Faculty Bibliography

T-cell acute lymphoblastic leukaemia (T-ALL) is a blood malignancy afflicting mainly children and adolescents. T-ALL patients present at diagnosis with increased white cell counts and hepatosplenomegaly, and are at an increased risk of central nervous system (CNS) relapse. For that reason, T-ALL patients usually receive cranial irradiation in addition to intensified intrathecal chemotherapy. The marked increase in survival is thought to be worth the considerable side-effects associated with this therapy. Such complications include secondary tumours, neurocognitive deficits, endocrine disorders and growth impairment. Little is known about the mechanism of leukaemic cell infiltration of the CNS, despite its clinical importance. Here we show, using T-ALL animal modelling and gene-expression profiling, that the chemokine receptor CCR7 (ref. 5) is the essential adhesion signal required for the targeting of leukaemic T-cells into the CNS. Ccr7 gene expression is controlled by the activity of the T-ALL oncogene Notch1 and is expressed in human tumours carrying Notch1-activating mutations. Silencing of either CCR7 or its chemokine ligand CCL19 (ref. 6) in an animal model of T-ALL specifically inhibits CNS infiltration. Furthermore, murine CNS-targeting by human T-ALL cells depends on their ability to express CCR7. These studies identify a single chemokine-receptor interaction as a CNS 'entry' signal, and open the way for future pharmacological targeting. Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS-targeted therapy, thus reducing its associated short- and long-term complications

OBJECTIVES: We evaluated and compared tumor antigen precursor protein (TAPP) profiles in adult and pediatric brain tumors of 31 genes related to tumor associated antigens (TAA) for possible use in immunotherapy. Antigens were selected based on their potential to stimulate T cell responses against tumors of neuroectodermal origin. METHODS: Thirty-seven brain tumor specimens from 11 adult and 26 pediatric patients were analyzed by quantitative real-time PCR for the relative expression of 31 TAPP mRNAs. The age range of adults (4F:7M) was 27-77 years (median 51.5 +/- 14.5 years) and for pediatrics (12F:14M) was 0.9-19 years (median 8.3 +/- 5.5 years). Histological diagnoses consisted of 16 glioblastomas, 4 low grade astrocytomas, 10 juvenile pilocytic astrocytomas, and 7 ependymomas. RESULTS: The adult gliomas expressed 94% (29 of 31) of the TAPP mRNAs evaluated compared with pediatric brain tumors that expressed 55-74% of the TAPP mRNAs, dependent on tumor histological subtype. Four types of TAPP expression patterns were observed: (1) equal expression among adult and pediatric cases, (2) greater expression in adult than pediatric cases, (3) expression restricted to adult GBM and (4) a random distribution. The pediatric brain tumors lacked expression of some genes associated with engendering tumor survival, such as hTert and Survivin. CONCLUSIONS: The potential TAA targets identified from the TAPP profiles of 31 genes associated with adult and pediatric brain tumors may help investigators select specific target antigens for developing dendritic cell- or peptide-based vaccines or T cell-based immunotherapeutic approaches against brain tumors

Previously, we identified noscapine as a small molecule inhibitor of the hypoxia-inducible factor-1 pathway in hypoxic human glioma cells and human umbilical vein endothelial cells. Noscapine is a nontoxic ingredient in cough medicine currently used in clinical trials for patients with non-Hodgkin's lymphoma or chronic lymphocytic leukemia to assess antitumor efficacy. Here, we have evaluated the sensitivity of four human glioma cell lines to noscapine-induced apoptosis. Noscapine was a potent inhibitor of proliferation and inducer of apoptosis. Induction of apoptosis was associated with activation of the c-jun N-terminal kinase signaling pathway concomitant with inactivation of the extracellular signal regulated kinase signaling pathway and phosphorylation of the antiapoptotic protein Bcl-2. Noscapine-induced apoptosis was associated with the release of mitochondrial proteins apoptosis-inducing factor (AIF) and/or cytochrome c. In some glioma cell lines, only AIF release occurred without cytochrome c release or poly (ADP-ribose) polymerase cleavage. Knock-down of AIF decreased noscapine-induced apoptosis. Our results suggest the potential importance of noscapine as a novel agent for use in patients with glioblastoma owing to its low toxicity profile and its potent anticancer activity

BACKGROUND AND PURPOSE: MR imaging can measure tissue perfusion and the integrity of the blood-brain barrier. We hypothesize that a combined measure of cerebral blood volume and vascular permeability using vascular-space occupancy (VASO) MR imaging, a recently developed imaging technique, is of diagnostic value for predicting tumor grade. MATERIALS AND METHODS: Thirty-nine patients (9 World Health Organization [WHO] grade II, 20 grade III, and 10 grade IV as determined by histopathologic assessment) were examined using VASO MR imaging, and regions-of-interest analysis was performed in tumoral regions, as well as in regions contralateral to the tumor. A Mann-Whitney test was conducted on the resulting VASO indices for a pairwise comparison across tumor grades. Nominal logistic regression was used to evaluate the use of VASO parameters for predicting group membership (by the percentage of correct classifications). RESULTS: The ratio between tumor side and contralateral side, VASO(Ratio), showed significant differences in all 3 of the pairwise comparisons (P < .01). VASO values in the tumoral regions, VASO(Tumor), showed significant difference between grade II and III and between II and IV but not between III and IV. Both VASO(Tumor) and VASO(Ratio) were found to be significant predictors of tumor grade, giving diagnostic accuracies of 66.7% and 71.8%, respectively. When testing to discriminate grade II tumors from higher grade tumors, the areas under the receiver operating characteristic curve were found to be 0.974 and 0.985 for VASO(Tumor) and VASO(Ratio), respectively. CONCLUSION: VASO MR imaging can be used for noninvasive tumor grade prediction based on cerebral blood volume and vascular permeability. VASO is more effective in separating WHO grade II from higher grades than in separating grade III from grade IV