Targeted Therapies for High-Risk Pediatric Brain Tumor Subtypes

What This Project Does

Richard Gilbertson
  • Richard Gilbertson, MD, PhD
  • University of Cambridge, Cambridge, England

A team of researchers at the University of Cambridge in England, lead by Dr. Richard Gilbertson, was awarded $834,000 to discover and develop novel therapies for high-risk pediatric brain cancers. Brain cancers are the most common solid tumors in children, accounting for 20% of all childhood cancers. Many of these cancers are high-risk, meaning that they are prone to relapse and have a low 5-year survival rate. Among the most lethal are three brain tumor subtypes including Group-3 medulloblastoma, C11orf95-RELA translocation positive ependymoma (EPFUS+), and ‘chromosome 1q gain’ infant choroid plexus carcinoma (CPC). These high-risk brain cancers account for a large proportion of childhood deaths. Each brain tumor includes subtypes with radically different origins, biology and prognoses, yet current treatments – a combination of surgery, radiation and conventional chemotherapy, are not effective at curing the cancer.

Through a CureSearch Acceleration Initiative 2 grant, Dr. Richard Gilbertson and his team will develop sub-type specific treatments for each of these high-risk brain cancers that he hopes will improve the outcome for brain cancer patients. This international, multidisciplinary team at the University of Cambridge in England is testing the novel hypothesis that “high risk subtypes of pediatric brain tumors are biologically distinct, rendering them susceptible to different chemotherapies that require subtype-specific treatments”.

Using genomic analysis of different brain tumor subtypes, Dr. Gilbertson and his team hope to identify novel targeted therapies (a drug that is specific for a cancer promoting gene) for each type of brain cancer. They will test at least 10 compounds for each type of cancer – a total of 30 compounds. The 30 compounds will be a combination of known drugs that are commercially available (FDA approved) and new compounds. The goal of the research is to select 2-3 compounds for each cancer subtype as lead drugs. These drugs will then be tested using “preclinical trials” where they will conduct combined surgery, radiation and chemotherapy trials of candidate therapies using mouse models of each high-risk pediatric brain tumor. By using a protocol that combines the new drugs with “standard of care” treatments, the researchers hope to better replicate the treatment regimen of patients in the clinic, thereby producing a more effective therapy. The ultimate goal is to inform clinical practice with these combined treatment approaches to cure high-risk brain tumors that have previously not been treatable.

Project Updates

12 Month Research Update

In the first year of the research project, Dr. Gilbertson’s team is working hard to develop new treatments for 3 high-risk brain tumors: Group 3 Medulloblastoma, Ependymoma Fus+ and Chorioid Plexus Carcinoma (CPC). They have successfully established 5 preclincial models (2 MB, 3 EP) for these cancers using patient derived samples and are close to having models for CPC. They are performing molecular and genomic profiling of these tumors to identify potential novel therapeutic targets. The targets will then be matched with FDA approved compounds or used for novel drug screening and development.

In an effort to repurpose existing drugs or identify new chemical entities (novel compounds), the team has identified two existing compounds (FDA approved for adults) with selectivity for MB and CPC and one novel compound showing activity for EP. Finally, the team is refining and testing the use of radiation and surgery in the preclinical models with plans to incorporate the recently identified targeted agents into the protocol.

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