Evaluating Heterogeneity and Response to Treatment in Melanoma Using Circulating Tumor Cells
Abstract
Metastatic melanoma 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, particularly PD-1 immunotherapy. However, resistance has been reported to develop, and understanding how this resistance occurs will be very important clinically in order to better predict which patients will have maximal and sustained response. In advanced cases of melanoma, 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 cancer and may be the source of cells that cause spread (metastasis) of the cancer. We have developed a new technology for isolating these CTCs from the blood of patients with advanced melanoma, which we call the Vortex Chip. These CTCs hold promise for exploring variability in 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 melanoma treatments by following CTC count before, during, and after treatment. We will also isolate individual CTCs and analyze these to determine if any changes in the tumor have occurred. Simultaneously, we plan to sample the original primary and metastatic tumors from matched patients, and compare the results from the CTCs to these solid tumors. We are planning to monitor treatment response in patients receiving PD-1 inhibitor treatment, an immune modulatory treatment that has shown promise in 30%-40% of cases, but reasons for treatment failure are unknown. We hope that the proposed studies will allow us to better understand the reasons for treatment failure, both primary failure (when the drug never works) or secondary failure (when the drug stops working after an initial period of response). We also hope that the proposed studies will allow us to better understand the variability in melanoma and may help us to design improved treatments for future patients. This work will help all patients with melanoma, but particularly those with advanced or metastatic disease. These studies will help us to better predict those who will have good and sustained response to PD-1 inhibition and to identify treatment failures earlier so that alternate treatments can be started. The training and research in this proposal will help me to attain my goals of continuing as a physician-scientist focused on melanoma and immunotherapy with an active research program to translate lab advances directly towards clinical questions. The training program includes specialized research training in the laboratory of Dr. Dino Di Carlo, a well-renowned bioengineer and cancer researcher at the University of California, Los Angeles. This research training will be combined with coursework and methods in clinical research and guidance of secondary mentors Drs. Delphine Lee, Steven Dubinett, and David Baltimore. 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 melanoma biology and immunotherapy and in translating lab advances to the clinic, with the ultimate goal of reducing deaths from melanoma. Overall, the proposed project will be highly applicable towards patients with advanced melanoma by validating use of CTCs as a noninvasive marker to understand how tumors evolve in response to treatment, and will help us to better understand resistance to immunotherapy, which may be directly useful for guiding patient treatment in the next 3-5 years. These studies will help us better understand the mechanisms of immunotherapy resistance in melanoma and may help identify new
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710514
Entities
People
- Rajan P Kulkarni
Organizations
- United States Army
- University of California, Los Angeles