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.

Public Health Relevance

; 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA098131-12
Application #
8764758
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
2014-09-01
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
12
Fiscal Year
2014
Total Cost
$154,430
Indirect Cost
$54,437
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Santos Guasch, Gabriela L; Beeler, J Scott; Marshall, Clayton B et al. (2018) p73 Is Required for Ovarian Follicle Development and Regulates a Gene Network Involved in Cell-to-Cell Adhesion. iScience 8:236-249
Croessmann, Sarah; Sheehan, Jonathan H; Lee, Kyung-Min et al. (2018) PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3K? Inhibitors. Clin Cancer Res 24:1426-1435
Elion, David L; Cook, Rebecca S (2018) Harnessing RIG-I and intrinsic immunity in the tumor microenvironment for therapeutic cancer treatment. Oncotarget 9:29007-29017
Williams, Michelle M; Lee, Linus; Werfel, Thomas et al. (2018) Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers. Cell Death Dis 9:21
Hyman, David M; Piha-Paul, Sarina A; Won, Helen et al. (2018) HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 554:189-194
Luo, Na; Nixon, Mellissa J; Gonzalez-Ericsson, Paula I et al. (2018) DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer. Nat Commun 9:248
Sudhan, Dhivya R; Schwarz, Luis J; Guerrero-Zotano, Angel et al. (2018) Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial. Clin Cancer Res :
Werfel, Thomas A; Wang, Shan; Jackson, Meredith A et al. (2018) Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival. Cancer Res 78:1845-1858
Zhao, Shilin; Li, Chung-I; Guo, Yan et al. (2018) RnaSeqSampleSize: real data based sample size estimation for RNA sequencing. BMC Bioinformatics 19:191
Jia, Peilin; Zhao, Zhongming (2017) Impacts of somatic mutations on gene expression: an association perspective. Brief Bioinform 18:413-425

Showing the most recent 10 out of 341 publications