Institution:  University of California, San Francisco
Study Name:  Clinical Trial: Determinants of Response and Resistance in PLGG – Everlomius 
Principal Investigator:  Dr. Michael Prados/Dr. Daphne Haas-Kogan
Study date:  December 2013

This proposal fills a critical unmet need for a pediatric population with few other therapeutic alternatives and addresses an important problem in PLGG therapy, namely, how to best target dysregulated components within signaling pathways. This study will elucidate mechanisms by which the most common genetic aberrations in PLGGs influence responses to novel, promising, translatable agents and will enable the next generation of clinical trials in which rational drug combinations are administered to appropriate patients in hypothesis-driven studies. This proposal steps beyond the usual approach of testing agents empirically in response-based trials. It utilizes a novel clinical trial statistical design to establish if specific molecular features are predictive markers of response to a targeted agent and establishes a new paradigm for PLGGs in which tumor tissue is acquired from each child in order to identify biomarkers of response.

Specific Aims:

  1. In the context of a multi-institutional Phase II study, to identify, through molecular profiling of tumors, those children most likely to benefit from mTOR inhibition. We will employ an adaptive Simon two-stage design for Phase II studies of targeted therapies to evaluate whether everolimus is active only in PLGGs with PI3K/AKT/mTOR activation. We will also analyze key molecular features including activation of the PI3K, mTOR and MAPK pathways, aberrations in PTEN and p53, PDGFRA amplification, CDKN2A loss, and activating mutations in BRAF. Additional genomic profiling studies will be performed in collaboration with Adam Resnick at the Children’s Hospital of Philadelphia including additional targeted sequencing, RNA sequencing, and/or exome(plus) next generation sequencing.
  2. In the context of preclinical strategies to prevent emergence of resistance, to test combination therapy using everolimus and MAPK pathway inhibitors in BRAF activated PLGG. We will investigate viability, flow cytometry, and clonogenicity assays, to ask whether BRAF activation (the most common aberration in PLGGs) confers resistance to everolimus, comparing effects of BRAFV600E and KIAA1549:BRAF.

For more information, please contact Dr. Daphne Haas-Kogan at

For more information about other clinical trials through the Pacific Pediatric Neuro-Oncology Confortium, please see their website at