BAP1 Mutations in Malignant Pleural Mesothelioma: Biology, Clinical Phenotypes, Radiotherapy Response, and Target Discovery for Somatic and Germline Mutations
Abstract
Despite the continuing increase in mesothelioma incidence around the world, no efficacious therapies exist for the treatment of this almost universally lethal disease. Median overall survival after diagnosis is only 9-18 months. Many attempts over the past decade to improve upon current treatments have been unsuccessful. Essential to advances in other tumors were better understandings of the molecular aberrations in each tumor type. Recently, BAP1 was identified as a commonly mutated gene in mesothelioma and BAP1 is thought to be important for DNA damage repair. Additionally, families with inherited mutations in BAP1 are predisposed to mesothelioma and uveal melanoma as well as several other cancers, but the full spectrum of disease associated with this new cancer predisposition syndrome has yet to be defined. The current project seeks to better understand the role of BAP1 mutation in mesothelioma in several ways. First, the frequency of inherited BAP1 mutations will be determined as well the characteristics of patients and tumors with BAP1 mutation. By studying families with inherited BAP1 mutations, the full spectrum of diseases associated with this mutation will be described. Additionally, family members identified as carriers of BAP1 mutation can be screened for malignant diseases, which will consequently be identified earlier, thereby improving the chance of cure. Future efforts will be directed to determining the optimal screening instruments and intervals as well as the role of any preventive interventions. Another aspect of the project will seek to identify any molecular markers of radiation sensitivity. Radiation is an important component of multimodality therapy for the treatment of mesothelioma. While the radiation delivered is very uniform, responses are quite variable. Because BAP1 has a role in DNA damage repair and radiation induces DNA damage, BAP1 mutation may predict increased sensitivity to radiation therapy. The results of this analysis will immediately transform how physicians decide on treatment plans for patients. Those unlikely to respond to radiation will be diverted to other therapies and avoid radiation toxicity. The final aspect of this project will identify potential treatment targets that would be particularly efficacious in BAP1 mutant disease. Because BAP1 is important for DNA repair, the targeted screening in this project will start with other proteins important in DNA repair. Given that BAP1 mutation is common in mesothelioma and several other cancers, future work will include additional preclinical study of these newly identified targets as well as the design and execution of clinical trials using these novel compounds. With this comprehensive BAP1 translational research program, Dr. Zauderer will transform care in mesothelioma, one of the Fiscal Year 2014 Peer Reviewed Cancer Research Program Topic Areas. In combination with the robust and multifaceted career plan she has outlined, which includes superb mentorship as well as the other key elements necessary for her to advance as an independent researcher, this work will establish Dr. Zauderer as a lead researcher in mesothelioma. The proposed work will also dramatically benefit active duty Service members and Veterans as they are disproportionately affected by mesothelioma due to asbestos exposure during their service time as well as in many of the trade industries they entered after military service. Furthermore, while asbestos use is now restricted in the United States, deployed troops may have exposure, such as in demolished buildings, in other parts of the world where its use is not yet regulated. Because BAP1 mutation is also associated with other diseases such as melanoma and kidney cancer, this work will benefit active duty Service members, their families, and other military beneficiaries irrespective of asbestos exposure.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510210
Entities
People
- Marjorie Zauderer
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army