Targeted Chemoprevention in a Mouse Model for DCIS
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Introduction: Current strategies for chemoprevention and adjuvant therapy for women at high risk for breast cancer (estrogen receptor positive) for the most part rely on anti-estrogen therapy. Anti-estrogen therapy is an effective strategy for chemoprevention, but it is evident that such therapy is not effective in all patients and could be improved. In turn, combination therapy has shown to be effective for invasive carcinomas, and there is no reason to doubt that the use of combination therapy for chemoprevention may offer improved efficacy and duration. The studies detailed in this proposal will explore this paradigm in order to prove that the combination of different therapeutics can be synergistic and improve efficacy for chemoprevention. 
 
 
 
 
 
 
 
 Hypotheses: We hypothesize that anti-estrogen therapy (anastrozole/Arimidex) combined with the concurrent or intermittent addition of clinically available therapeutics (rapamycin and celecoxib) that have synergistic mechanisms will yield improved therapeutic efficacy and have the potential to eradicate preneoplastic disease in the breast.
 
 
 
 
 
 
 
 Methodology: For these studies, we will utilize a mouse model that we have developed that mimics the biology, pathology, and behavior of human ductal carcinoma in situ (DCIS). Mice will be treated with different dosages and combinations of agents, and the efficacy and toxicity of each treatment regimen will be assessed. These data will be used to additionally treat and compare mice using an intermittent combinational therapeutic regimen, with the theory that intermittent therapy would have a more benign side effect profile and thus be more amenable to future human clinical trials. For all treatments, preneoplasias and tumors will be snap-frozen for molecular studies to confirm the therapeutic mechanisms of action and to correlate the clinical endpoints with molecular data.
 
 
 
 
 
 
 
 Innovative elements:
 
 The use of combinational therapy for chemoprevention has not been utilized or discussed in earnest as a treatment option for women at high risk of breast cancer. This project aims to determine if this therapeutic regimen can offer improved outcomes in one of the only mouse models for ductal carcinoma in situ (DCIS) or preneoplastic breast disease. Because this model recapitulates most of the aspects of preneoplastic disease of the breast in women, these results will have direct impact on the evaluation of this strategy as a therapeutic option in women. Therefore, if the results of these studies support the hypothesis that combinational therapy is more effective than current therapies, they will provide a genesis for new clinical trials. 
 
 
 
 
 
 
 
 Advocacy involvement and human issues: New therapeutic strategies for treating women at high risk for breast cancer are required. The use of combinational therapy, with agents that can act synergistically and target complementary mechanisms, whether given continuously or intermittently, offers a new paradigm with significant potential for improved efficacy. The grant proposal detailed here describes a method of testing this strategy in a unique mouse model for DCIS. If these studies prove that this strategy is superior to that of single-agent therapy, new therapeutic strategies for chemoprevention using multi-modality therapy can be explored. Specifically, clinical trials utilizing combinational therapy comprised of clinically available therapeutics can be initiated.