Pemetrexed and Gemcitabine Show Promise Against Aggressive Childhood Brain Tumor
The quest to improve survival of children with a high-risk brain tumor has led investigators at St. Jude Children's Research Hospital to two drugs already used to treat adults with breast, pancreatic, lung, and other cancers. The study by Morfouace at al was published today in Cancer Cell. Researchers demonstrated that combination pemetrexed (Alimta) and gemcitabine was effective against mouse and human group 3 medulloblastoma cells. Of the four distinct medulloblastoma subtypes, patients with group 3 medulloblastoma have the worst prognosis.
Used together, pemetrexed and gemcitabine doubled life expectancy of mice with human group 3 medulloblastoma, compared to untreated mice. When pemetrexed and gemcitabine were combined with two chemotherapy drugs currently used to treat pediatric medulloblastoma, the mice lived even longer.
Study Details
The drugs were identified by screening the St. Jude library of 7,389 compounds looking for ones that targeted group 3 mouse tumor cells rather than normal mouse brain cells. Pemetrexed and gemcitabine emerged as the top candidates, based in part on their ability to kill group 3 medulloblastoma tumor cells at concentrations that researchers showed were safe and achievable in patients.
"Our focus was to identify drugs that we could move quickly from the laboratory to the clinic where new chemotherapy options are desperately needed for these high-risk medulloblastoma patients," said the study's corresponding author Martine Roussel, PhD, a member of the St. Jude Department of Tumor Cell Biology.
For this study, researchers relied on mice with group 3 medulloblastoma grown from patient tumors. Researchers used the mice to show that pemetrexed and gemcitabine worked against human group 3 tumors and that the drugs could be used in combination with existing chemotherapy agents to boost treatment effectiveness without undue risk. Cisplatin and cyclophosphamide were the other drugs used in this study.
"The finding provides a strong rationale for combination therapy with pemetrexed and gemcitabine for treatment of group 3 medulloblastoma," Dr. Roussel said. Researchers found no evidence that mouse tumor cells develop resistance to the drugs.
Pemetrexed works by disrupting the ability of cancer cells to proliferate. Gemcitabine kills cells by triggering their suicide pathway. Researchers also found evidence the drugs work specifically against group 3 medulloblastoma. The drugs did not extend survival of mice with a different medulloblastoma subtype.
Clinical Trial Launched
Based on results from this and previous studies, pemetrexed and gemcitabine were included in a multicenter clinical trial of children and adolescents newly diagnosed with medulloblastoma. The drugs are already approved for treatment of patients with advanced breast cancer as well as ovarian, pancreatic, and certain lung cancers. No safety concerns were identified in previous studies of pemetrexed and gemcitabine for treatment in children with other cancers.
Most group 3 medulloblastoma tumors feature excessive levels of the c-MYC protein, which helps to regulate cell growth. The protein is overexpressed in many cancers and is associated with a poor outcome. About 40% of patients with c-MYC overexpression and other characteristics of group 3 medulloblastoma become long-term survivors, compared to 80% of other medulloblastoma patients.
"The drugs identified in this study will hopefully close that survival gap and improve cure rates for children with group 3 medulloblastoma," said coauthor Amar Gajjar, MD, Co-Chair of the St. Jude Department of Oncology.
Dr. Roussel is the corresponding author for the Cancer Cell article.
The research was funded in part by grants from the National Institutes of Health, the French National Cancer Institute, CNRS, Institut Curie, Necker Hospital, the V Foundation, and ALSAC.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
