Elucidate the Mechanism of Telomere Maintenance in STAG2 Mutated Tumor Cells
Abstract
Career Goals in Cancer Research: My goal is to establish a cancer research lab in an academic setting where I would study how mutations of specific genes contribute to cancer. To reach my goal, I have successfully completed the required coursework, and now I am completely dedicated to research. Obtaining the Horizon Award will be a perfect platform for me to start my career in the cancer research field, and it will help me achieve my career goal. It will permit me to go forward with my research project in genetic cancer research to investigate tumors that have a specific mutation in the cohesin subunit STAG2 and to develop strategies to target these tumors in cancer therapy. My work will be relevant to the Fiscal Year 2015 Military Focus Areas of genetic cancer research as well as pancreatic cancer and melanoma, where STAG2 tumors are found. My research development plan will allow me to broaden my horizons and gain new insights in the cancer field. I regularly attend the seminar series organized by the New York University (NYU) Cancer Center. Also, I regularly attend the New York Academy of Sciences Genome Integrity discussion meetings. Next year I plan to attend and present my work at a cancer conference. I will receive intellectual guidance and the technical training necessary to fulfill this project from my mentor, Dr. Smith, as well as the senior postdocs in our lab. Any equipment needed for different laboratory techniques is available in the Skirball Institute, where our lab is located, and also in the other facilities of the NYU medical center. Scientific Objective/Rationale: Telomeres are repetitive sequences found at the ends of the chromosomes. Telomeres shorten with each cell division, and very short telomeres will prevent cells from dividing and can lead to cell death. Cancer cells, in order to keep dividing, have developed a way to elongate their telomeres. They can elongate their telomeres either by upregulating an enzyme called telomerase that adds telomeric repeats or they can activate a recombination-based mechanism to elongate their telomeres. Most cancer cells use one or the other, but not both. The telomere maintenance mechanism is a promising target for cancer treatment. The Smith lab has recently demonstrated that cancer cells that utilize recombination to elongate their telomeres have defective telomere cohesion. Targeting the telomere cohesion results in rampant recombination and cell death, indicating this pathway as a target of cancer therapy. Since I joined the Smith lab, I started working on the STAG2 protein, which is important for maintaining chromosome cohesion and is frequently mutated in cancer. To address the role of STAG2 mutations in cancer, we obtained a panel of STAG2 mutated cancer lines. My preliminary analysis indicates that STAG2 cancers have persistent telomere cohesion and high levels of telomere recombination similar to cancer cells that utilize recombination to elongate their telomeres. Interestingly, these same STAG2 tumors have detectable telomerase activity. I will determine the mechanism by which STAG2 mutated cancers elongate their telomeres and will target that mechanism to promote STAG2 tumor cell death. Overall, this study will provide new insights into the telomere maintenance mechanism of STAG2 mutated tumors and will reveal new therapeutic approaches for cancer treatment. How the Research Will Benefit Active Duty Service Members, Their Families, and Other Military Beneficiaries: Cancer impacts the quality of life for active duty Service members, their families, and the American public. Due to exposure to ionizing radiation, chemicals, and environmental carcinogens, military personnel are at particularly high risk for DNA damage that can lead to increased gene mutations and promote cancer formation. Gene mutations are thought to be central to cancer formation and development. In this study, we will address how tumors carrying mutations in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610590
Entities
People
- Zharko Daniloski
Organizations
- Grossman School of Medicine
- United States Army