PREVENT PRECLINICAL EFFICACY AND INTERMEDIATE BIOMARKER ENDPOINTS TASK ORDER: USE OF CARNOSIC ACID AND VIVOX40 FOR BREAST CANCER PREVENTION

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Ductal Carcinoma In-Situ (DCIS) of the breast is the most common form of non-invasive breast cancer, with a marked increase in detection rate with improved breast imaging in the last few decades. About 16-30% of DCIS develop a recurrence in 10 years if treated with wide excision alone. DCIS is currently managed by surgical resection combined with radiotherapy. Following resection, the risk of recurrence is reduced by about one-half with breast radiotherapy and by an additional one-third with added anti-hormonal therapy such as tamoxifen or aromatase inhibitors, a benefit that is exclusive to individuals with hormone receptor positive DCIS. Anti-hormonal therapies, while effective, are associated with many side effects including hot flashes, night sweats, thrombogenesis, bone loss, stroke, and endometrial cancers. Consequently, the rate of non-compliance is as high as 50%. In contrast to hormone receptor positive DCIS, there are currently no preventive options for hormone receptor negative breast cancers. At the same time, evidence from observational studies suggests that a large fraction of DCIS, ~50%, are indolent and may not require surgical resection or radiotherapy. Therefore, there is an unmet need for the development of safer and more effective therapies for the prevention of human invasive breast cancer, for which ductal carcinoma in situ (DCIS) is a precursor. Non-clinical models of non-invasive breast tumors are limited, and the existing in vivo models do not mimic inter- and intratumoral heterogeneity. With the prevailing notion that human DCIS initiates inside the ducts, Behbod et al. developed the mouse intraductal (MIND) model to show whether subtypes of human DCIS might contain distinct subpopulations of tumor-initiating cells. The intraductal MIND transplantation model provides an invaluable tool that mimics human breast heterogeneity at the noninvasive stages and allows the study of the distinct molecular and cellular mechanisms of breast cancer progression. Similar to the evolution of human DCIS, DCIS cells injected intraductally into mice form in situ lesions followed by invasion into the surrounding stroma as cancer cells infiltrate the natural barriers of the myoepithelial cell layer and basement membrane. The MIND model mimics the progression of breast neoplasia from non-invasive (ductal carcinoma in situ) to invasive disease. This step is widely recognized as a critical transition, in that most invasive breast cancers are thought to evolve though a DCIS phase. Previous studies showed a significant association between high nuclear BCL9 and pathological characteristics indicative of high-risk DCIS. The in vivo silencing of BCL9 in DCIS MIND models, led to inhibition of DCIS invasion, reversal of epithelial mesenchymal transition (EMT), and a significant reduction in DCIS cellular proliferation. Additionally, de la Roche and colleagues performed a screen for small-molecule inhibitors of β-catenin binding to BCL9 and discovered carnosic acid, a natural compound found in rosemary extract (RE). Their studies showed that carnosic acid was non-toxic, induced proteosomal degradation of active β-catenin and attenuated BCL9/β-catenin-dependent transcription in HeLa and SW480 cells. In humans, RE has already been approved as a safe food additive by the United States Food and Drug Administration (USFDA) and by the European Food Safety Authority. Further, RE has been categorized by the FDA as “generally recognized as safe” or GRAS and Rosemary is widely available as dietary supplement in the United states. Numerous in vivo studies have provided strong evidence for the anti-cancer effects of rosemary extract and its principal component carnosic acid in various cancer types. The overall goal of the project is to evaluate chemopreventive effects of rosemary extract VivOX40 and carnosic acid in DCIS cell lines MIND graft, patient derived (PDX) DCIS MIND graft models and genetically engineered mouse models that recapitulate human breast cancer progression.