Teaching an Old Drug New Tricks:

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Teaching an Old Drug New Tricks: Utilizing a Novel Formulation of Niclosamide to Treat Metastatic Osteosarcoma Gireesh B. Reddy, MSIII Eward Lab, Department of Orthopaedic Surgery, Duke University School of Medicine Consortium for Canine Comparative Oncology (C3O) Symposium Durham Convention Center February 23, 2018

Challenge: Therapeutic advances for metastatic osteosarcoma have stagnated MAP ± HDMTX + FA 1970s – HDMTX + VC + FA Osteosarcoma survival in patients 0 to 24 years old delineated by stage. Increased incidence, disease progression, and similar histologic and genetic pathogenesis of canine OS enable initial study of potential next-generation chemotherapeutics. Mirabello L, et al. Cancer. 2009;115(7):1531-1543.

NSNPs inhibit human and canine OS growth and downregulate dysregulated OS pathways

Solution: Lipid encapsulated niclosamide stearate nanoparticles (NSNPs) Niclosamide – An old anthelminthic that demonstrates inhibition of Wnt, JAK/STAT3, and Akt/mTOR/S6. Poor bioavailability limits therapeutic utility outside the gut. Taking advantage of 1) Increased LDL-R expression in cancer and 2) Hydrophobic packaging capabilities of lipoproteins, we developed a novel lipid nanoparticle formulation of niclosamide stearate (NSNPs). Specifically the LRP5 Wnt co-receptor Hoang BH, et al. Int J Cancer. 2004;109(1):106-111. Shrivastava M, et al. Sci Pharm. 2014;82(4):873-888.

NSNPs slow metastasis progression and prolong survival without treatment-derived morbidity Mean tumor burden, by treatment PBS NSNPs Dox Change in weight over time, by treatment Kaplan-Meier survival curves, by treatment

Acknowledgements Will Eward, DVM, MD David Hsu, MD, PhD Jason Somarelli, PhD David Kerr Kathryn Ware, PhD Erdem Altunel, MD Suzanne DeWitt, DVM Sneha Rao Tim Kreulen Brooke Robbins Terese Camp David Needham, PhD, DSc Artak Tovmasyan, PhD Greg Palmer, PhD Gabi Hanna, PhD