ACCURATE PRECLINICAL TRIALS OF NEW EPENDYMOMA THERAPIES

Abstract:

Current treatment of ependymoma is limited to surgery and radiation since chemotherapy has been deemed generally ineffective. Potential new chemotherapies often fail in the clinic because they are not tested rigorously or appropriately preclinically. To identify new treatment approaches, we developed a preclinical approach that tests candidate drug efficacy against mouse models recapitulating two types of supratentorial ependymoma - C11orf95-RELA fusion positive (EPRELA+) and fusion negative (EPRELA-) disease - in the context of standard of care (surgery and fractionated irradiation). First, the efficacy of single modality neuro-surgical resection was established in mice bearing intracranial ependymomas, demonstrating a significant increase in survival (p < 0.05). Single-modality fractionated irradiation (54 Gy/30 fractions) was also shown to increase mouse survival, particularly those bearing EPRELA+ (p < 0.0001). Next, we combined these two treatment approaches with candidate chemotherapies that we identified through in vitro high-throughput drug screening (HTDS). Several highly active drugs were taken into preclinical, pharmacokinetically guided single agent studies but failed to show efficacy. Gemcitabine, however, given as a 3 hour infusion at 0.805 mg/kg/min prolonged the survival of ependymoma bearing mice (p < 0.0001). Therefore, we randomized cohorts of mice to receive sequential surgery, radiation and gemcitabine treatment or surgery and radiation alone. The treatment combination including gemcitabine improved survival, achieving first time “cures” in some mice relative to surgery and radiation alone. Combining multi-modal clinically relevant treatment regimens to treat preclinical models may better identify effective chemotherapies for translation to human clinical trials.

Authors:

N Boulos, J Dapper, Y Patel, M DeCuypere, B Bianski, T Merchant, B Freeman, R Guy, C Stewart, K Wright, R Gilbertson

Journal:

NEURO-ONCOLOGY

Citation info:

18:140-140

Publication date:

1st Jun 2016

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