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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA166009-02
Application #
8758850
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Amherst
Department
Type
DUNS #
City
Amherst
State
MA
Country
United States
Zip Code
Dawson, Ted M; Golde, Todd E; Lagier-Tourenne, Clotilde (2018) Animal models of neurodegenerative diseases. Nat Neurosci 21:1370-1379
Hossain, Fokhrul; Sorrentino, Claudia; Ucar, Deniz A et al. (2018) Notch Signaling Regulates Mitochondrial Metabolism and NF-?B Activity in Triple-Negative Breast Cancer Cells via IKK?-Dependent Non-canonical Pathways. Front Oncol 8:575
Chandiran, Karthik; Lawlor, Rebecca; Pannuti, Antonio et al. (2018) Notch1 primes CD4 T cells for T helper type I differentiation through its early effects on miR-29. Mol Immunol 99:191-198
Hossain, Fokhrul; Majumder, Samarpan; Ucar, Deniz A et al. (2018) Notch Signaling in Myeloid Cells as a Regulator of Tumor Immune Responses. Front Immunol 9:1288
Ran, Yong; Hossain, Fokhrul; Pannuti, Antonio et al. (2017) ?-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. EMBO Mol Med 9:950-966
Sgolastra, Federica; Backlund, Coralie M; Ilker Ozay, E et al. (2017) Sequence segregation improves non-covalent protein delivery. J Control Release 254:131-136
Sarapas, Joel M; Backlund, Coralie M; deRonde, Brittany M et al. (2017) ROMP- and RAFT-Based Guanidinium-Containing Polymers as Scaffolds for Protein Mimic Synthesis. Chemistry 23:6858-6863
Aquila, Giorgio; Fortini, Cinzia; Pannuti, Antonio et al. (2017) Distinct gene expression profiles associated with Notch ligands Delta-like 4 and Jagged1 in plaque material from peripheral artery disease patients: a pilot study. J Transl Med 15:98
Moyano, Daniel F; Liu, Yuanchang; Ayaz, Furkan et al. (2016) Immunomodulatory effects of coated gold nanoparticles in LPS-stimulated in vitro and in vivo murine model systems. Chem 1:320-327
Pannella, Micaela; Caliceti, Cristiana; Fortini, Francesca et al. (2016) Serum From Advanced Heart Failure Patients Promotes Angiogenic Sprouting and Affects the Notch Pathway in Human Endothelial Cells. J Cell Physiol 231:2700-10

Showing the most recent 10 out of 37 publications