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Immunoprevention of BRCA1-associated breast cancer

Ashley Cimino-Mathews, M.D.
Associate Professor, Johns Hopkins University
Johns Hopkins University School of Medicine

Carriers of germline BRCA1 gene mutations run a 50-65% lifetime risk of developing breast and/or ovarian cancer. Preventing these cancers will have a major impact on health and survival. Surgically removing both breasts and ovaries almost completely prevents breast and/or ovarian cancer, and is currently the option chosen by approximately half of BRCA1 mutation carriers despite significant short- and long-term challenges such surgeries cause. In addition, these individuals remain at elevated risk for cancer in other organs outside the breasts and ovaries. Thus, an equally effective non-surgical approach to cancer prevention would be attractive to many BRCA1 mutation carriers.

The overarching hypothesis of this project is that evasion of the immune system plays a key role in allowing BRCA1-associated cancers to become invasive and life threatening. Consequently, the goal is to develop an immunological approach to stop precancers in BRCA1-gene mutation carriers from ever becoming invasive. The eventual solution may include a vaccine to enhance the anti-tumor immune response, combined with agents to accelerate the immune system.

Many BRCA1-associated breast cancers have a mutated TP53 gene and this mutation is a required step towards development of cancer. In addition, patients with TP53 mutant cancers can mount an immune response to TP53 mutations. Furthermore, p53 vaccines have already been shown to stimulate an immune response in patients with advanced cancer, and different types of vaccines can effectively treat p53 mutant tumors in mice. Therefore, this project will test whether a p53 vaccine can effectively prevent breast cancer in BRCA1 mutation carriers.

The two main goals of this project are to identify (1) recurrent oncoantigens that are expressed early on during BRCA1-associated breast cancer development and that could be targeted using a synthetic long peptide (SLP) vaccine with adjuvant; and (2) immunosuppressive conditions in the tissue microenvironment that may have to be overcome to achieve optimal immunoprotection. To this end, the team proposes to (1) Validate mutant p53 as a preventive vaccine target in BRCA1-associated breast cancer development; (2) Identify predominant immunosuppressive conditions within the tissue microenvironment of BRCA1-associated (pre)invasive breast cancer; (3) Identify recurrent oncoantigens other than TP53 in BRCA1 mutant preinvasive breast lesions. These studies will help the team design a phase I trial to test the safety and the ability to induce and immune response of a candidate p53 vaccine in carriers of a BRCA1 gene mutation.

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CPI is a 501(c)(3) organization 47-3425850 



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