Michael W Bishop1, Katherine A Janeway, Richard Gorlick. 1. aDepartment of Oncology, St. Jude Children's Research Hospital bDepartment of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee cDana-Farber Cancer Institute, Boston, Massachusetts dDivision of Pediatric Hematology/Oncology, The Children's Hospital At Montefiore, Bronx, New York, USA.
Abstract
PURPOSE OF REVIEW: Overall survival rates for osteosarcoma have remained essentially unchanged over the past 3 decades despite attempts to improve outcome via dose intensification and modification based on response. This review describes recent findings from contemporary clinical trials, advances in the comprehension of osteosarcoma biology and genomic complexity, and potential opportunities using targeted and immune-mediated therapies. RECENT FINDINGS: Recent results from international collaborative trials have failed to demonstrate an ability to improve outcomes using a design in which the randomized question is dictated based on histologic response to preoperative chemotherapy. Novel prognostic markers assessable at diagnosis are vital to identifying subsets of osteosarcoma. Clinical trials focus has now shifted to serial phase II studies of novel agents to evaluate for activity in recurrent and refractory disease. In-depth analyses have revealed profound genomic instability and heterogeneity across patients, with nearly universal TP53 aberration. Although driver mutational events have not clearly been established, frequent derangements in specific pathways may suggest opportunities for therapeutic exploitation. Genomic complexity may lend support to a role for immune-mediated therapies. SUMMARY: Rigorous preclinical investigations are potentially generating novel strategies for the treatment of osteosarcoma that will inform the next generation of clinical trials, with the opportunity to identify agents that will improve survival outcomes.
PURPOSE OF REVIEW: Overall survival rates for osteosarcoma have remained essentially unchanged over the past 3 decades despite attempts to improve outcome via dose intensification and modification based on response. This review describes recent findings from contemporary clinical trials, advances in the comprehension of osteosarcoma biology and genomic complexity, and potential opportunities using targeted and immune-mediated therapies. RECENT FINDINGS: Recent results from international collaborative trials have failed to demonstrate an ability to improve outcomes using a design in which the randomized question is dictated based on histologic response to preoperative chemotherapy. Novel prognostic markers assessable at diagnosis are vital to identifying subsets of osteosarcoma. Clinical trials focus has now shifted to serial phase II studies of novel agents to evaluate for activity in recurrent and refractory disease. In-depth analyses have revealed profound genomic instability and heterogeneity across patients, with nearly universal TP53 aberration. Although driver mutational events have not clearly been established, frequent derangements in specific pathways may suggest opportunities for therapeutic exploitation. Genomic complexity may lend support to a role for immune-mediated therapies. SUMMARY: Rigorous preclinical investigations are potentially generating novel strategies for the treatment of osteosarcoma that will inform the next generation of clinical trials, with the opportunity to identify agents that will improve survival outcomes.
Authors: C Scheel; K L Schaefer; A Jauch; M Keller; D Wai; C Brinkschmidt; F van Valen; W Boecker; B Dockhorn-Dworniczak; C Poremba Journal: Oncogene Date: 2001-06-28 Impact factor: 9.867
Authors: Jacson K Shen; Gregory M Cote; Edwin Choy; Pei Yang; David Harmon; Joseph Schwab; G Petur Nielsen; Ivan Chebib; Soldano Ferrone; Xinhui Wang; Yangyang Wang; Henry Mankin; Francis J Hornicek; Zhenfeng Duan Journal: Cancer Immunol Res Date: 2014-04-21 Impact factor: 11.151
Authors: Paul A Meyers; Cindy L Schwartz; Mark Krailo; Eugenie S Kleinerman; Donna Betcher; Mark L Bernstein; Ernest Conrad; William Ferguson; Mark Gebhardt; Allen M Goorin; Michael B Harris; John Healey; Andrew Huvos; Michael Link; Joseph Montebello; Helen Nadel; Michael Nieder; Judith Sato; Gene Siegal; Michael Weiner; Robert Wells; Lester Wold; Richard Womer; Holcombe Grier Journal: J Clin Oncol Date: 2005-03-20 Impact factor: 44.544
Authors: Jennifer A Perry; Adam Kiezun; Peter Tonzi; Eliezer M Van Allen; Scott L Carter; Sylvan C Baca; Glenn S Cowley; Ami S Bhatt; Esther Rheinbay; Chandra Sekhar Pedamallu; Elena Helman; Amaro Taylor-Weiner; Aaron McKenna; David S DeLuca; Michael S Lawrence; Lauren Ambrogio; Carrie Sougnez; Andrey Sivachenko; Loren D Walensky; Nikhil Wagle; Jaume Mora; Carmen de Torres; Cinzia Lavarino; Simone Dos Santos Aguiar; Jose Andres Yunes; Silvia Regina Brandalise; Gabriela Elisa Mercado-Celis; Jorge Melendez-Zajgla; Rocío Cárdenas-Cardós; Liliana Velasco-Hidalgo; Charles W M Roberts; Levi A Garraway; Carlos Rodriguez-Galindo; Stacey B Gabriel; Eric S Lander; Todd R Golub; Stuart H Orkin; Gad Getz; Katherine A Janeway Journal: Proc Natl Acad Sci U S A Date: 2014-12-15 Impact factor: 11.205
Authors: Jason Glover; Mark Krailo; Tanya Tello; Neyssa Marina; Katherine Janeway; Don Barkauskas; Timothy M Fan; Richard Gorlick; Chand Khanna Journal: Pediatr Blood Cancer Date: 2014-12-08 Impact factor: 3.167
Authors: G Grignani; E Palmerini; P Dileo; S D Asaftei; L D'Ambrosio; Y Pignochino; M Mercuri; P Picci; F Fagioli; P G Casali; S Ferrari; M Aglietta Journal: Ann Oncol Date: 2011-04-28 Impact factor: 32.976
Authors: Paul A Meyers; Cindy L Schwartz; Mark D Krailo; John H Healey; Mark L Bernstein; Donna Betcher; William S Ferguson; Mark C Gebhardt; Allen M Goorin; Michael Harris; Eugenie Kleinerman; Michael P Link; Helen Nadel; Michael Nieder; Gene P Siegal; Michael A Weiner; Robert J Wells; Richard B Womer; Holcombe E Grier Journal: J Clin Oncol Date: 2008-02-01 Impact factor: 44.544
Authors: Vincent I Poon; Michael Roth; Sajida Piperdi; David Geller; Jonathan Gill; Erin R Rudzinski; Douglas S Hawkins; Richard Gorlick Journal: Clin Sarcoma Res Date: 2015-01-24
Authors: Tewodros Mamo; Ann C Mladek; Kris L Shogren; Carl Gustafson; Shiv K Gupta; Scott M Riester; Avudaiappan Maran; Mario Galindo; Andre J van Wijnen; Jann N Sarkaria; Michael J Yaszemski Journal: Biochem Biophys Res Commun Date: 2017-03-12 Impact factor: 3.575
Authors: Lisa M Kopp; Suman Malempati; Mark Krailo; Yun Gao; Allen Buxton; Brenda J Weigel; Thomas Hawthorne; Elizabeth Crowley; Jeffrey A Moscow; Joel M Reid; Victor Villalobos; R Lor Randall; Richard Gorlick; Katherine A Janeway Journal: Eur J Cancer Date: 2019-10-03 Impact factor: 9.162