Chemoprevention of Breast Cancer by Targeting Glucose Metabolism with HJC0152 About 60-70% of breast cancers (BCs) are estrogen receptor (ER)-positive BCs (EPBCs), and the remaining 30-40% are ER-negative BCs (ENBCs). Currently available anti-ER-based chemopreventive therapies, such as selective ER modulators and aromatase inhibitors, are effective in preventing only about half of EPBCs and do not prevent any ENBCs, meaning that almost 60% of BCs cannot be prevented with existing anti-ER-based preventive agents. In particular, the majority of ENBCs are triple-negative BCs (TNBCs), which grow faster, spread earlier, and recur more often than other BC subtypes do, and the incidence of TNBC is higher among young African American and Hispanic/Latina women and women with BRCA1 mutations. BC survivors, particularly ENBC and TNBC survivors are at a predictable increased risk of developing a new BC in the breasts. Thus, the prevention of BC in those ?healthy? women and BC survivors represents a huge, urgent but unmet need, since currently available preventive agents are anti-ER-based, and is ineffective to protect women from developing BC. Those women or BC survivors will likely benefit most from effective, non?ER-based preventive drugs. The proposed research will directly address this overarching challenge by defining new intervention points and developing effective agents for preventing all BC subtypes. We recently discovered a small molecule, HJC0152, which can modulate glucose metabolism and effectively block premalignant lesions and ENBC/TNBC formation in transgenic mouse models of human ENBC. We hypothesize that effective modulation, reprograming, and restoration of dysregulated glucose metabolism with HJC0152 will reverse precancerous changes and block BC development. We will test this hypothesis through 3 specific aims.
In Aim 1, we will determine the preventive efficacy of HJC0152 in ENBC and TNBC models in various clinically relevant prevention settings. Preclinical assessments and safety profiling will also be performed.
In Aim 2, we will identify the physically interacting targets of HJC0152 that are essential to ENBC/TNBC development through multiple approaches including bait-molecule affinity binding to capture potential targets of HJC0152. In preliminary studies, we have identified a list of bona fide targets for HJC0152 for further investigation.
In Aim 3, we will characterize and validate the top-ranked high-confidence target of HJC0152, arginase, by performing affinity binding determination, co-complex of ligand-target interaction, gain- /loss-of-function assessments, and expression determination experiments in breast cells and tumors. These studies will elucidate the drivers of BC development and provide a solid foundation for further preclinical and clinical development of HJC0152 as a non-ER-based preventive drug candidate. Given the demonstrated preventive efficacy of HJC0152, low toxicity profiles, identification of high-confidence HJC0152 targets and ongoing validation, and the convenience of oral administration of HJC0152, outcomes from this project will have high translational potential to foster new strategies of chemoprevention for BC, particularly ENBC/TNBC.
Prevention of estrogen receptor (ER)-negative, triple-negative, and the selective ER modulator-resistant ER- positive breast cancer (BC) is an urgent but unmet need in BC care, however, to date there is no targeted preventive therapy available for these BC subtypes. In our study, we found that our newly developed orally active glucose metabolism modulator HJC0152 significantly prevented/delayed mammary tumor formation in animal models for human ER-negative and triple-negative BCs by blocking premalignant lesions, via targeting aberrant glucose and energy metabolism. To provide the foundation and rationale to target glucose metabolism pathway as a new non-ER-based strategy for preventing BC and bring novel cancer-preventive drugs for human trials, we propose to characterize the preventive efficacy for HJC0152 in clinically relevant prevention settings, define the HJC0152-targeting molecules important in BC development, and charactrize and validate the identified high-confidence targets of HJC0152.
