Triple Negative Breast Cancers (TNBC), if considered its own disease, would rank as the fifth or sixth leading cause of cancer deaths in women in the USA. The only treatment option for these patients is multi-agent chemotherapy, and TNBC tumors are highly variable in terms of their chemotherapy sensitivity. TNBC is also known to be highly metastatic, with most patients who succumb to this disease dying of complications caused by their metastatic disease burden. Most preclinical studies of metastasis, however, study the dissemination and colonization of metastasis, and have failed to focus on the treatment of established metastases. The overall goal of our proposed studies, therefore, is to utilize preclinical Genetically Engineered (GEM) and Patient Derived Xenografts (PDX) models of TNBC to determine the efficacy of standard-of-care chemotherapy regimens for the treatment of established metastatic disease. Specifically, these studies will uniquely compare the therapeutic response of TNBCs in their orthotopic site versus the response of established lung metastases, both in immunocompromised models and those with an intact immune system. Recent technological advances using lentiviral vectors allow the efficient introduction of fluorescent and bioluminescent markers into primary tumors to facilitate both non-invasive imaging of metastases as well as re-isolation of transduced cells following treatment for detailed genomic analyses. The proposed therapeutic regimens have been chosen based upon their known efficacy for the treatment of primary TNBC disease in humans. In addition we will also examine the frequency and biology of Tumor Initiating Cells within these TNBC models, and determine if and how these TIC properties change according to microenvironment, and according to treatment. Because metastases are culpable for >90% of cancer-associated mortality, truly efficacious anti-metastatic therapies are desperately needed and our preclinical studies, therefore, should provide a new paradigm for testing these therapies.

Public Health Relevance

Breast cancer is the most frequent type of cancer that occurs in women (>200,000 cases/year) and accounts for ~40,000 deaths each year in the United States. In part through our own gene expression profiling studies, breast cancer is now appreciated as being composed of multiple genetically unique subtypes with different etiologies and outcomes. Triple Negative Breast Cancers are an important clinical subtype of breast cancer because they lack the three known important therapeutic targets used in the breast cancer clinic, namely the Estrogen Receptor, the Progesterone Receptor, and the HER2 protein. In addition, we and others have shown that TNBC are more frequent in African Americans (AA), which partially explains the outcomes disparity difference seen for AA in the USA. From a therapeutic perspective, TNBC patients only systemic treatment option is chemotherapy. Importantly, we do know that a 1/3rd of TNBC patients respond well to chemotherapy, and thus for this group, this is an effective treatment. In this application, we propose study directly the chemotherapy responsiveness of TNBC in the metastatic setting as compared to the in breast primary tumor setting, and then to explore the hypothesis that much of the resistance seen in in the metastatic setting is due to intra-tumoral heterogeneity, and/or the tumors ability to change phenotype from one type of cellular 'differentiation state' into a more resistant 'state', which vital organs such as the lung may further promote. If this hypothesis is found to be true, then we have identified a mechanism of drug resistance, and found the key pathways and gene(s) for which additional therapeutic interventions might be able to overcome these metastatic tumor resistance effects.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA195754-01
Application #
8903957
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Marks, Cheryl L
Project Start
2015-08-01
Project End
2018-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Pfefferle, Adam D; Agrawal, Yash N; Koboldt, Daniel C et al. (2016) Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers. Dis Model Mech 9:749-57
Hoadley, Katherine A; Siegel, Marni B; Kanchi, Krishna L et al. (2016) Tumor Evolution in Two Patients with Basal-like Breast Cancer: A Retrospective Genomics Study of Multiple Metastases. PLoS Med 13:e1002174