Despite the promise of targeted therapies, cytotoxic chemotherapy remains the mainstay of treatment for triple negative breast cancer (TNBC) patients. Due to the heterogeneity of TNBC, the identification of biomarkers is critical to select patients for various therapies. We recently identified TNBC subtypes with corresponding molecular drivers and preclinical models to develop effective therapeutic approaches. Herein, we propose three specific aims to test the following interrelated hypotheses: In TNBC patients with the luminal, androgen receptor (AR)-expressing subtype, AR and PISK signaling synergistically drive tumor growth, and treatment of these patients with an AR antagonist (bicalutamide) in combination with a PISK pathway inhibitor will be an effective therapy. In the remaining 90% of TNBC patients, the high frequency of p5S mutations and PISK signaling pathway alterations in their tumors will result in therapeutic vulnerability to the genotoxic agent cisplatin given in combination with a PISK inhibitor.
Specific Aim 1 : a) To evaluate the efficacy, as measured by clinical benefit rate of bicalutamide + the pan-PISK inhibitor (GDC-0941) in patients with AR+ metastatic TNBC. b) To evaluate the efficacy, as measured by overall response rate of cisplatin + GDC-0941 versus cisplatin alone in patients with AR- metastatic TNBC. We will determine if a set of genomic markers can predict sensitivity or resistance to these therapeutic regimens tested.
Specific Aim 2 : To determine mechanisms of inherent and acquired resistance to cisplatin and PISK inhibitors in the TNBC setting.
Specific Aim S: To develop validated clinical biomarkers for TNBC subtyping and use in selection of patients for future clinical trials or new standard treatments. Comprehensive analysis of well-characterized tumors from patients on hypothesis-driven clinical trials will allow discovery of mechanisms of sensitivity and resistance as well as biomarkers that can be used in the development of new treatment regimens and selection of patients for future trials.

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; The proposed research will investigate new therapeutic approaches for triple negative breast cancer (TNBC) based on the molecular drivers of the disease. We are translating our preclinical findings to innovative, targeted, subtype-specific clinical trials for TNBC patients. We will discover new biomarkers to predict response and resistance to known (cisplatin and bicalutamide) and new therapies (PISK inhibitors);the latter has implications for use in many cancer types.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Vanderbilt University Medical Center
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Bhola, Neil E; Jansen, Valerie M; Bafna, Sangeeta et al. (2015) Kinome-wide functional screen identifies role of PLK1 in hormone-independent, ER-positive breast cancer. Cancer Res 75:405-14
Sanders, Melinda E; Schuyler, Peggy A; Simpson, Jean F et al. (2015) Continued observation of the natural history of low-grade ductal carcinoma in situ reaffirms proclivity for local recurrence even after more than 30 years of follow-up. Mod Pathol 28:662-9
Abramson, Vandana G; Lehmann, Brian D; Ballinger, Tarah J et al. (2015) Subtyping of triple-negative breast cancer: implications for therapy. Cancer 121:16-Aug
Guo, Yan; Zhao, Shilin; Lehmann, Brian D et al. (2014) Detection of internal exon deletion with exon Del. BMC Bioinformatics 15:332
Barnes, Stephanie L; Quarles, C Chad; Yankeelov, Thomas E (2014) Modeling the effect of intra-voxel diffusion of contrast agent on the quantitative analysis of dynamic contrast enhanced magnetic resonance imaging. PLoS One 9:e108726
Grieb, Brian C; Chen, Xi; Eischen, Christine M (2014) MTBP is overexpressed in triple-negative breast cancer and contributes to its growth and survival. Mol Cancer Res 12:1216-24
Su, Pei-Fang; Li, Chung-I; Shyr, Yu (2014) Sample size determination for paired right-censored data based on the difference of Kaplan-Meier estimates. Comput Stat Data Anal 74:39-51
Bi, Xiaohong; Rexer, Brent; Arteaga, Carlos L et al. (2014) Evaluating HER2 amplification status and acquired drug resistance in breast cancer cells using Raman spectroscopy. J Biomed Opt 19:025001
Jiang, Junfeng; Jia, Peilin; Shen, Bairong et al. (2014) Top associated SNPs in prostate cancer are significantly enriched in cis-expression quantitative trait loci and at transcription factor binding sites. Oncotarget 5:6168-77
Jiang, Junfeng; Jia, Peilin; Zhao, Zhongming et al. (2014) Key regulators in prostate cancer identified by co-expression module analysis. BMC Genomics 15:1015

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