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1.  High-Dose Chemotherapy with Autologous Hematopoietic Stem-Cell Rescue for Pediatric Brain Tumor Patients: A Single Institution Experience from UCLA 
Journal of Transplantation  2011;2011:740673.
Background. Dose-dependent response makes certain pediatric brain tumors appropriate targets for high-dose chemotherapy with autologous hematopoietic stem-cell rescue (HDCT-AHSCR). Methods. The clinical outcomes and toxicities were analyzed retrospectively for 18 consecutive patients ≤19 y/o treated with HDCT-AHSCR at UCLA (1999–2009). Results. Patients' median age was 2.3 years. Fourteen had primary and 4 recurrent tumors: 12 neural/embryonal (7 medulloblastomas, 4 primitive neuroectodermal tumors, and a pineoblastoma), 3 glial/mixed, and 3 germ cell tumors. Eight patients had initial gross-total and seven subtotal resections. HDCT mostly consisted of carboplatin and/or thiotepa ± etoposide (n = 16). Nine patients underwent a single AHSCR and nine ≥3 tandems. Three-year progression-free and overall survival probabilities were 60.5% ± 16 and 69.3% ± 11.5. Ten patients with pre-AHSCR complete remissions were alive/disease-free, whereas 5 of 8 with measurable disease were deceased (median followup: 2.3 yrs). Nine of 13 survivors avoided radiation. Single AHSCR regimens had greater toxicity than ≥3 AHSCR (P < .01). Conclusion. HDCT-AHSCR has a definitive, though limited role for selected pediatric brain tumors with poor prognosis and pretransplant complete/partial remissions.
PMCID: PMC3087896  PMID: 21559259
2.  Asparagine Depletion Potentiates the Cytotoxic Effect of Chemotherapy Against Brain Tumors 
Molecular cancer research : MCR  2014;12(5):694-702.
Targeting amino acid metabolism has therapeutic implications for aggressive brain tumors. Asparagine is an amino acid that is synthesized by normal cells. However, some cancer cells lack asparagine synthetase (ASNS), the key enzyme for asparagine synthesis. Asparaginase (ASNase) contributes to eradication of acute leukemia by decreasing asparagine levels in serum and cerebrospinal fluid. However, leukemic cells may become ASNase-resistant by up-regulating ASNS. High expression of ASNS has also been associated with biological aggressiveness of other cancers, including gliomas. Here, the impact of enzymatic depletion of asparagine on proliferation of brain tumor cells was determined. ASNase was used as monotherapy or in combination with conventional chemotherapeutic agents. Viability assays for ASNase-treated cells demonstrated significant growth reduction in multiple cell lines. This effect was reversed by glutamine in a dose-dependent manner -- as expected, because glutamine is the main amino group donor for asparagine synthesis. ASNase treatment also reduced sphere formation by medulloblastoma and primary glioblastoma cells. ASNase-resistant glioblastoma cells exhibited elevated levels of ASNS mRNA. ASNase co-treatment significantly enhanced gemcitabine or etoposide cytotoxicity against glioblastoma cells. Xenograft tumors in vivo showed no significant response to ASNase monotherapy and little response to temozolomide (TMZ) alone. However, combinatorial therapy with ASNase and TMZ resulted in significant growth suppression for an extended duration of time. Taken together, these findings indicate that amino acid depletion warrants further investigation as adjunctive therapy for brain tumors.
PMCID: PMC4020976  PMID: 24505127
Asparaginase; deamination; glutamine; glioblastoma; medulloblastoma; temozolomide
3.  Autologous Tumor Lysate-pulsed Dendritic Cell Immunotherapy for Pediatric Patients with Newly Diagnosed or Recurrent High-grade Gliomas 
Anticancer research  2013;33(5):2047-2056.
Immunotherapy has the potential to improve clinical outcomes with little toxicity for pediatric patients with brain tumors. We conducted a pilot feasibility study of tumor lysate-pulsed dendritic cell (DC) vaccination in pediatric patients (1 to 18 years old) with newly diagnosed or recurrent high-grade glioma (HGG). A total of nine DC vaccine doses, each containing 1×106 cells per dose were administered to three out of the seven originally enrolled patients. Toxicities were limited to mild side-effects, except in one case of elevated alkaline phosphatase, which resolved without clinical consequences. Two patients with primary lesions amongst the three vaccinated were alive at the time of writing, both without evidence of disease. Pre- and post-vaccination tumor samples from a patient with an anaplastic oligoastrocytoma that recurred failed to demonstrate immune cell infiltration by immunohistochemistry. Peripheral cytokine levels were evaluated in one patient following DC vaccination and demonstrated some changes in relation to vaccination. DC vaccine is tolerable and feasible with some limitations for pediatric patients with HGG. Dendritic cell based immunotherapy may provide some clinical benefit in pediatric patients with glioma, especially for patients with minimal residual disease, but further investigation of this modality is required.
