Designing drugs for pediatric brain tumors
Medulloblastomas are the most common pediatric brain malignancy and the most common cause of cancer death in children. Glioblastoma multiforme is an aggressive brain tumor that has a median survival of about 14 months. Current treatments for these cancers, which combine surgery, chemotherapy and radiation, are especially challenging for younger patients.
To develop more-effective therapies for pediatric brain tumors, researchers at Mayo Clinic in Rochester, Minn., are designing novel drugs aimed at inhibiting the STAT3 signaling pathway. STAT3 is a key signaling molecule in several cancers including medulloblastoma and glioblastoma, affecting tumor-cell proliferation, growth and apoptosis.
"If we can develop therapies that inhibit signaling pathways, we might eventually be able to treat these high-risk tumors with resection and the drug," says David J. Daniels, M.D., Ph.D., a neurosurgeon and research chemist at Mayo Clinic in Minnesota. "We typically hammer these kids hard with radiation and chemotherapy, and they pay a price for that neurocognitively."
Mayo researchers have synthesized several compounds that kill medulloblastoma and glioblastoma tumor cells in vitro. Dr. Daniels is currently testing the compounds in mouse models at St. Jude Children's Research Hospital, where he is completing a clinical-research fellowship. The compounds are also being tested in an adult glioblastoma mouse model at Mayo in Minnesota.
Rather than screening millions of compounds for potential therapeutic use, Dr. Daniels uses a rational design process aimed at a specific target. "We started with a 3-D model for STAT3 and then did a computer screening for compounds that can bind to it," Dr. Daniels explains. "Then we went to the lab and made the drugs by synthesis."
The central structure of the compounds being tested is based on celecoxib, a rheumatoid arthritis medication approved by the Food and Drug Administration (FDA). "Based on computer modeling, that compound was predicted to bind into STAT3," Dr. Daniels says. "We essentially 'de-engineered' that molecule and modified it to fit into the STAT3 pocket better."
This unique, structure-based approach modifies an FDA-approved drug to select a new target. "Our hypothesis is that small changes can be made to the drug structure that can profoundly affect target binding but have minimal effect on pharmacokinetic properties and toxicity," Dr. Daniels says.
Mayo researchers hope to conduct clinical trials of the compounds and, eventually, to investigate inhibitors for other pathways. "We're starting to learn that STAT3 is just one pathway for medulloblastomas," says Dr. Daniels. "If we know which pathways the various subtypes of medulloblastoma are using, we can develop therapies aimed at these specific pathways. The goal is to learn as much as we can about these high-risk tumors and then develop novel drugs for those specific types."