Chimeric RNA driven neopeptide vaccine for prevention of breast cancer in germline BRCA1/2 carriers

Project Summary Background: Carriers of germline BRCA 1 and 2 (gBRCA1/2) mutations harbor substantial (60-80%) lifetime risk of breast cancer. Current strategies for management of this high risk population are limited to either bilateral mastectomy to reduce risk or breast MRI surveillance for early detection of cancer. Both strategies are associated with significant risks and morbidities. Therefore, there is a clear need to develop effective, low toxicity approaches as alternatives to current standard of care. Advances in genomics and bioinformatics have opened the door for novel mRNA and peptide vaccines for treatment of cancer. These advances offer as yet untapped opportunities for prevention of breast cancer, including gBRCA 1/2 related disease. However, to realize these opportunities, it is first necessary to identify the antigenic repertoire that arises during tumorigenesis that can be harnessed to develop preventive vaccines. Our group has made the observation that breast tumors, including those from BRCA 1/2 mutation carriers, as well as risk breast tissue harbors significant numbers of chimeric mRNA which give rise to de novo, immunogenic neoantigens that we believe represent an ideal opportunity as vaccine targets. Objective/Hypothesis: We hypothesize that an approach of genomic characterization of preneoplastic breast tissue from gBRCA1/2 carriers to identify novel fusion proteins arising from chimeric mRNAs, coupled with bioinformatics prediction of immunogenic peptides, will provide a robust opportunity for developing vaccines for prevention of breast cancer in this high risk population. We will test our hypothesis through the following aims: UG3 phase Specific Aim 1: Using our established pipeline, we will identify and validate MHC Class I immunogenic peptides generated from chimeric mRNA transcripts as potential vaccines for prevention of gBRCA 1 and gBRCA 2 related breast cancer. UH3 phase Specific Aim 2: Using a transgenic mouse model of BRCA 1 breast cancer, we will provide proof of principle that the framework proposed in aim 1 will yield an effective chimeric mRNA derived vaccine for prevention of breast cancer. UH3 phase Specific Aim 3: we will delineate the mechanism of immuno-prevention by a multiantigen mRNA vaccine in BRCA1 mouse model. Impact This application provides a paradigm shift in breast cancer prevention by bringing together genomics, bioinformatics and immunology to create an innovative, integrated, multi-disciplinary framework that will address many of the current barriers to primary prevention of hereditary breast cancers and provide a path to developing off-the shelf cancer immuno- prevention vaccine that would be applicable to most women at risk for germline BRCA1/2 driven breast cancer. If effective, this framework could readily be extended to hereditary cancers associated with additional high penetrance germline mutations. Given this broad applicability, our proposed strategy is positioned to make significant impact toward the overall goal of reducing the incidence of breast cancer.