PMCID: PMC4018463  PMID: 23645755
Pediatric neuro-oncology; high grade glioma; dendritic cell vaccine; immunotherapy
4.  Clinical Outcome in Pediatric Glial and Embryonal Brain Tumors Correlates With In Vitro Multi-Passageable Neurosphere Formation 
Pediatric blood & cancer  2010;55(4):644-651.
Cultured brain tumors can form neurospheres harboring tumorigenic cells with self renewal and differentiation capacities. Renewable neurosphere formation has clinical predictive value in adult malignant gliomas, yet its prognostic role for pediatric brain tumors is unknown.
Established neurosphere conditions were used for culturing samples from glial, embryonal and mixed glioneuronal tumors from 56 pediatric patients. Potential associations between neurosphere formation and clinical outcome were analyzed retrospectively.
Thirty-seven percent of all samples formed renewable neurospheres. Analysis of available clinical outcome data from 51 patients demonstrated significantly increased hazard ratios (HR) for both disease progression (HR=9.9, P < 0.001) and death (HR=16.6, P < 0.01) in the neurosphere forming group. Furthermore, neurosphere formation correlated with adverse progression free survival (PFS) in glial and embryonal tumors, but not in mixed glioneuronal tumors. Overall survival (OS) was significantly worse for neurosphere-forming patients with embryonal tumors, as a group and amongst the subgroup with medulloblastoma, but not in the glial group. Multivariate analysis showed that neurosphere formation was associated with diminished PFS and OS independent of age, gender, or treatment. Neurosphere formation was an independent predictor of diminished PFS of glial tumors after adjusting for grade. Multivariate analysis, adjusting for both Ki67 staining and neurosphere formation, demonstrated that neurosphere formation remained predictive of progression whereas Ki67 did not.
Neurosphere formation is more predictive of pediatric brain tumor progression than semi-quantitative Ki67 staining. Pediatric brain tumor derived neurospheres may provide a predictive model for preclinical explorations.
PMCID: PMC4017922  PMID: 20589659
brain; brain tumors; cancer biology; CNS tumors; neuro-oncology; outcomes research; tumors
5.  A molecular screening approach to identify and characterize inhibitors of glioblastoma stem cells 
Molecular cancer therapeutics  2011;10(10):1818-1828.
Glioblastoma multiforme (GBM) is amongst the most lethal of all cancers. GBM consist of a heterogeneous population of tumor cells amongst which a tumor initiating and treatment-resistant subpopulation, here termed GBM stem cells (GSC), have been identified as primary therapeutic targets. Here, we describe a high-throughput small molecule screening approach that enables the identification and characterization of chemical compounds that are effective against GSC. The paradigm uses a tissue culture model to enrich for GSC derived from human GBM resections and combines a phenotype-based screen with gene target-specific screens for compound identification. We used 31,624 small molecules from seven chemical libraries that we characterized and ranked based on their effect on a panel of GSC-enriched cultures as well as their effect on the expression of a module of genes whose expression negatively correlates with clinical outcome: MELK, ASPM, TOP2A and FOXM1b. Of the 11 compounds meeting criteria for exerting differential effects across cell types used, 4 compounds demonstrated selectivity by inhibiting multiple GSC-enriched cultures compared to non-enriched cultures: Emetine, N-Arachidonoyldopamine (NADA), N-Oleoyldopamine (OLDA), and N-Palmitoyldopamine (PALDA). ChemBridge compounds #5560509 and #5256360 inhibited the expression of the 4 mitotic module genes. OLDA, Emetine, and compounds #5560509 and #5256360 were chosen for more detailed study and inhibited GSC in self-renewal assays in vitro and in a xenograft model in vivo. These studies demonstrate that our screening strategy provides potential candidates as well as a blueprint for lead compound identification in larger scale screens or screens involving other cancer types.
PMCID: PMC3191241  PMID: 21859839
5256360; 5485415; 5560509; 6-Formylindolo Carbazole; Anisomycin; Benzethonium; Biomol; C8 Ceramine; Camptothecin; Cancer; Chelidonine monohydrate; ChemBridge; Chrysenequinone; Emetine; Methiazole; N-Arachidonoyldopamine; NADA; Neurosphere; N-Oleoyldopamine; OLDA; N-Palmitoyldopamine; PALDA; Prestwick; Ro 31-8220; Cancer Stem Cell; Glioma; Neural Stem Cell; Chemical Screen

Results 1-5 (5)