The Program’s clinical trials arm has two specific aims: the first is to improve the translation of laboratory findings into clinical trials for children with low-grade gliomas and the second is to increase the Program’s access to biological materials that can be used to support the scientific investigations.
As the majority of pediatric low-grade gliomas carry BRAF mutations that activate the RAS/RAF/MEK pathway, the inhibitors presently under investigation in clinical trials focus on this pathway. However, there are a number of other pathways that we have recently identified in pediatric low-grade astrocytomas, including the MYBL1 pathway by Keith Ligon, MD, PhD and the MybQKI pathway by Rameen Beroukhim, MD, PhD and Pratiti Bandopadhayay, PhD, MBBS. While those corresponding mutations are less common than the BRAF mutations, early preclinical experiments are already underway to begin testing possible drugs that could be used clinically for tumors with signaling through these alternative pathways. Additionally, fusion genes involving receptor tyrosine kinases (FGFR, NTRK2/3) have been identified in small numbers of low grade gliomas. Inhibitors of these kinases are further candidates in trials.
More information on the clinical efforts, including trials currently recruiting can be found at https://www.dana-farber.org/research/clinical-trials/find-a-clinical-trial/ and at https://clinicaltrials.gov/ct2/home
Tissue Banking
Tissue samples collected from patients undergoing experimental therapies are one of the most valuable resources for development of new treatments of Pediatric Low-Grade Gliomas (PLGG) and understanding patterns of treatment resistance. The tissue bank directed by Keith Ligon, MD, PhD and with AKBTC support provides central pathology coordination for clinical trials with tissue analysis components. These trials include PI initiated as well as Children’s Oncology Group (COG) and national consortium trials. The tissue bank is currently receiving samples for genomic analysis from three active trials (one BRAF inhibitor and one MEK inhibitor, and one chemotherapeutic study). In the past year they completed accrual of Phase 1 in the MEK162 study. These samples were profiled by Oncopanel for more than 500 genes for annotation of BRAF V600E, BRAF fusion, and other LGG driver events to better understand the responses to MEK inhibitors. Phase 2 collection is ongoing and includes collection and processing. In addition they have arranged to collaborate in the analysis of samples on 2 other PLGG clinical therapeutic trials including Pacific Pediatric Neuro-Oncology Consortium (PNOC), COG and other consortia.
