Project Impact – Working Group Meeting

On August 21, 2014, the National Brain Tumor Society hosted the most recent in a series of working group meetings in conjunction with our latest pediatric initiative, Project Impact. This meeting primarily focused on the development of a preclinical drug testing platform to optimize the drug discovery and development pipeline for aggressive childhood brain tumors known as pediatric high-grade gliomas. [Click here to learn more about preclinical drug testing models and platforms, and why they are so important to pediatric brain tumor drug development.]

Background Information

Project Impact is a new, multi-faceted initiative to address the key interrelated barriers that are slowing drug development for pediatric brain tumors, specifically high-grade gliomas. Efforts seek to optimize the entire pediatric brain cancer drug discovery and development pipeline and create significant advances in treatment options for children with brain tumors. This integrated initiative will leverage funded research projects and policy efforts to address inefficiencies in both the pediatric brain tumor preclinical research and clinical trial settings.

Project Impact is Co-chaired by leading pediatric neuro-oncologists, Drs. Roger Packer (Children’s National Medical Center), Suzanne Baker (St. Jude Children’s Research Hospital), and Maryam Fouladi (Cincinnati Children’s Hospital Medical Center).

The preclinical core of Project Impact is led by an expert Advisory Committee consisting of Drs. W.K. Alfred Yung (MD Anderson Cancer Center), Stefan Pfister (German Cancer Research Center), and Nada Jabado (Montreal Children’s Hospital).

In attendance at the meeting were representatives from the following organizations and institutions:

Meeting Summary

After some brief updates from leaders of the clinical trial core of Project Impact and officials from the National Cancer Institute (NCI) on federally-funded efforts in pediatric cancer research, the group dove into discussions on building a more effective and sustainable platform for testing potential drug candidates for pediatric high-grade gliomas in the preclinical setting.

These discussions began with a presentation from Dr. Packer, who proposed an infrastructure/governance structure that would help support the development of the preclinical drug-testing platform.

Dr. Packer offered as an example for this structure the organizational approach that the National Brain Tumor Society has already employed with our Defeat GBM Initiative.

This construct would allow for the creation of a preclinical/translational research consortium that would have the ability to launch major, collaborative projects based on a unified preclinical research platform with the aim to increase survival for children with high-grade glioma.

This preclinical consortium would be made-up of highly integrated projects that would simultaneously work to accelerate the discovery of treatment targets and their corresponding biomarkers, model discovery research for rapid and predictive drug screening, and more easily move promising targets and drugs into early clinical trial settings.

Like in Defeat GBM, all projects would be highly collaborative, share data, and use their findings to inform other projects. In this structure, the National Brain Tumor Society would serve as the central core that would: 1) facilitate all projects/coordination, 2) work with the biopharmaceutical industry, NCI, and others, 3) mandate specimen, cell line, data, and drug sharing, and 4) promote and endorse clinical trial efforts.

After Dr. Packer’s presentation, a facilitated discussion began to examine his proposal further, including planning what next steps and setting priorities and goals for a would-be new pediatric brain tumor preclinical consortium.

From there, the conversation moved from this broader focus on structure to the narrower task of defining what the new preclinical testing platform, specifically, should look like.

A preclinical platform would need to consist of cell lines, animal models, and a standard set of tests to perform. A platform whose cell lines and models more accurately correspond to the human tumors has been identified as an area of need by both the biopharmaceutical industry and academics to facilitate the testing of new potential treatments. Thus, the full group explored the state of the field; identified actionable items; and acknowledged needs that must be addressed to successfully build a pediatric brain tumor preclinical testing platform. The group began to define model characteristics and measures required to move more potential treatments into trials, and faster.

Dr. Jabado presented on the progress made to date, as well as the ongoing and future goals of the research community. Specifically noted was that a large subset of children with high-grade gliomas have the same mutations in important proteins in their tumor cells called histone 3. Furthermore, these mutations seem to have “partners in crime,” that they work with in order to make tumor cells grow and divide. Dr. Jabado noted that some of these mutations can be targeted for treatment if we can first correctly model them.

Dr. Baker picked-up on this topic and reviewed with the group what models currently available could be a starting point. It was determined that, although numerous mouse xenograft and human neurosphere lines exist for many type of pediatric high-grade gliomas, the extent of their quality and effectiveness varies, and work is needed to determine the reliability of these models. Dr. Baker concluded that to move forward with Project Impact, we need to develop a “catalog” of existing models and determine what defining characteristics are missing. Dr. Baker also noted that the catalog must continuously be updated with the newest models that represent the latest in discovery science and cutting-edge research findings. All models in the catalog will also need to be validated and categorized in a standard way.

When it came to considering what to include in the catalog, Dr. Baker asked the group to think about what their ideal models consist of (i.e. How many animals per model? Which models best represent a tumor from initiation through the natural history of disease progression? And which best represent a human tumor environment?), and what are the characterizations that need to happen to each (i.e. the tests to perform on each that validate the models are truly representative of the human disease and produce the data needed to move potential treatments forward).

Dr. R. Kiplin Guy, of St. Jude Children’s Research Hospital, next discussed additional aspects of preclinical modeling and drug testing. He made sure the group remained cognizant of further features that will be needed for success including, establishment of standard operating procedures and metrics, discussion of intellectual property right and ownership expectations up front, in addition to focusing on model accuracy and precision and building the suite of models to capture disease variability (i.e. subgroups).

The core of the meeting ended with an open discussion focused on the additional needs of an optimal preclinical testing platform and concluded with remarks from Dr. Packer reminding everyone that Project Impact is a collaborative initiative involving input and support from all members of the pediatric brain tumor community.

This group is committed to continuing to work on the development of a preclinical drug testing platform in pediatric high-grade gliomas that allows more potential treatments to enter into the important clinical trial phase faster, and with more chance for success.

Meanwhile, the clinical trial core of Project Impact will continue working on a whitepaper of possible solutions to improve and de-risk the pediatric clinical trial environment and encourage more trials and more participation from biopharmaceutical companies.