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 multidisciplinary translational program established at the University of Michigan for evaluating the central nervous system (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.

Figure 1

Drug properties and CNS penetration. This figure depicts each of the five targeted agents’ abilities to cross the blood-brain barrier, based on molecular properties and clinical and pre-clinical data. Green boxes denote favorable properties or evidence that supports CNS penetration of the agent, yellow boxes indicate equivocal or mixed properties/evidence, and red boxes denote suboptimal properties or lack of data supporting CNS penetration of the agent.

Figure 2

Treatment of a patient with NF1 loss and H3.3 K27M hotspot mutation with combination of MEK and HDAC inhibitors. A–C: Results of MI-ONCOSEQ tumor/germline sequencing revealed homozygous somatic NF1 loss, a missense mutation (H179R) and copy neutral loss of heterozygosity in TP53, an H3.3 K27M hotspot mutation, and a frameshift mutation (D1313fs) in ATRX. D: The patient was treated with radiotherapy and the HDAC inhibitor, vorinostat, followed by adjuvant therapy with vorinostat and the MEK inhibitor, trametinib, resulting in a good partial response.

Figure 3

Common pathways targeted in CNS precision medicine. Here, we illustrate several cellular pathways likely involved in driving tumor growth and development in the five pediatric CNS tumor patients presented in this series. Each pathway identifies the locations of specific actionable mutations (red circles), as well as a corresponding agent which may inhibit the involved pathway (green circles), with the numbers corresponding to the cases in the order in which they have been presented. Abbreviations: FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; mTOR, mammalian target of rapamycin; HDAC, histone deacetylase; HAT, histone acetyltransferase; Ac, acetyl group; CDK, cyclin-dependent kinase; TSC, tuberous sclerosis complex