Developing Mouse Models of Stomach Cancer with CRISPR/Cas9 Technologies and Environmental Exposures
Abstract
This proposal addresses the Peer Reviewed Cancer Research Program Topic Area of Stomach Cancer and the Military Relevance Focus of military-relevant risk factors for cancer. Stomach cancer is an incredibly lethal disease that kills over 700,000 people every year across the world. There is a great and urgent need to develop new therapies for this disease and to advance our basic research into its underlying biology. The overarching goal of this proposal is to develop new, powerful mouse model systems that can be used to study stomach cancer in the research laboratory. Generation of these new mouse models will provide a new set of tools to dramatically empower the stomach cancer research community, greatly expanding our ability to test new therapies, to investigate stomach cancer biology, and to understand how the chemical/infectious hazards that military members are exposed to can contribute to cancer formation. Therefore, this research has the potential to help all patients with gastric cancer by allowing the field to have better models for testing therapies. These models will also help investigators develop methods to screen and prevent these cancers and further provide benefit to investigators studying how chemical and infectious exposures collaborate with DNA mutations to cause stomach cancer. One key way that we have worked to increase our understanding of stomach cancer in recent years has been to investigate how the genome (or DNA) is mutated in stomach cancers. We know that a key reason that cancers form is that individual cells accumulate DNA mutations leading to activation of key growth-promoting genes and inactivation of growth-suppressing genes. As we learn which genes are commonly mutated in gastric cancers, we can learn how stomach cancers develop and how cancer cells differ from normal cells of the body. Moreover, finding which genes are turned on by gene mutations helps us find therapeutic targets for new generations of treatments. However, merely finding the broken genes in stomach cancer is not enough. Once we discover the genomic mutations, we must take these results into the laboratory to study how these mutant genes act to promote stomach cancers and how we can effectively try to treat tumors with these particular gene mutations. To do this work, we need models of stomach cancer that we can study in the laboratory. Lack of effective model systems for stomach cancer remains a major barrier to our field. In many other tumor types, an extremely powerful system for studying cancers in the laboratory has been the use of genetically engineered mouse models, mice that are designed so that gene mutations found in cancer are placed into the cells of a particular tissue of the mouse so that the mouse develops cancers that resemble human disease. These models are extraordinarily valuable for testing new therapies and for investigating tumor biology. In this proposal, we aim to dramatically advance our capability to develop new mouse models of stomach cancer. The traditional methods to develop mouse models of cancer are extremely cumbersome, time-consuming, and expensive. Fortunately, there are new revolutionary technologies that have been developed in recent years that have the capacity to dramatically speed our ability to produce mouse models of cancer, including gastric cancer. For diseases such as gastric cancer that have many different DNA mutations, these new technologies are especially essential as they would allow us to flexibly develop models with the different genetic lesions that are present across human tumors. These methods can also be combined with studying effects of chemical exposures on tumor formation, thus providing tools that can help study military-related toxic exposures. During the time of this award, we anticipate that we can optimize these new systems for making mouse models of stomach cancer. These models can then be rapidly adopted by researchers across the field,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610238
Entities
People
- Adam Bass
Organizations
- Dana–Farber Cancer Institute
- United States Army