Blood-brain barrier–adapted precision medicine therapy for pediatric brain tumors

Abstract

Targeted chemotherapeutics provide a promising new treatment option in neuro-oncology. The ability of these compounds to penetrate the blood brain barrier is crucial for their successful incorporation into patient care. “CNS Targeted Agent Prediction” (CNS-TAP) is a multi-institutional and multi-disciplinary translational program established at the University of Michigan for evaluating the CNS activity of targeted therapies in neuro-oncology. In this report, we present the methodology of CNS-TAP in a series of pediatric and adolescent patients with high-risk brain tumors, for which molecular profiling (academic and commercial) was sought and targeted agents were incorporated. Four of five of the patients had potential clinical benefit (partial response or stable disease greater than 6 months on therapy). We further describe the specific drug properties of each agent chosen and discuss characteristics relevant in their evaluation for therapeutic suitability. Finally, we summarize both tumor and drug characteristics that impact the ability to successfully incorporate targeted therapies into CNS malignancy management.

Development of the CNS TAP tool for the selection of precision medicine therapies in neuro-oncology

“…The tool’s design and weighting was further adjusted after obtaining consensus opinion with clinicians and researchers at multiple academic institutions that participated in the University of Michigan Precision Medicine Brain Tumor Conference. [9] To allow for dissemination of the tool to outside centers while maintaining its integrity, the CNS TAP Working Group has developed a web-based application for prospective use by clinicians and researchers.…”

“…The sample was evaluated for genomic alterations, including base pair substitutions, indels, copy number alterations, and rearrangements. [9]…”

“…Selection of targeted therapies is influenced by evolving factors, such as Food and Drug Administration (FDA) approval, availability on a clinical trial, and physician/provider comfort level or familiarity with a particular agent. [8, 9] Additionally, given the rapidity of new published data and FDA approval of precision medicine therapies, many providers may not be aware of all possible agents that target a particular pathway. With the increasing availability of molecular information about each individual tumor, it is difficult for the treating clinician to fully interpret the likelihood of a tumor alteration driving tumor growth.…”

“…[10, 11] Compounding these issues for brain tumor patients is that a majority of targeted therapies and chemotherapeutic compounds have little to no central nervous system (CNS) penetration. [9, 12] A large proportion of targeted therapies are substrates of efflux pumps, significantly limiting activity in brain tumors [13–18]. Thus, the ability to provide an objective, systematic tool to synthesize and quantify the above factors for available precision medicine agents is of critical importance to the treating neuro-oncologist.…”

CSF H3F3A K27M circulating tumor DNA copy number quantifies tumor growth and in vitro treatment response

“…Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brain cancer and patients face a grim prognosis with few treatment options [ 7 ]. Targeted therapies based on actionable genetic mutations may offer DIPG patients novel treatment regimens [ 9 , 10 ]. Although whole exome sequencing (WES) of tumor tissue can fully characterize the somatic mutational profile, it requires a surgical procedure and is relatively costly and time consuming.…”