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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, led 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 percent 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 medulloblastoma (MB), ependymoma (EP), and 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 and current treatments – a combination of surgery, radiation and conventional chemotherapy, are not effective at curing the cancer.

With the support of a CureSearch Acceleration Initiative 2 grant, Dr. Richard Gilbertson and his team will develop subtype-specific treatments for each of these high-risk brain cancers that he hopes will improve the outcome for brain cancer patients. The 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 (drugs that are specific for a cancer-promoting protein) for each type of brain cancer. They will test at least 10 compounds for each type of cancer. 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 in preclinical animal models. Dr. Gilbertson’s team 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 regimens used in the clinic. 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

30 Month Research Update

The Gilbertson lab and collaborators are performing molecular profiling (sequencing) of MB, EP, and CPC patient tumor samples to identify potential novel therapeutic targets. They are then validating these targets using a core set of research tools that his lab has developed. Dr. Gilbertson and his team have completed generation of eight MB and four EP patient-derived xenograft (PDX) mouse models. Two CPC PDX models are also in development. PDX models are made when patient tumor cells are injected into a mouse. In addition to the PDX models, the Gilbertson lab has developed genetically engineered mouse models, including two EP models, and are in the process of developing a CPC model. These models are now being used to perform combination drug screens. Combination therapy with gemcitabine and the CDK4/6 inhibitor Ribociclib in preclinical studies was so successful in MB models that a new phase I clinical trial for recurrent, refractory MB patients opened in February at St. Jude (NCT03434262).

In an effort to repurpose existing drugs or identify new chemical entities, 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.

Notably, thanks in part to the strength of the work supported by CureSearch, Dr. Gilbertson led a successful bid to be the first Cancer Research UK Children’s Brain Tumour Centre of Excellence.

Targeted Therapies for High-Risk Pediatric Brain Tumor Subtypes was last modified: November 11th, 2018 by Geoff Duncan
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