mechanism will have important implications, particularly from a therapeutic standpoint, as there are drugs currently under preclinical evaluation that target Rac-GEFs/Rac and have anti-tumorigenic and anti-metastatic effects, including in prostate cancer. Therefore, my research has the potential to be translated to patients with advanced stages of disease. Addressing the relevance of the Rac-GEF/Rac pathway in advanced prostate cancer is a challenging project. However, I believe that my previous training, as well as my current position, presents the perfect opportunity to tackle this problem. My graduate research provided me with an in-depth knowledge and expertise of the Rac signaling pathway, yet I was not fully exposed to prostate cancer research or cancer research in general. My present post-doctoral training in the laboratory of Dr. Marcelo Kazanietz, a world leading cancer researcher, is providing me with incredible opportunities and training in prostate cancer research. In conjunction with my mentor, we have developed a comprehensive training plan, which is explained in great detail in the application. This not only includes learning fundamental prostate cancer techniques, but also attending seminars and conferences, including those organized by the Philadelphia-based Prostate Cancer Working Group (http://phillyprostate.org), and presenting my data in national prostate cancer and general cancer meetings. Consequently, this Department of Defense award, if
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810274
Entities
People
- Martin J Baker
Organizations
- United States Army
- University of Pennsylvania