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The Alkylphospholipid Perifosine Induces Apoptosis and p21-Mediated Cell Cycle Arrest in Medulloblastoma
Molecular Cancer Research, 11/06/09

Kumar A et al. – Lower perifosine concentrations induced cell cycle arrest at the G1 and G2 cell cycle checkpoints, accompanied by increased expression of the cell cycle inhibitor p21cip1/waf1. Treatment with p21 small interfering RNA prevented perifosine–induced cell cycle arrest. These findings indicate that perifosine, either alone or in combination with other chemotherapeutic drugs, might be an effective therapeutic agent for the treatment of medulloblastoma.

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Timothy Van Meter, 11/06/09

This work demonstrates the therapeutic potential of enhancing the efficacy of standard treatment plans, by co-administration of selective kinase inhibitors like perifosine and chemotherapy or radiotherapy. The greatest benefit in efficacy was observed with etoposide in this study. Targeting kinases that are essential to the sustained growth and therapeutic resistance in malignant pediatric brain cancers, may allow us to more successfully treat these cancers, the leading the cause of cancer related mortality in children. The successful synergy between orally administered inhibitors such as perifosine, and low toxicity profiles, make this an attractive avenue to minimize the debilitating cognitive and neuro-developmental deficits that often result from current treatment paradigms. Detailed molecular biological profiling studies over the past few years have led us to identify molecular subtypes of medulloblastoma and other malignant pediatric brain cancers, and the most relevant druggable targets within tumor subtypes. Perifosine is a multi-kinase inhibitor with significant activity against the AKT kinases, a vulnerability point for most, if not all primitive neuro-ectodermal tumors (PNETs). Our work also suggests this drug may have indications for ependymoma and other clinically intractable pediatric brain cancers. We hope to test perifosine, and similar targeted therapeutics tailored to the specific biology of tumor subtypes, in children suffering brain tumors in the near future. Perifosine will likely be approved for testing in larger cohorts of pediatric patients, following completion of Phase I clinical trials currently being performed at Memorial Sloan Kettering Cancer Center in New York.

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