Clinical and Biological Insight into MAPK Signaling and Tumor Heterogeneity Using Circulating Tumor Biomarkers
Abstract
Metastatic prostate cancer can be caused by a variety of changes in the original cancer cells. Understanding this variability will be critical to predicting response to newer therapies for prostate cancer. However, resistance has been reported to develop even to these newer therapies, and understanding how this resistance occurs will be very important clinically in order to better predict which patients will have maximal response. In advanced cases of prostate cancer, small quantities of cells will break off from the tumor and travel through the bloodstream. These cells, called circulating tumor cells (CTCs), are thought to contribute to progression of prostate cancer and may be the source of cells that cause spread (metastasis) of the cancer. We have developed a new technology for isolating these prostate CTCs from the blood of patients with metastatic prostate cancer, which we call the Vortex Chip. These CTCs hold promise for exploring variability in prostate cancer because it is much easier and less painful to serially collect blood samples and study the collected cancer cells than to perform invasive biopsies every few weeks. The Vortex Chip will allow us to monitor response to different prostate cancer treatments by following CTC count before, during, and after treatment. We will also isolate individual CTCs and analyze these to determine if any new mutations have occurred. Simultaneously, we plan to sample the original primary and metastatic prostate cancer tumors from matched patients and compare the results from the CTCs to these solid tumors. We are also planning to test a new therapy (MEK inhibitors trametinib or cobimetinib) for treatment of drug-resistant metastatic prostate cancer. These MEK inhibitors were initially developed for melanoma but animal studies strongly suggest that some patients will have a good response to MEK inhibitors. We also have data from a couple of patients who have received trametinib and have shown excellent response. We plan to treat additional patients with MEK inhibitors and simultaneously study their response to identify those who respond well versus those who become resistant. We hope that the proposed studies will allow us to better understand the variability in metastatic prostate cancer and may help us to design improved treatments for future patients. This work will help all patients with prostate cancer, but particularly those with advanced or metastatic disease. These studies will help us to better predict those who will have good response to MEK inhibition and we hope that in 3-4 years, patients will directly benefit as we may be utilizing MEK inhibition as an option for treating patients with metastatic prostate cancer. The training and research in this proposal will help me to attain my goals of becoming a physician-scientist focused on prostate cancer with an active research program to translate lab advances directly towards clinical questions. The training program includes specialized research training in prostate cancer biology and genetics in the laboratory of Dr. Matthew Rettig, a well-renowned prostate cancer researcher at the University of California, Los Angeles. This research training will be combined with coursework and methods in clinical research under guidance of Dr. David Elashoff, an expert in clinical trial design and biostatistics. The research plan, which consists of an innovative translational project to bridge the gap between the clinic and the bench using Vortex Chip to isolate and analyze CTCs, is well integrated into the training plan. Overall, the research and training will allow me to develop expertise in prostate cancer biology and in translating lab advances to the clinic, with the ultimate goal of reducing deaths from prostate cancer. Overall, the proposed project will be highly applicable towards patients with advanced prostate cancer by validating use of CTCs as a noninvasive marker to understand how tumors evolve i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710098
Entities
People
- Rajan P Kulkarni
Organizations
- United States Army
- University of California, Los Angeles