Co-Occurrent Mutations in Chromatin Regulators Define Genetically Distinct Forms of Cancer
Abstract
We address the Fiscal Year 2015 (FY15) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of Genetic Cancer Research and Liver Cancer and the FY15 PRCRP Military Relevance Focus Area of Militarily relevant risk factors associated with cancer. In addition, the approach we suggest may be applicable with only slight modification to several other PRCRP Topic Area cancers. Rationale: Cancer is a disease characterized by genetic changes. Different combinations of mutations lead to different tumors even in a single tissue. Precision therapies are predicated on finding drugs that are effective for tumors with a specific mutation or mutations. However, each tumor has many mutations and identifying which combinations of mutations cause the tumor to form and which can be targeted remains challenging. The process of identifying mutations that drive tumor formation, creating mouse models of these tumors, and then finding therapeutic targets is time-consuming. However, methods to address each of these steps exist. The laborious nature of this process has resulted in few models for many cancer types, usually based on only the most commonly mutated tumors. Increasing the speed of translating genetic information about tumors into therapies is a major challenge for cancer research and precision therapeutics. Our approach is to use catalogs of tumor mutations to guide design of many new cancer models. Using new genome-editing techniques, we can more rapidly apply this approach, enabling us to study to many more mutations. Only by increasing the scale of these studies can we hope to understand how different combinations of mutations cause tumors and to create new therapies specific to different combinations of mutations. Applicability: The goal of the proposed research is to improve our understanding of what mutations drive liver cancer and how different genetic mechanisms for tumor formation can be precisely targeted. The techniques and principles we propose have been previously used successfully, and recent advances in our ability to edit the genome of mice will allow us to greatly expand the number of mutations we can test. This is important so that we can select many less frequent mutations, or pairs of mutations, that overall may not be the most frequent but may be important for a particular patient s tumor. Because over 24,000 people a year die of liver cancer, mutations present even in 3% of those tumors affect over 700 patients each year. To target mutations for all patients, we need to improve the rate at which determine how mutations cause cancer and identify new targets specific to each type of mutation. Our work is a focused effort to create a preclinical pipeline to prioritize the co-occurring mutations, develop and characterize models based on these mutations, and find therapeutic targets to which each model is vulnerable. Once these targets are identified, we can then identify current drugs that target the identified pathway, or if needed find new drugs, to target these tumors. Currently, only the most frequent mutations are examined using this approach due to the long time it takes to create mouse models with mutations in multiple genes using traditional breeding methods. Our approach is to directly create mutations in the liver in a single step using new genome-editing techniques to more rapidly create these models. We expect in the 2-year period of this grant to examine nearly 50 mutations in cell-culture models and 10 pairs of mutations in animals. This enables us to explore the mechanisms of tumor formation at a scale 5 to 10 times greater than is commonly done. We expect this approach can accelerate the time needed to identify new therapeutic targets based on somatic mutations from a particular tumor. Relevance to Military Population: Rates of liver cancer and deaths from liver cancer have been rising in both the civilian and military populations. Liver cancer is specifically el
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610233
Entities
People
- Terry Magnuson
Organizations
- United States Army
- University of North Carolina at Chapel Hill