Basal-like carcinomas comprise 10-15% of the six breast cancer subtypes, and include those that are 'triple negative'(lacking ER-alpha, PR and HER2 expression), denoting clinically poor prognosis with few treatment options. The mesenchymal cell adhesion molecule, cadherin-11 is expressed only in poorly differentiated, highly invasive basal-like cells and is absent in normal breast epithelium and well-differentiated breast cancer cells. Preliminary data shows that cadherin-11 is commonly increased as an early event in a subset of human breast cancers and ductal carcinomas in-situ and is also elevated in CNS tumors and those of the GI system. Unlike HER2 positive breast cancers for which small molecule and antibody treatment is quite effective;there are no targeted therapies for highly aggressive tumors such as basal-like breast cancer and glioblastomas. However, cadherin-11 is a therapeutic target in the inflammatory disease rheumatoid arthritis (RA) and we found that cadherin-11 monoclonal antibodies, humanized versions of which will shortly be in clinical trials for RA, inhibited the growth of aggressive basal-like breast cancer xenografts in mice. Cadherin-11 attenuation also decreased tumorigenesis, proliferation, colony formation and migration of MDA-MB-231 basal-like breast cancer cells and LN229 glioblastoma cells. These data directly demonstrate that cadherin-11 is a bona-fide therapeutic target in inflammatory diseases such as RA and cancer and prompted us to develop small molecule inhibitors that specifically inhibit the growth and migration of cadherin-11 positive cells. We also found that cadherin-11 regulates CCL2 and other inflammatory mediators and growth regulatory pathways in both RA and cancer cells and further indicates that """"""""some drugs commonly and chronically used for other indications, such as an anti-inflammatory drug, can protect against cancer incidence and mortality, can we determine the mechanism by which any of these drugs work?"""""""" as posited in Provocative Question 5. The proposal will combine the activities of the Cancer Biology and Drug Discovery Group that first described the role of cadherin-11 in breast cancer (Byers, Georgetown), the Rheumatology Group that discovered the role of cadherin-11 in this disease (Brenner, Harvard) and the Structural Biology Group that first determined the crystal structure of cadherin-11 (Shapiro, Columbia). Together we have the following aims. 1. To reposition approved drugs as cadherin-11 inhibitors. Preliminary in silico repositioning identified the anti- inflammatory drug, celecoxib as a cadherin-11 inhibitor. 2. Determine the role of CCL2 and other cadherin-11 regulated genes in mediating its effects on tumorigenesis, invasion and metastasis. 3. Determine the role of tyrosine kinase activation in mediating cadherin-11 signaling.

Public Health Relevance

Basal-like breast cancers and brain tumors of the glioblastoma type are among the poorest prognosis cancers with no effective treatments. This proposal links a molecular pathway elevated in these tumors to a similar pathway important in the inflammatory disease rheumatoid arthritis. We propose that drugs currently in use for arthritis as well as drugs repurposed to inhibit the common pathway will be useful as novel cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA170653-01
Application #
8384229
Study Section
Special Emphasis Panel (ZCA1-SRLB-9 (M1))
Program Officer
Woodhouse, Elizabeth
Project Start
2012-09-01
Project End
2016-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$615,290
Indirect Cost
$137,091
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Mizoguchi, Fumitaka; Slowikowski, Kamil; Wei, Kevin et al. (2018) Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun 9:789
Peran, Ivana; Madhavan, Subha; Byers, Stephen W et al. (2018) Curation of the Pancreatic Ductal Adenocarcinoma Subset of the Cancer Genome Atlas Is Essential for Accurate Conclusions about Survival-Related Molecular Mechanisms. Clin Cancer Res 24:3813-3819
Simbulan-Rosenthal, Cynthia M; Dakshanamurthy, Sivanesan; Gaur, Anirudh et al. (2017) The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma. Oncotarget 8:12576-12595
Wathieu, Henri; Issa, Naiem T; Byers, Stephen W et al. (2016) Harnessing Polypharmacology with Computer-Aided Drug Design and Systems Biology. Curr Pharm Des 22:3097-108
Issa, Naiem T; Kruger, Jordan; Wathieu, Henri et al. (2016) DrugGenEx-Net: a novel computational platform for systems pharmacology and gene expression-based drug repurposing. BMC Bioinformatics 17:202
Noss, Erika H; Watts, Gerald F M; Zocco, Davide et al. (2015) Evidence for cadherin-11 cleavage in the synovium and partial characterization of its mechanism. Arthritis Res Ther 17:126
Issa, Naiem T; Peters, Oakland J; Byers, Stephen W et al. (2015) RepurposeVS: A Drug Repurposing-Focused Computational Method for Accurate Drug-Target Signature Predictions. Comb Chem High Throughput Screen 18:784-94
Assefnia, Shahin; Dakshanamurthy, Sivanesan; Guidry Auvil, Jaime M et al. (2014) Cadherin-11 in poor prognosis malignancies and rheumatoid arthritis: common target, common therapies. Oncotarget 5:1458-74
Issa, Naiem T; Byers, Stephen W; Dakshanamurthy, Sivanesan (2014) Big data: the next frontier for innovation in therapeutics and healthcare. Expert Rev Clin Pharmacol 7:293-8
Brouxhon, Sabine M; Kyrkanides, Stephanos; Teng, Xiaofei et al. (2014) Soluble-E-cadherin activates HER and IAP family members in HER2+ and TNBC human breast cancers. Mol Carcinog 53:893-906

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