title: Systematic Screening Identifies Dual PI3K and mTOR Inhibition as a Conserved Therapeutic Vulnerability in Osteosarcoma.
abstract: OBJECTIVE
  Osteosarcoma is the most common cancer of bone occurring mostly in teenagers. Despite rapid advances in our knowledge of the genetics and cell biology of osteosarcoma, significant improvements in patient survival have not been observed. The identification of effective therapeutics has been largely empirically based. The identification of new therapies and therapeutic targets are urgently needed to enable improved outcomes for osteosarcoma patients.
  
  
  METHODS
  We have used genetically engineered murine models of human osteosarcoma in a systematic, genome-wide screen to identify new candidate therapeutic targets. We performed a genome-wide siRNA screen, with or without doxorubicin. In parallel, a screen of therapeutically relevant small molecules was conducted on primary murine- and primary human osteosarcoma-derived cell cultures. All results were validated across independent cell cultures and across human and mouse osteosarcoma.
  
  
  RESULTS
  The results from the genetic and chemical screens significantly overlapped, with a profound enrichment of pathways regulated by PI3K and mTOR pathways. Drugs that concurrently target both PI3K and mTOR were effective at inducing apoptosis in primary osteosarcoma cell cultures in vitro in both human and mouse osteosarcoma, whereas specific PI3K or mTOR inhibitors were not effective. The results were confirmed with siRNA and small molecule approaches. Rationale combinations of specific PI3K and mTOR inhibitors could recapitulate the effect on osteosarcoma cell cultures.
  
  
  CONCLUSIONS
  The approaches described here have identified dual inhibition of the PI3K-mTOR pathway as a sensitive, druggable target in osteosarcoma, and provide rationale for translational studies with these agents.
authors: St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
authors: Ankita
authors: A
authors: Gupte
authors: St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
authors: Emma K
authors: EK
authors: Baker
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors: Soo-San
authors: SS
authors: Wan
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors: Elizabeth
authors: E
authors: Stewart
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors: Amos
authors: A
authors: Loh
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors: Anang A
authors: AA
authors: Shelat
authors: Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors: Cathryn M
authors: CM
authors: Gould
authors: St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
authors: Alistair M
authors: AM
authors: Chalk
authors: St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
authors: Scott
authors: S
authors: Taylor
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors: Kurt
authors: K
authors: Lackovic
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors: Åsa
authors: Å
authors: Karlström
authors: St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia. Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
authors: Anthony J
authors: AJ
authors: Mutsaers
authors: Department of Medical Oncology, Royal Melbourne Hospital, Melbourne, Victoria, Australia. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors: Jayesh
authors: J
authors: Desai
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors: Piyush B
authors: PB
authors: Madhamshettiwar
authors: Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia. Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors: Andrew C W
authors: AC
authors: Zannettino
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors: Chris
authors: C
authors: Burns
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors: David C S
authors: DC
authors: Huang
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee. Howard Hughes Medical Institute, Chevy Chase, Maryland. cwalkley@svi.edu.au michael.dyer@stjude.org.
authors: Michael A
authors: MA
authors: Dyer
authors: Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Kaylene J
authors: KJ
authors: Simpson
authors: St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia. ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia. cwalkley@svi.edu.au michael.dyer@stjude.org.
authors: Carl R
authors: CR
authors: Walkley
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005818:Genetic Engineering; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D012516:Osteosarcoma / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases