Publications by authors named "Giselle L S Sholler"

2 Publications

  • Page 1 of 1

Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors.

Pediatr Blood Cancer 2014 Jan 17;61(1):128-33. Epub 2013 Aug 17.

Department of Paediatrics, University of Toronto and New Agent and Innovative Therapy Programme, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background: The combination of vinblastine and mammalian target of rapamycin (mTOR) inhibitor sirolimus inhibits the growth of neuroblastoma xenografts through pro-apoptotic and anti-angiogenic mechanisms. This phase I study aimed to explore the safety and toxicity of this combination in pediatric patients with advanced solid tumors.

Procedure: Patients ≤21 years of age with recurrent/refractory solid tumors (including CNS) were eligible. Sirolimus was administered daily by mouth or nasogastric (NG) tube, with doses adjusted to achieve a target trough concentration of 10-15 ng/ml, with weekly intravenous vinblastine (dose escalated 4-6 mg/m(2)/dose according to 3 + 3 phase I design).

Results: Fourteen patients were enrolled (median age 8.7 years; range 2.3-19) of whom 12 were evaluable for toxicity and 11 for response. One patient experienced a dose-limiting toxicity (grade 3 mucositis) at the highest vinblastine dose level. Myelosuppression was the most common toxicity. Dose-adjusted sirolimus trough concentrations were significantly lower in patients receiving drug via NG tube (1.50 ± 0.75 ng/ml/mg vs. 2.25 ± 1.07 ng/ml/mg for oral administration). Correlative biomarker analysis demonstrated a significant reduction in serum concentration of soluble vascular endothelial growth factor receptor (sVEGFR2) at 28 days compared to baseline consistent with inhibition of angiogenesis. One patient had a partial response and three had stable disease for more than 3 months.

Conclusions: The combination of mTOR inhibitor and vinblastine given over an extended continuous schedule is safe, associated with a reduction in circulating angiogenic factor (CAF) VEGFR2 and resulted in clinical responses. Future studies using the intravenously administered mTOR inhibitor temsirolimus are planned.
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January 2014

Chemotherapeutic effect of calcidiol derivative B3CD in a neuroblastoma xenograft model.

Chem Biol Drug Des 2010 Aug 11;76(2):164-73. Epub 2010 May 11.

Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital of RI, Warren Alpert Medical School of Brown University, Providence, RI 02905, USA.

Bromoacetoxy-calcidiol (B3CD), a pro-apoptotic and cytotoxic agent in neuroblastoma (NB) cell lines, displayed therapeutic potential in vivo as an anticancer drug in a NB xenograft mouse model. Tumors of all animals treated intraperitoneally with B3CD went into regression within 10-30 days of treatment, while tumors in control animals grew aggressively. The response mechanisms of NB cells to B3CD in vitro were studied and included differential targeting of cell cycle key regulators p21 and cyclin D1 on the transcriptional and expression level leading to arrest in G0/G1 phase. In contrast to the effect in ovarian cancer cells, B3CD-induced cell death in SMS-KCNR NB cells was only marginally mediated by the p38 MAPK signaling pathway. Signaling induced by exogenous recombinant EGF leads to a partial restoration of the negative effects of B3CD on SMS-KCNR cell proliferation and survival. Upon combinational treatment of SMS-KCNR cells with B3CD and recombinant EGF, the EGF receptor (EGF-R) was highly activated. We suggest future studies to include analysis of the effects of B3CD in combination therapy with pharmacological inhibitors of cell cycle regulators or with EGF-R-targeting inhibitors, -toxins or -antibodies in vitro and their translation into in vivo models of tumor development.
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August 2010