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.

Grant Number: 1UG3CA290454-01A1
NIH Institute/Center: NIH
Principal Investigator: ISABELLE BEDROSIAN