Development of Targeted Molecular Therapy for Cancers Harboring BAP1 Mutations
Abstract
The most common reason that cancers cause death is by spread or metastasis to vital organs. However, the molecular mechanisms by which cancers metastasize remain poorly understood, and there are virtually no cancer drugs available that are designed specifically for treating the metastatic process. A major problem is that most research in this field involves the study of cancer cells in culture, which does not adequately represent what is happening in the whole body. Mouse models have been used with limited success, but mice are not amenable to high-throughput drug screening to identify new cancer drugs. In this proposal, we have taken an innovative new approach to identifying cancer drugs that target metastasis. Our approach is based on several observations. Mutations in the BRCA1-associated protein 1 (BAP1) tumor suppressor gene are frequently associated with cancer progression and metastasis in melanoma, mesothelioma, kidney cancer, and other tumors. When we mimic the effects of BAP1 mutation in Xenopus laevis (African clawed frog) embryos, they develop a striking appearance that is easy to detect without special equipment. Since thousands of Xenopus laevis embryos can be screened per week, we can treat the embryos with hundreds of different therapeutic compounds to identify ones that can reverse the effects of BAP1 mutations. The therapeutic compounds that pass this screening will be checked and validated in mice carrying human tumors that harbor BAP1 mutations. Therapeutic compounds that are identified by this project could progress quickly to clinical trials in patients with cancers harboring BAP1 mutations. Many patients could benefit from new cancer drugs identified by this research, particularly those with melanomas, mesotheliomas, and kidney cancers harboring BAP1 mutations. Such new drugs could potentially be used to treat advanced metastatic cancers, and they could possibly be used in the adjuvant setting (before metastasis is detected) to prevent cancer progression. The proposal has the potential for direct clinical application and benefit through the identification of new cancer drugs that could be tested in human clinical trials. Indeed, potential new cancer drugs identified by this project could progress to human clinical trials within 1-2 years. In a broader sense, this research represents one of the first attempts to develop a drug that targets a tumor suppressor gene. The knowledge gained during this research could have a far-reaching impact on similar research on other tumor suppressor genes and cancer types. This proposal addresses several Fiscal Year 2014 (FY14) Peer Reviewed Cancer Research Program Topic Areas, including melanoma, mesothelioma, kidney cancer and genetic cancer research, and it addresses the FY14 Military Relevance Focus Area of improving treatment for cancers that have a particularly profound impact on military health. There is a desperate need to identify more effective treatments for highly lethal cancers such as melanoma, mesothelioma, and kidney cancer. This project seeks to identify such therapy, which could have a powerful impact on active duty Service members, their families, and other military beneficiaries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510578
Entities
People
- James Harbour
Organizations
- United States Army
- University of Miami