Triple-negative breast cancer (TNBC) accounts for approximately 15% of invasive breast cancers and disproportionately affects African-American and younger women. These patients have high risk of recurrence and metastasis. Treatment options remain limited and new targeted agents are urgently needed. We and others have shown that y-secretase inhibitors (GSI) are active in breast cancer preclinical models, including TNBC. GSIs are being tested in TNBC based on the notion that Notch and other y-secretase substrates play important roles in breast cancer biology. However, critical knowledge gaps may compromise the clinical development of GSIs in TNBC. This project will test the hypothesis that: A) GSIs affect tumor growth both directly and through tumor host effects that vary between the drugs in this class;and B) the effects of GSIs are at least in part mediated through cross-talk with the VEGF and AKT pathways. Our data show that GSIs differ in the quality and potency of their effects on TNBC cells, endothelial cells and T-cells. There was no obvious correlation between the ability of GSIs to inhibit expression of canonical Notch target HES1 and their biological activity in vitro or in patients. GSIs have significant pharmacologic interactions with tyrosine kinase inhibitor sunitinib and AKT inhibitor perifosine. A GSI-perifosine combination is more active in TNBC xenografts than either drug alone. GSI inhibit Th17 T-helper responses, which play a crucial role in tumor development and angiogenesis. We plan to compare several investigational GSIs including Notch-sparing and Notch-selective agents to each other and to direct Notch inhibitors such as dominant negative MAML1 peptides in TNBC cells, endothelial cells and T-cells. We will explore the effects of selected GSIs, alone and in combination with sunitinib or perifosine, on angiogenesis and T-helper responses in tumors, using a novel transgenic mouse model of TNBC. We will identify candidate biomarkers of anti-tumor activity to be tested in the clinic. Finally, we will explore the role of Notch-mediated AKT activation in the anti-tumor activity of GSIs in TNBC.
Our project will significantly expand our understanding of how GSIs affec TNBC. These experiments are designed to provide a mechanism-based framework to select the most effective GSIs for TNBC, identify mechanistically relevant biomarkers to be validated in the clinic, and design therapeutic combinations that can be rapidly translated to the clinic.
|Ozay, E Ilker; Gonzalez-Perez, Gabriela; Torres, Joe A et al. (2016) Intracellular Delivery of Anti-pPKCÎ¸ (Thr538) via Protein Transduction Domain Mimics for Immunomodulation. Mol Ther 24:2118-2130|
|deRonde, Brittany M; Posey, Nicholas D; Otter, Ronja et al. (2016) Optimal Hydrophobicity in Ring-Opening Metathesis Polymerization-Based Protein Mimics Required for siRNA Internalization. Biomacromolecules 17:1969-77|
|Gordon, Mallory R; Canakci, Mine; Li, Longyu et al. (2015) Field Guide to Challenges and Opportunities in Antibody-Drug Conjugates for Chemists. Bioconjug Chem 26:2198-215|
|Yun, Jieun; Espinoza, Ingrid; Pannuti, Antonio et al. (2015) p53 Modulates Notch Signaling in MCF-7 Breast Cancer Cells by Associating With the Notch Transcriptional Complex Via MAML1. J Cell Physiol 230:3115-27|
|Kuksin, Christina Arieta; Minter, Lisa M (2015) The Link between Autoimmunity and Lymphoma: Does NOTCH Signaling Play a Contributing Role? Front Oncol 5:51|
|Park, Hyo-Jin; Ran, Yong; Jung, Joo In et al. (2015) The stress response neuropeptide CRF increases amyloid-Î² production by regulating Î³-secretase activity. EMBO J 34:1674-86|
|Wongchana, Wipawee; Lawlor, Rebecca G; Osborne, Barbara A et al. (2015) Impact of Notch1 Deletion in Macrophages on Proinflammatory Cytokine Production and the Outcome of Experimental Autoimmune Encephalomyelitis. J Immunol 195:5337-46|
|deRonde, Brittany M; Torres, Joe A; Minter, Lisa M et al. (2015) Development of Guanidinium-Rich Protein Mimics for Efficient siRNA Delivery into Human T Cells. Biomacromolecules 16:3172-9|
|Jung, Joo In; Price, Ashleigh R; Ladd, Thomas B et al. (2015) Cholestenoic acid, an endogenous cholesterol metabolite, is a potent Î³-secretase modulator. Mol Neurodegener 10:29|
|Arieta Kuksin, Christina; Gonzalez-Perez, Gabriela; Minter, Lisa M (2015) CXCR4 expression on pathogenic T cells facilitates their bone marrow infiltration in a mouse model of aplastic anemia. Blood 125:2087-94|
Showing the most recent 10 out of 24 publications