Breast cancers that lack estrogen and progesterone receptor expression as well as HER2 amplification have a distinct gene expression profile, exhibit a poor prognosis and do not respond to commonly used chemotherapeutic agents. A better understanding of the molecular basis of this subset of breast cancers, called triple negative, may lead to the development of new therapeutic strategies against it. The p53 family of transcription factors, including p53, p63 and p73, are key regulators of tumor suppressor signaling pathways in breast cells. The p53 tumor suppressor is mutated in -30% of breast cancer, but incidence of p53 mutation is higher in aggressive (ER)-negative breast cancers and shows strong association with the triple negative, 'basal-like'subgroup. Although the ancestral p53 family member, p63, is not detectable in the majority of invasive breast carcinomas, it is expressed in -25-30% of triple negative, basal-like tumors. The p63 isoforrn that is expressed (deltaNp63alpha) is one that has potent transcriptional repression activity and plays a role in epithelial cell survival and differentiation. In a fraction of triple-negative tumors, p63 is coordinately expressed with another p53 family member, p73, and may be antagonizing p73 transcriptional and tumor suppressive activity. Using a gene expression-based chemical genomics approach we have identified a class of drugs (insulin sensitizers) that modulate p73 activity as well as other drugs that elevate p73 and decrease p63, which is of relevance given that these agents may 'tip'the p63/p73 signaling axis towards pro-apoptotic signaling. In this application, we propose that the p63/p73 signaling axis is a robust molecular target for the treatment triple negative tumors and we will determine if modulation of this axis plays a critical role in drug-induced breast tumor cell apoptosis. Based on recent findings from our laboratory and others we propose the following interrelated hypotheses: In triple negative tumors that express both p63 and p73, p63 promotes tumor cell survival through repression of p73. Further, the combined use of drugs that impinge on the p63/p73 signaling axis will have synergistic activity. In the remaining fraction of triple negative tumors that lack p63 expression, but express p73, other pathways are selected for that abrogate p73 pro-apoptotic activity or promote tumor cell survival.
Three aims are proposed to test these hypotheses. In the first, we will determine the degree of tumor response to neoadjuvant cisplatin, paclitaxel, and the TOR inhibitor everolimus (RAD001) versus cisplatin and paclitaxel therapy in patients with triple negative tumors. In the second, we will use gene expression profiling to sub-classify triple negative cancers and identify gene signatures, such as those of p63 and p73, that predict sensitivity and response to neoadjuvant therapy in triple negative breast cancers. Lastly, we will return to preclinical studies to analyze a panel of insulin sensitizers for their ability to activate p73 and induce apoptosis alone or in combination with known chemotherapeutic agents in triple negative breast cancer cells, and in parallel determine the mechanism by which p73 activity is stimulated. The translational goal and clinical impact of this project is the identification of effective therapeutics for patients with triple negative breast tumors.
|Mayer, Ingrid A; Abramson, Vandana G; Formisano, Luigi et al. (2016) A Phase Ib Study of Alpelisib (BYL719), a PI3KÎ±-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. Clin Cancer Res :|
|Lee, Taekyu; Bian, Zhiguo; Zhao, Bin et al. (2016) Discovery and Biological Characterization of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors. FEBS Lett :|
|Harris, Leonard A; Frick, Peter L; Garbett, Shawn P et al. (2016) An unbiased metric of antiproliferative drug effect in vitro. Nat Methods 13:497-500|
|Zhao, Min; Kim, Pora; Mitra, Ramkrishna et al. (2016) TSGene 2.0: an updated literature-based knowledgebase for tumor suppressor genes. Nucleic Acids Res 44:D1023-31|
|Bhola, Neil E; Jansen, Valerie M; Koch, James P et al. (2016) Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population. Cancer Res 76:440-52|
|Degnim, Amy C; Dupont, William D; Radisky, Derek C et al. (2016) Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women. Cancer 122:2971-8|
|Zhao, Junfei; Cheng, Feixiong; Wang, Yuanyuan et al. (2016) Systematic Prioritization of Druggable Mutations in âˆ¼5000 Genomes Across 16 Cancer Types Using a Structural Genomics-based Approach. Mol Cell Proteomics 15:642-56|
|Pelz, Nicholas F; Bian, Zhiguo; Zhao, Bin et al. (2016) Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods. J Med Chem 59:2054-66|
|Jansen, Valerie M; Mayer, Ingrid A; Arteaga, Carlos L (2016) Is There a Future for AKT Inhibitors in the Treatment of Cancer? Clin Cancer Res 22:2599-601|
|Hassanein, Mohamed; Hight, Matthew R; Buck, Jason R et al. (2016) Preclinical Evaluation of 4-[18F]Fluoroglutamine PET to Assess ASCT2 Expression in Lung Cancer. Mol Imaging Biol 18:18-23|
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