Identifying Novel Genes and Pathways Correlated with Group 3 and Group 4 Medulloblastoma Metastasis to the Spine

Medulloblastoma (MB) is a cancer of the cerebellum and the most common childhood brain malignancy. For children with high-risk MB, mortality is nearly always the result of the primary tumour having metastasized to the leptomeninges. This is due to the fact that current therapy for metastatic MB is less effective than that for primary disease. This is a product of the fact that most MB research has focused on primary tumours rather than metastases, due to the low availability of metastatic MB tissues for research, and, until recently, the absence of mouse models of metastatic MB. With greater understanding of primary MB has come a more rounded foundation upon which to build a better therapy. Thus, it is exciting to note that mouse models of MB dissemination now exist, and with these models has come first glimpses of mechanisms that may be driving MB metastasis. In an effort to build upon this new body of knowledge our lab engaged in a process of repeated selection for increased metastasis propensity among spine metastases from mouse patient-derived xenograft (PDX) models of human Group 3 and Group 4 MB. By phenotypically selecting for increased metastasis propensity, we would necessarily also select for increased activity of the genes and pathways necessary and sufficient for increased metastasis propensity, some of which might represent valuable new therapeutic targets. In this manner, we have identified several long non-coding RNAs (lncRNAs) and Cancer Testis Antigen (CTA) genes increasingly transcribed in correlation with metastasis. Further, we have found that their increased transcription is followed closely by the activation of several well- known metastasis pathways. So lncRNAs and CTA genes may represent novel new components of the complex systems regulating MB metastasis.Ph.D

Divergent clonal selection dominates medulloblastoma at recurrence

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

Divergent clonal selection dominates medulloblastoma at recurrence

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

Divergent clonal selection dominates medulloblastoma at recurrence

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