Radiation-enhanced therapeutic targeting of galectin-1 enriched malignant stroma in triple negative breast cancer

// Meenakshi Upreti 1, 3 , Amar Jyoti 1, 3 , Sara E. Johnson 2 , Elden P. Swindell 4 , Dana Napier 3 , Pallavi Sethi 1, 3 , Ryan Chan 1 , Jonathan M. Feddock 5 , Heidi L. Weiss 3 , Thomas V. O’Halloran 4 , B. Mark Evers 3, 6 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA 2 Markey Cancer Center, University of Kentucky, Lexington, KY, USA 3 Department of Pathology, University of Kentucky, Lexington,KY, USA 4 Department of Chemistry, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA 5 Department of Radiation Medicine, University of Kentucky Chandler Hospital, Lexington, KY, USA 6 Department of Surgery, University of Kentucky, Lexington, KY, USA Correspondence to: Meenakshi Upreti, email: m.upreti@uky.edu Keywords: galectin-1, triple negative breast cancer, stromal-targeting, TNBC tumor model, tumor tissue analog (TTA) Received: February 18, 2016      Accepted: May 04, 2016      Published: May 19, 2016 ABSTRACT Currently there are no FDA approved targeted therapies for Triple Negative Breast Cancer (TNBC). Ongoing clinical trials for TNBC have focused primarily on targeting the epithelial cancer cells. However, targeted delivery of cytotoxic payloads to the non-transformed tumor associated-endothelium can prove to be an alternate approach that is currently unexplored. The present study is supported by recent findings on elevated expression of stromal galectin-1 in clinical samples of TNBC and our ongoing findings on stromal targeting of radiation induced galectin-1 by the anginex-conjugated arsenic-cisplatin loaded liposomes using a novel murine tumor model. We demonstrate inhibition of tumor growth and metastasis in response to the multimodal nanotherapeutic strategy using a TNBC model with orthotopic tumors originating from 3D tumor tissue analogs (TTA) comprised of tumor cells, endothelial cells and fibroblasts. The ‘rigorous’ combined treatment regimen of radiation and targeted liposomes is also shown to be well tolerated. More importantly, the results presented provide a means to exploit clinically relevant radiation dose for concurrent receptor mediated enhanced delivery of chemotherapy while limiting overall toxicity. The proposed study is significant as it falls in line with developing combinatorial therapeutic approaches for stroma-directed tumor targeting using tumor models that have an appropriate representation of the TNBC microenvironment.