Epigenetic Regulation of Histone Demethylase JARID1B in Melanoma
Abstract
Career Goals: My career goal is to become an independent melanoma researcher and to cure patients with melanoma. I am a postdoctoral associate in the Department of Pathology at Yale University. This Peer Reviewed Cancer Research Program (PRCRP) Horizon Award will provide the necessary training on melanoma biology and cancer epigenetics for my career development. Emerging evidence suggests that proper epigenetic states are critical for the maintenance of cancer stem cells, which drive tumor formation, relapse, and metastasis. My current work showed that deletion of the histone demethylase JARID1B could delay melanoma initiation and progression in a mouse melanoma model. This PRCRP Horizon Award will help me elucidate the detailed mechanisms of how JARID1B regulates melanoma stem cells. It will set the stage for rational drug design of JARID1B inhibitors to target melanoma stem cells more effectively. I will be formally mentored by two senior cancer biologists, Dr. Marcus Bosenberg and Dr. Qin Yan. Their expertise is in melanoma biology and cancer epigenetics, perfectly matching the main research focus of my proposal. I will also strengthen my knowledge and technique skills in melanoma biology, cancer epigenetics, stem cell biology and bioinformatics by actively participating in seminars, workshops and symposiums in those related fields. I will also take courses in bioinformatics and collaborate with other experts in those fields. Scientific Objective and Rationale: Melanoma is the deadliest form of skin cancer. The rate of melanoma is much higher for people exposed to heavy sunlight, such as military Service members in areas like Iraq and Afghanistan. Despite remarkable progress in the past decade, the prognosis for patients with advanced melanoma is still poor. This is because development of drug resistance frequently leads to relapse and because only a subset of patients responds to immunotherapy. My proposed study is aimed at understanding the regulatory role of histone demethylase JARID1B on the maintenance of propagation and self-renewal in melanoma stem cells. This study will ultimately help us to design inhibitors of JARID1B based on the detailed mechanisms of how JARID1B regulates melanoma stem cells. JARID1B-targeting drugs will specifically target melanoma stem cells, which are responsible for the metastasis, drug resistance, relapse, and escape from immune surveillance. All melanoma patients will benefit from this work, and especially advanced melanoma patients, who have higher risk of metastasis, relapse, and resistance to current chemotherapy. Currently there are extensive drug screenings for JARID1B inhibitors in Dr. Yan s laboratory. I plan to test the most promising candidates both in melanoma cells and in mouse melanoma models. Therefore, the proposed studies will lead to clinical application of these lead compounds in 3 years. My proposed studies will also provide novel companion biomarkers for JARID1B activity, which will help doctors to be able to quickly identify patients with higher risk of melanoma in 2 years. Combined with the knowledge from my proposed mechanistic studies, a clearer picture will emerge of exactly how JARID1B functions in melanoma stem cells, allowing us to design specific inhibitors based on its function. Military Relevance: Military Service members and Veterans face higher risk for melanoma and other skin cancers. There is much room for improvement in cancer prevention and early detection for the military population. My preliminary work has shown that deletion of JARID1B delayed melanoma initiation and progression. This indicates that JARID1B inhibitors could also be used for melanoma prevention, in addition to treatment. This will allow doctors to begin earlier and more personalized treatment, enhancing patient health, and reducing the harm caused by melanoma throughout the world.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610306
Entities
People
- Shang-min Zhang
Organizations
- United States Army
- Yale University