Improved therapeutic targets in prevalent pediatric malignancies.

摘要

Together, medulloblastoma, astrocytoma, and acute lymphoblastic leukemia (ALL) account for approximately 40% of pediatric cancer diagnoses and 32% of childhood cancer deaths. While a majority of patients diagnosed with each of these diseases are cured, many still respond poorly to treatment. We used gene expression profiling in good- and poor-prognosis cancers and identified differentially expressed genes that may serve as novel therapeutic targets.; We first identified 85 genes differentially expressed between primary metastatic and non-metastatic medulloblastoma tumors. Notably, expression of platelet-derived growth factor receptor alpha (PDGFRA) and members of the downstream RAS/mitogen-activated protein kinase signal transduction pathway were dysregulated in metastatic tumors. Blocking this signaling pathway inhibits adhesion and migration of metastatic medulloblastoma cells, suggesting that this pathway may mediate medulloblastoma metastasis. Inhibitors of PDGFRA and RAS proteins are currently being investigated as possible novel therapeutic strategies.; We next identified genes differentially expressed between high-grade malignant astrocytomas (HGA) and low-grade benign astrocytomas (LGA). Because one of the hallmarks of HGA is increased tumor vasculature, we concentrated on the expression pattern of 133 angiogenesis-related genes. Forty-four of these genes were differentially expressed between HGA and LGA. A novel finding was overexpression of hypoxia-inducible transcription factor 2 alpha (HIF-2a) and several HIF-associated genes by HGA. HIF and its downstream targets may therefore represent new therapeutic targets.; Finally, we expression profiled patient-matched pairs of ALL bone marrows from the time of initial diagnosis and eventual bone marrow relapse. Tissue heterogeneity between diagnosis and relapse bone marrow was corrected for through informatics and cell-sorting, and thus we identified genes differentially expressed between diagnosis and relapse. Notably, we observed underexpression at relapse of the inositol 1,4,5-triphosphate receptor and overexpression at relapse of STAT1, genes previously implicated in mediating the response of ALL cells to chemotherapeutic agents. These data also include other novel genes that may play a role in ALL bone marrow relapse and resistance to therapy. The new molecular targets for therapy will hopefully improve outcome in these commonly occurring pediatric cancers.