Targeting BRCAness in Gastric Cancer
Abstract
Scientific Objective and Rationale: Cancer of the stomach, a 2015 Peer Reviewed Cancer Research Program Congressionally Directed Topic Area, remains to be a significant treatment challenge. In the United States, 24,500 new cases are diagnosed each year, and nearly half of the patients eventually die from the disease. Therefore, new treatments are urgently needed. With this proposal, we will pursue one very promising avenue of research that could lead to the development of highly active therapies. This is based on the recognition that in many cases, stomach cancer cells are not fully able to repair damages sustained to their DNA. Members of our team have previously demonstrated that this weakness of this type of stomach cancer cells can be attacked with drug known as PARP inhibitors that further disable the ability of a cancer cell to repair its DNA, resulting in death of these cells while normal cells remain unharmed. We have designed a clinical trial (expected to start enrolling patients in early 2016) that tests the treatment effects of such inhibitor in combination with chemotherapy. Tumor samples from patients obtained as part of this trial will be available for analysis as part of the following proposed studies: (1) Finding features within the tumor DNA that make such tumors particularly sensitive to PARP inhibition. Such features will allow us to better select patients for this treatment approach in the future therefore improving our ability to match patients with treatments. This will reduce the chance of patients receiving ineffective treatments that can cause significant side effects and are associated with high costs. (2) Identifying new ways by which the repair of DNA is regulated within cancer cells. This knowledge will allow us to design new and more efficacious drug combinations. (3) Characterizing immune cells within stomach cancers and their relationship to the cell s ability to repair DNA. This part of this proposal is based on the recent discovery of drugs that can make cancer cells "visible" to the immune system. Studies in stomach cancer patients show that about one-third of the patients might benefit from such treatment. Importantly tumor cells harboring many mutations in their DNA are particularly easily detected and attacked by immune cells. We therefore expect that stomach cancer cells lacking the ability to repair their DNA will harbor many mutations and should therefore be particularly good targets for this type of immune therapy. We will test this possibility by analyzing the genetic makeup of immune cells in the tumor. Applicability of Research: Overall, successful completion of these studies will allow us to design the next generation of treatments for stomach cancer that are personalized, have a greater anticancer effect, and are associated with fewer side effects. We expect that patients with advanced stomach cancers will particularly benefit from this innovation. However, information resulting from our studies can also be used to devise treatments that reduce the chance of tumor recurrence after surgery and even to prevent cancer from developing in patients at high risk for the disease. We have previously shown that discoveries from our research can be taken into clinical application rapidly. For example, it took approximately 2.5 years from the original publication by Dr. Ashworth s group showing that inability of a tumor to repair DNA should result in susceptibility to PARP inhibition to initiation of a clinical trial. Similarly, findings from Dr. Korn s laboratory were translated into a clinical trial within 3 years since first publication. Furthermore, Drs. Korn, Collisson, Fong, and Janjigian are all physician scientists experienced in the design and conduct of clinical trials. Therefore, we expect that any findings from these studies can be tested clinically very quickly. Military Relevance and Impact: Military personnel are exposed to an increased r
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610473
Entities
People
- Alan Ashworth
Organizations
- United States Army
- University of California, San Francisco