Elucidating the Mechanism of RET Kinase Activity in Neuroendocrine Prostate Cancer
Abstract
Scientific Objective: Currently, one in nine men will develop prostate cancer in his lifetime. Improved screening and earlier diagnosis, combined with new treatment therapies, have increased the prognosis for many men. Unfortunately, after undergoing treatment, many men develop recurrent prostate cancer that no longer responds to the therapies we have available. Some of these tumors, including neuroendocrine prostate cancer (NEPC), which is the focus of this grant, no longer express androgen receptor and have developed characteristics of other tumor types that are not typical of the prostate. This includes RET, a tyrosine kinase, which is important in cells with neuronal characteristics. Clinical trials have tested multi-tyrosine kinase inhibitors in prostate cancer, but they have not shown significant effectiveness. However, these trials did not differentiate adenocarcinomas from NEPC, and multi-tyrosine kinase inhibitors target multiple kinases that may or not be activated in NEPC and can result in side effects. In this proposal, we will address these issues by employing genetic techniques to reduce levels of RET kinase, directly determine whether RET kinase is important to NEPC growth, and define how the protein becomes activated in NEPC. In addition, we will determine how tumors become resistant to selective RET kinase inhibitors in this setting and test the ability of combination therapies to block the formation of resistance. Research Applicability: This research will help men who develop recurrent prostate cancer that has neuroendocrine characteristics. Currently, this type of recurrent tumor affects approximately 15% of men harboring recurrent prostate cancer, but its incidence has been increasing over the last few decades. Unfortunately, survival times after NEPC diagnosis remain very short. There is a desperate need for effective treatment options to address this type of cancer. Our research will define key molecular pathways that allow these tumors to grow aggressively. The target of this grant, RET kinase, already has clinically approved inhibitors that could be used to treat these tumors; however, we still do not know whether it is an important target in NEPC or have a way to accurately determine which patients would benefit from RET inhibition. While this proposal focuses on basic science research, defining how this kinase contributes to NEPC tumor growth will inform the design of clinical trials within the next 2-4 years with already available drugs and help identify which patients would benefit from these drugs. Career Goals: My career goal has always been to improve the lives of people who are dealing with the devastating effects of cancer. This led me down a path as a basic science researcher, where I focus on understanding what happens to make a cell ignore all negative growth signals and instead proliferate uncontrollably. My graduate school research focused on understanding how a single gene, a tumor suppressor protein, regulated multiple cellular processes during viral infection. While effective, the techniques I developed were very focused, often looking at only one or two proteins or pathways at a time. Under the mentorship of Dr. Drake and Dr. Dehm, I will gain experience in mass spectrometry and proteomics, which allow us to measure and learn information about a significant portion of the proteins in a cell or tumor sample at once. This gives us a much more comprehensive understanding of the changes that take place in a tumor cell and helps us identify new targets that we would not have thought to look at initially. After my postdoc, I want to use the skills and techniques that I have gained to either become a leader of my own academic laboratory or transition to industry, where I can help the development of new therapies in prostate cancer based on the type of research in this proposal. Contributions to Prostate Cancer Research: This study will define the role of RET
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910173
Entities
People
- Halena R. VanDeusen
Organizations
- United States Army
- University of Minnesota