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Glioblastoma is a heterogeneous, malignant brain tumour. Despite aggressive treatment with surgery, radiotherapy, and chemotherapy, patients have a median survival time from diagnosis of 15 months. Intratumoral heterogeneity and the ability of glioblastoma to rapidly evolve in response to selective pressures contribute to inevitable treatment failure and disease recurrence. Radiation is an integral component of most first line treatment regimens for glioblastoma. The results presented in this thesis demonstrate that radiation has the ability to drive glioblastoma evolution. In particular, radiation produced a reduction in clonal diversity. While the selection of subpopulations demonstrated in irradiated tumo urs may not lead to the emergence of radioresistant clones, as demonstrated by reirradiation protocols, the results do suggest changes in fundamental biology at tumour recurrence and an important role for the microenvironment in guiding the evolutionary process. Because intratumoral heterogeneity was not shown to yield differential radiosensitivities, future insights on radiation- induced glioblastoma evolution may contribute to improved therapies that enhance radioresponse for the entire tumour at both primary and recurrent stages.
Research Funding
Financial support for research described in Chapters 4-6 was provided by Division of Basic Sciences, Intramural Program, National Cancer Institute (Z1ABC011372, Z1ABC011373) to P.J. Tofilon. This project has also been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this thesis does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organisations imply endorsement by the U.S. Government.
Financial support for research described in Appendix A was provided by Brain Tumour Charity (RG89672), the National Institute for Health Research Cambridge Biomedical Research Center, and the Higher Education Funding Council for England. Tissue was accessed through the Human Research Tissue Bank supported by the NIHR Cambridge Biomedical Research Centre and Addenbrooke’s Hospital.
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