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Adjuvant Sirolimus Does Not Improve Outcome in Pet Dogs Receiving Standard of Care Therapy for Appendicular Osteosarcoma: a Prospective, Randomized Trial of 324 Dogs

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Adjuvant Sirolimus Does Not Improve Outcome in Pet Dogs Receiving Standard of Care Therapy for Appendicular Osteosarcoma: a Prospective, Randomized Trial of 324 Dogs Author Manuscript Published OnlineFirst on March 22, 2021; DOI: 10.1158/1078-0432.CCR-21-0315 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Adjuvant sirolimus does not improve outcome in pet dogs receiving standard of care therapy for 2 appendicular osteosarcoma: A prospective, randomized trial of 324 dogs 3 4 Authors: 5 Amy K. LeBlanc*‡1, Christina Mazcko1, Aswini Cherukuri1, Erika P. Berger2, William C. 6 Kisseberth3, Megan E. Brown3, Susan Lana4, Kristen Weishaar4, Brian K. Flesner5, Jeffrey N. 7 Bryan5, David M. Vail6, Jenna H. Burton7, Jennifer L. Willcox7, Anthony J. Mutsaers8, J. Paul 8 Woods8, Nicole C. Northrup9, Corey Saba9, Kaitlin M. Curran10, Haley Leeper10, Heather 9 Wilson-Robles11, Brandan G. Wustefeld-Janssens11, Stephanie Lindley12, Annette N. Smith12, 10 Nikolaos Dervisis13,14,15, Shawna Klahn13, Mary Lynn Higginbotham16, Raelene M. Wouda16, 11 Erika Krick17, Jennifer A. Mahoney17, Cheryl A. London18, Lisa G. Barber18, Cheryl E. 12 Balkman19, Angela L. McCleary-Wheeler19, Steven E. Suter20, Olya Martin21, Antonella 13 Borgatti22, Kristine Burgess18, Michael O. Childress23, Janean L. Fidel24, Sara Allstadt21, Daniel 14 L. Gustafson4, Laura E. Selmic3, Chand Khanna1,25,26, Timothy M. Fan27,28*‡. 15 *These authors contributed equally 16 1 Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, 17 Bethesda, Maryland 18 2Frederick National Laboratory for Cancer Research in the Comparative Oncology Program, 19 National Cancer Institute, Bethesda, Maryland 20 3 Department of Veterinary Clinical Sciences, The Ohio State University College of Veterinary 21 Medicine, Columbus, Ohio 22 4 Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, 23 Colorado State University, Fort Collins, Colorado 24 5 Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University 25 of Missouri, Columbia, Missouri 26 6 Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin- 27 Madison, Madison, Wisconsin 28 7 Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University 29 of California-Davis, Davis, California 30 8Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, 31 CA. 1 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 22, 2021; DOI: 10.1158/1078-0432.CCR-21-0315 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 32 9 Department of Small Animal Medicine & Surgery, College of Veterinary Medicine University 33 of Georgia, Athens, Georgia 34 10 Department of Clinical Sciences, Carlson College of Veterinary Medicine, Oregon State 35 University, Corvallis, Oregon 36 11 Department of Small Animal Clinical Sciences, College of Veterinary Medicine and 37 Biomedical Sciences, Texas A&M University, College Station, Texas 38 12 Department of Clinical Sciences, Wilford and Kate Bailey Small Animal Teaching Hospital, 39 Auburn University College of Veterinary Medicine, Auburn, Alabama 40 13 Department of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary 41 Medicine, Blacksburg, Virginia 42 14 ICATS Center for Engineered Health, Virginia Tech, Kelly Hall, Blacksburg, Virginia 43 15 Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, 44 Virginia 45 16 Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, 46 Manhattan, Kansas 47 17 Ryan Veterinary Hospital, University of Pennsylvania, Philadelphia, Pennsylvania 48 18 Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts 49 University, North Grafton, Massachusetts 50 19 Department of Clinical Sciences, Cornell University College of Veterinary Medicine, New 51 York 52 20 Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State 53 University, Raleigh, North Carolina 54 21 Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of 55 Tennessee, Knoxville, Tennessee 56 22 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of 57 Minnesota, St. Paul, Minnesota 58 23 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue 59 University, West