A Therapeutic TCR Mimic Monoclonal Antibody for Intracellular PRAME Protein in Melanomas
Abstract
My career goal is to become a tenure-track faculty leading high-impact cancer research at a prestigious university or research institute. I hope that I can utilize my research to not only answer fundamental questions of how cancers become malignant and identify preventative strategies, but also discover novel and effective therapeutic strategies to treat patients. The Horizon Award will advance my career in melanoma research because it will provide me the funding opportunity to explore well-constructed hypotheses of how melanoma interacts with the immune system. It will provide me with the opportunity to travel to scientific conferences to gain new ideas and learn from experts from around the country. This research will advance the melanoma field because it will identify the cellular mechanisms involved in regulating a validated immunotherapy target. Therefore, it will provide data and implications on how to best use immunotherapy to treat melanomas. The researcher development plan supports me in attaining these goals because my plan will provide me maximum mentorship with world-renowned faculty and access to the expertise of both clinicians and investigators. I will take advantage of the consistent line-up of world-renowned scientists and melanoma researchers based at or visiting Memorial Sloan Kettering Cancer Center. I will take advantage of lectures and seminars to enrich my knowledge of melanoma and to open myself to new techniques, technologies, and experimental study designs. The proposed research has significant applicability because it aims to develop Pr20, a therapeutic antibody against a fragment of the protein found in melanoma known as preferentially expressed antigen in melanoma (PRAME). PRAME is not found in most healthy tissue, but PRAME is highly expressed in melanoma and the protein is degraded by the cell s proteasome into fragments called peptides, which are presented on the cell surface. Pr20 binds to a peptide of PRAME on the cell surface and can recruit immune cells to kill the melanoma. The proteasome exists in two forms: the constitutive proteasome and the immunoproteasome. We aim to determine which form is more efficient in degrading PRAME into our target peptide. If successful, this work can be rapidly translated to help melanoma patients in the United States. In the United States, the American Cancer Society publishes that in 2015 there will be an estimated 74,000 new cases of melanoma and about 10,000 people are expected to die from melanoma. Fair-skinned individuals who have significant exposure to sunlight are most at risk. The benefits of the research would be an additional therapeutic strategy to treat melanoma that is mechanistically independent from traditional chemotherapy. This may have strong utility to treat chemotherapy-resistant melanomas. The clinical risk may be off-target cytotoxicity due to reported low level expression of our target protein in healthy testes, ovaries, and the uterus. This must be evaluated preclinically but represents minimal risk because PRAME expression is low in these tissues and they represent non-essential organs. We expect that if all our proposed work is successful, the mechanistic studies can be applied to current PRAME vaccine clinical trials immediately to determine which melanomas present PRAME peptides on the surface most efficiently and may respond best to immunotherapy against these peptides. The Pr20 antibody will require additional preclinical studies, but if data are promising, it may be primed for human clinical trials within an estimated 4-5 years. This research will likely further the field of tumor-associated antigens in melanoma and will provide data on what regulates the expression of the tumor-associated antigen PRAME in melanomas. Because anti-PRAME therapy is currently being evaluated in clinical trials, any mechanistic insight on its regulation may be directly applied. In addition, although we are studying PRA
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610242
Entities
People
- Aaron Chang
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army