Delineation of molecular targets for malignant brain tumors

One promising new approach to the treatment of cancer utilizes small molecule inhibitors directed at signaling pathways deregulated in cancer cells. Cancers commonly contain mutations and epigenetic alterations that result in constitutive, unregulated activation of signaling pathways. While these deregulated signaling networks define the biological behavior of cancer cells, they also provide a target for therapy. Because cancer cells, unlike normal cells, may become dependent on these constitutively activated signaling pathways, selected signaling inhibitors hold the promise of effective and non-toxic therapy. The work in this dissertation focuses on the development of targeted molecular therapy for two malignant brain tumors, medulloblastoma and glioblastoma, by elucidating targetable signaling pathways in each. Medulloblastomas arise from neural precursor cells and commonly express neurotrophin receptors, which have prognostic significance for these tumors. We have delineated important characteristics of the neurotrophin receptor, TrkA, including: variations in ligand-activation following interaction with its co-receptor, p75 NTR; a novel observation of its physical state prior to ligand-activation; and the identification of biochemical differences between TrkA-induced apoptosis and differentiation. We have also evaluated how this receptor promotes apoptosis of medulloblastoma cells, thus providing a rationale for the targeted manipulation of these pathways. For the adult brain tumor, glioblastoma, we utilized patient-derived glioblastoma cells cultured ex vivo to investigate the efficacy of two targeted inhibitors---the camptothecin, SN-38, and the rapamycin derivative, CCI-779---and defined positive indicators of drug response which may improve the clinical application of these drugs. First, as demonstrated for other cell types, markers of DNA replication correlate with glioblastoma sensitivity to SN-38. Second, glioblastoma cells harboring deregulation of the PI3'K-Akt pathway via diminished expression of PTEN exhibit enhanced sensitivity to CCI-779-mediated growth arrest, suggesting that patient tumors harboring low PTEN expression may exhibit preferential sensitivity to this drug. Based in part upon this finding, investigators at UCLA have initiated a Phase I trial to assess the validity of pre-screening patients for PTEN protein expression prior to rapamycin treatment.