title: Radiation-enhanced therapeutic targeting of galectin-1 enriched malignant stroma in triple negative breast cancer.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.|Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Upreti
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.|Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: Amar
authors.initials: A
authors.lastname: Jyoti
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Johnson
authors.affiliation: Department of Chemistry, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA.
authors.forename: Elden P
authors.initials: EP
authors.lastname: Swindell
authors.affiliation: Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Napier
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.|Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Sethi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Chan
authors.affiliation: Department of Radiation Medicine, University of Kentucky Chandler Hospital, Lexington, KY, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Feddock
authors.affiliation: Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Weiss
authors.affiliation: Department of Chemistry, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: O'Halloran
authors.affiliation: Department of Pathology, University of Kentucky, Lexington, KY, USA.|Department of Surgery, University of Kentucky, Lexington, KY, USA.
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
mesh_terms: D000328:Adult; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D059248:Chemoradiotherapy / Q000379:methods*; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D037483:Galectin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D009362:Neoplasm Metastasis; D010087:Oxides / Q000008:administration & dosage; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D001152:Arsenicals; D037483:Galectin 1; D010087:Oxides; D002945:Cisplatin; D000077237:Arsenic Trioxide
keywords: TNBC tumor model; galectin-1; stromal-targeting; triple negative breast cancer; tumor tissue analog (TTA)