Lafayette, Indiana 60 24 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington 61 State University, Pullman, Washington 62 25 Ethos Veterinary Health, Woburn, Massachusetts 63 26 Ethos Discovery, San Diego, California 64 27 Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of 65 Illinois at Urbana-Champaign, Urbana, Illinois 66 28 Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois 67 68 Running Title: Adjuvant sirolimus in canine appendicular osteosarcoma 69 70 Keywords: osteosarcoma, mTOR inhibition, canine, comparative oncology, clinical trials 71 2 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 22, 2021; DOI: 10.1158/1078-0432.CCR-21-0315 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 72 Additional Information: 73 74 Dr. Allstadt’s current address is: Veterinary Specialists of North Texas, 4631 Citylake Blvd 75 West, Ft. Worth Texas 76132 76 Dr. McCleary-Wheeler’s current address is: Department of Veterinary Medicine and Surgery 77 College of Veterinary Medicine, University of Missouri, Columbia, Missouri 78 Dr. Jenna Burton’s current address is: Flint Animal Cancer Center, College of Veterinary 79 Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80 Dr. Wustefeld-Janssens’s current address is: Flint Animal Cancer Center, College of Veterinary 81 Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 82 Dr. Krick’s current address is: Mount Laurel Animal Hospital, 220 Mount Laurel Rd., Mount 83 Laurel, New Jersey 84 85 ‡Corresponding authors: 86 Amy K. LeBlanc DVM DACVIM (Oncology) 87 Director, Comparative Oncology Program 88 Center for Cancer Research 89 National Cancer Institute, National Institutes of Health 90 37 Convent Drive, Room 2144 91 Bethesda, MD 20892 92 Phone: 240-760-7093 93 Email: [email protected] 94 95 Timothy M. Fan, DVM, PhD 3 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 22, 2021; DOI: 10.1158/1078-0432.CCR-21-0315 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 96 Comparative Oncology Research Laboratory 97 Department of Veterinary Clinical Medicine 98 College of Veterinary Medicine 99 Cancer Center at Illinois 100 University of Illinois at Urbana-Champaign 101 Urbana, IL 61802 102 Phone: 217-333-5375 103 Email: [email protected] 104 ORCID ID (AKL): 0000-0001-7656-9859 105 106 The authors declare no conflicts of interest. 107 108 Statement of Translational Relevance 109 Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that serves as a key 110 nutrient sensor that regulates diverse cellular functions including ribosome biosynthesis, protein 111 translation, growth, and cytoskeletal rearrangement. Identified as a driver of metastasis, mTOR 112 and its downstream signaling pathways mediated by mTORC1 and mTORC2, serve as attractive 113 druggable targets for delaying metastatic progression in solid tumors including osteosarcoma. 114 However, given osteosarcoma’s orphan disease status, the scalable and rapid assessment of 115 mTOR inhibitors used in the upfront adjuvant setting would be protracted, necessitating the 116 employment of higher throughput model systems that faithfully recapitulate the biologic 117 complexities of the human disease. This study utilizes canine osteosarcoma patients as a means 118 to efficiently evaluate the mTOR inhibitor, sirolimus, as a potential antimetastatic agent. Our 119 results provide high-value biologic evidence for the translational value of canine osteosarcoma 4 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 22, 2021; DOI: 10.1158/1078-0432.CCR-21-0315 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 120 for prioritizing novel antimetastatic strategies that might be advanced for pediatric osteosarcoma 121 clinical trials. 122 5 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 22, 2021; DOI: 10.1158/1078-0432.CCR-21-0315 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 123 Abstract 124 Purpose: The mTOR pathway has been identified as a key nutrient signaling hub that 125 participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling 126 is biologically-achievable with sirolimus, and might slow the outgrowth of distant metastases. In 127 this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic 128 models for pediatric osteosarcoma,
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