Research Grants Awarded
Prevention of Early Pre-malignant Breast Lesions by an Aurora Kinase Inhibitor during Estrogen-induced ACI Rat Breast Oncogenesis
Background. Estrogens (E) play a major role in the causation/development of sporadic breast cancer (BC). We reported that E-induced breast tumors in female ACI rats remarkably resemble histopathologic and molecular changes seen in human invasive ductal breast cancer (IDBC), including overexpression of c- myc /MYC, cyclin D1, E, MDM2, Aurora A/B (AurA/B) kinases, centrosome amplification (CA), chromosomal instability (CIN), aneuploidy, and amplified c- myc . Over-expression and activity of AurA/B result in duplication, segregation, and cytokinesis errors leading to CA, CIN, aneuploidy, and malignancy. We propose to use a potent inhibitor of AurA/B; VX-680•HCl, to determine whether AurA/B suppression will block the cascade of CA/CIN/aneuploidy/(pre-)malignancy. Objectives/Hypothesis . VX-680•HCl inhibition of AurA/B will provide crucial evidence to determine whether: 1. Persistent AurA/B overexpression and activity is a critical event in E-driven mammary oncogenesis, and responsible for eliciting the CA\CIN\aneuploidy cascade. 2. When over-expressed, AurA/B promotes the progression of dysplasias to ductal carcinoma in-situ (DCIS), and 3 . From DCIS to IDBC in the presence of low levels of E and VX-680•HCl. Specific Aims . 1. Synthesize and characterize VX-680•HCl, and develop sustained release tablets to be applied at periodic intervals to inhibit the rise in AurA/B activity seen in pre-malignant stages of E-induced breast oncogenesis in female ACI rats. 2. To determine whether VX-680•HCl will block the progression of pre-malignant stages to IDBCs in this model. Study Design. For chemoprevention of early E-induced pre-malignant stages in female ACI rats, we will synthesize VX-680•HCl. To ascertain whether VX-680•HCl has estrogenic (anti-) activity; competitive binding studies will be done. Using the H3 kinase assay in-vitro and in-vivo , we will determine the minimal dose of VX-680•HCl that completely inhibits AurA/B activity. VX-680•HCl sustained release tablets will be used to block pre-malignant progression at well-defined periods of E-induced rat breast oncogenesis. Potential Outcomes and Benefits . AurA/B over-expression is an oncogenic event and a critical factor in the development of IDBC. Thus, AurA/B inhibition studies may herald a novel chemopreventive approach that targets a key family of mitotic kinases. If AurA/B has a major role in eliciting CA\CIN\aneuploidy, then VX-680•HCl will greatly reduce DCIS and IDBC incidence and multiplicity.
Background. Most chemopreventive strategies for breast cancer (BC) in women involve modifying blood estrogen (E) levels and/or interactions with the estrogen receptor- a (ER a ). While dietary interventions have met with only modest success lowering E levels, a 49% reduction in BC risk after tamoxifen (TAM) (20 mg/day) treatment was shown in the BC Prevention Trial. However, TAM use developed adverse outcomes (i.e., endometrial cancer, stroke). Consequently, there is reluctance among physicians to prescribe TAM to reduce BC risk. Objectives/Hypothesis. A novel approach is needed to make significant in-roads in the prevention of early human pre-malignant [dysplasia, atypical hyperplasia, ductal carcinomas in-situ (DCIS)] progression to invasive ductal BC (IDBC). We propose to inhibit a specific mitotic enzyme family, Aurora A/B (AurA/B), which exhibit over-expression and elevated activity in a vast majority of DCIS and in IDBC in women. We reported similar changes in female ACI rat E-induced mammary pre-malignant stages and in BC. Aur A/B are responsible for triggering chromosome gains/losses (aneuploidy) and progression to malignancy, common to human DCIS and IDBC. Study Design. In female ACI rats, we reported a series of E-driven histopathological and molecular mammary changes which remarkably resemble those seen in human sporadic BC development. The over-expression of myc gene/protein in breast cells is an early event leading to cell cycle deregulation. As a result, the persistent rise of AurA/B expression leads to errors in cell division. These events commonly seen in human DCIS and IDBC are E-mediated in ACI rats, and will be used to target AurA/B by a novel inhibitor to block pre-malignant progression. Specific Aims. We propose to use VX-680•HCl, a potent and selective inhibitor of Aur A/B, to prevent the development of aneuploidy, a fundamental defect and defining feature of early human BC pre-malignancy and IDBCs. We propose to: 1. Synthesize VX-680•HCl. Treat ACI rats with this inhibitor to prevent E-driven progression from 2. Dysplasias to DCIS and; 3. DCIS to IDBC. Potential Outcomes and Benefits. This approach heralds a new class of potent chemopreventive agents, targeting a specific entity, AurA/B. One advantage over TAM treatment is that only 64-66% of IDBC are ER a + , whereas AurA over-expression occurs in >90% of IDBC. These studies may have a major impact in the prevention of BC by targeting AurA/B in breast pre-malignancy.