Identifying a Therapeutic Partner for TAK228 for Pediatric Phase II Brain Tumor Studies
Co-investigators: Dr. Kristine Glunde, Dr. Barbara Slusher and Dr. Charles Eberhart
Background: The goal of this proposal is to find new drugs that work together to kill pediatric brain tumor cells. As part of a previous Alex’s Lemonade Stand Foundation project, we found that a drug called TAK228 could kill pediatric brain tumor cells. This drug gets into the brain well and is currently in clinical trials in adults for breast and other cancer types. We found that TAK228 works well with some therapies we currently use in pediatric brain tumors. But those therapies may be too toxic for patients who have relapsed or refractory disease and who have already received heavy doses of chemotherapy and radiation.
Project Goal: We now propose to use our knowledge of the biology of TAK228 as well as the ways that cancer cell metabolism differs from normal cells to find new agents that could combine with TAK228 to kill pediatric brain tumor cells and spare normal cells. TAK228 is currently in the planning stages for a US-government-funded phase I study in pediatric brain tumors. At the end of this grant, we anticipate that we will have discovered at least one new drug that can be combined with TAK228 in phase II studies for patients with relapsed or refractory pediatric brain tumors.
Project Update 2021: We continue to learn more about how pediatric brain tumor cells adapt to treatment with drugs that block a signaling pathway called "mTOR." There are several mTOR inhibitors now in clinical trials for adults with brain tumors, and some of these are showing promising results. Funding from ALSF has allowed us to show that this pathway is active in pediatric brain tumors and that some of these new inhibitors suppress the growth of medulloblastoma and DIPG. Using metabolomics, we have identified potential partner drugs that work together with mTOR inhibitors, and we have found that these drugs synergize with mTOR inhibitors in medulloblastoma and DIPG. We published our medulloblastoma manuscript in Cancer Letters in 2021. We have another manuscript on DIPG in preparation.
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