Dysregulation of G3BPs Defines a New Subclass of Prostate Cancer
Abstract
Scientific Objective and Rationale for the Proposed Project: Messing up with androgen receptor (AR) signaling is the major problem underlying prostate cancer (PCa) progression, and agents targeting AR represent the mainstay of pharmacologic therapy for PCa. Cancer cells are found to make both GTPase Activating Protein (SH3 Domain) Binding Protein (G3BP) 1 (G3BP1) and 2 (G3BP2) proteins at abnormally high levels than normal cells. It has been reported that breast, head and neck, colon, thyroid, and pancreatic cancers all make a lot more G3BP proteins than normally needed. Cancer cells overloaded with G3BPs were shown to grow rapidly and were more powerful in invading adjacent tissues in human lung cancer and sarcomas. We found that G3BPs strongly inhibit the tumor suppressor protein SPOP (Speckle-type POZ protein). Earlier studies by my co-mentor, Dr. Mark Rubin, showed that SPOP is the most frequently mutated protein in localized PCa patients (~10%). SPOP mutation is now considered a new molecular subclass of aggressive PCa. Our recent findings demonstrated that G3BP1 is overproduced in PCa, binds to and interferes with a known function of SPOP, i.e., the ubiquitin ligase activity that adds ubiquitin to AR and sends it to the 26S proteasome for destruction. Based on published literature and our unpublished novel findings, I propose to test the hypothesis that G3BPs bind to and suppress the ubiquitin ligase function of SPOP, thereby contributing to PCa progression by altering the steady-state levels of key components in the AR signaling pathway. Ultimate Applicability of the Research: Patients with PCa, especially castration-resistant prostate cancer (CRPC) will be benefited from this proposed study. This current study is expected to reveal G3BP deregulation as a new means of inactivating the SPOP tumor suppressor, thus defining a new subclass of PCa that is independent of SPOP mutations. Our proposed study will identify a new signaling axis (G3BPs-SPOP-AR) and assess its value as therapeutic targets in PCa, especially in CRPCs. This study will provide an opportunity to design precise treatment options where G3BPs-SPOP-AR signaling axis is abnormally active. The current proposal will elucidate the relationship of G3BP1, G3BP2, and SPOP, and how they dictate the PCa stage, grade, and survivability. It is anticipated to expedite the translation of our newly defined G3BPs-SPOP-AR signaling axis into new therapeutic targets in PCa, especially in CRPC. In fact, by inhibiting G3BPs, we are expecting to recue SPOP ubiquitin ligase function and restore normal level of androgen receptor signaling output. These studies are expected to open new frontiers of PCa research and set the stage for me to develop new research programs as an independent PCa investigator. My mentor, Dr. Zhou, and co-mentor, Dr. Rubin, have been collaborating on the studies of SPOP tumor suppressor for 5 years. They have already provided large amount of effort and resources in helping me design the research proposal and collect supporting preliminary data for this proposal. They are both very supportive of my pursuit of an independent career in academia. The project is estimated to take 24 calendar months to achieve a patient-related outcome. My Career Goals in Prostate Cancer Research: In multiple ways and in a timely manner, the current research plan will support me in achieving my aims, and ultimately my overall career goal. My mentor, Dr. Zhou, is an expert in the field of cancer biology, especially in ubiquitin proteosomal system, and my co-mentor, Dr. Rubin, is a leading expert in prostate cancer biology. Dr. Zhou and Dr. Rubin will be available for daily supervision of experimentation and monthly meetings to evaluate the progress and will provide necessary advice to achieve goals as mentioned in the current proposal. Both of them will be important resource for me in establishing myself as an independent investigator actively wor
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710176
Entities
People
- Chandrani Mukhopadhyay
Organizations
- United States Army
- Weill Cornell Medicine