The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
Bibliographical noteFunding Information:
Acknowledgements The MAGIC project is financially supported by: Genome Canada, Genome BC, Terry Fox Research Institute, Ontario Institute for Cancer Research, Pediatric Oncology Group Ontario, Funds from ‘The Family of Kathleen Lorette’ and the Clark H. Smith Brain Tumour Centre, Montreal Children’s Hospital Foundation, Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, B.R.A.I.N. Child, and BC Childhood Cancer Parents Association. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is supported by The Canadian Cancer Society Research Institute, The Garron Family Chair in Childhood Cancer Research, and grants from the Cure Search for Children’s Cancer Foundation, the National Institutes of Health (R01CA148699 R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, Brainchild and The McLaughlin Centre at the University of Toronto. M.D.T. is also supported by the Swifty Foundation. L.G. was supported by the Davis M. Ferguson Memorial Fund at ABTA. Alex’s Lemonade Stand Young Investigator Award supported V.R. This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. This work was also supported by a Program Project Grant from the Terry Fox Research Institute, and a Grand Challenge Award from CureSearch for Children’s Cancer. Additionally, this work was supported by the PedBrain Tumour Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and NGFNplus 01GS0883). Funding by the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung) to S.M.P., G.F. and T.P. The study was also financed by the Hungarian Brain Research Program Grant No. KTIA_13_NAP-A-V/3. and NAP-A-II/7. A.K. was supported by the János Bolyai scholarship of the Hungarian Academy of Sciences. E.G.V.M. was supported by NIH R01 grants CA163722 and NS096236, and St. Baldrick’s and Cure Childhood Cancer Foundations . We would like to acknowledge R. P. Hill (Ontario Cancer Institute), the Labatt Brain Tumour Research Centre Tumour and Tissue Repository, which is supported by B.R.A.I.N. Child and Megan’s Walk. M.R. is supported by a fellowship from the Dr. Mildred Scheel Foundation for Cancer Research/ German Cancer Aid. F.M.G.C. is supported by the Stephen Buttrum Brain Tumour Research Fellowship, granted by Brain Tumour Foundation of Canada. V.R. is supported by a CIHR fellowship and an Alberta Innovates-Health Solutions Clinical Fellowship. We would like to thank the Toronto Centre for Phenogenomics for animal housing and veterinary support, and the Preclinical Core II and animal research facility at STTARR (Spatiotemporal Targeting and Amplification of Radiation Response) in Toronto for assistance with CT-guided radiation experiments. We would like to thank Z. Wang for technical help with IHC, S. Archer for technical writing and C. Smith for artwork.