Investigational new drugs for brain cancer

Abstract

Introduction: Despite substantial improvements in standards of care, the most common aggressive pediatric and adult high-grade gliomas (HGG) carry uniformly fatal diagnoses due to unique treatment limitations, high recurrence rates and the absence of effective treatments following recurrence. Recent advancements in our understanding of the pathophysiology, genetics and epigenetics as well as mechanisms of immune surveillance during gliomagenesis have created new knowledge to design more effective and target-directed therapies to improve patient outcomes.

Areas covered: In this review, the authors discuss the critical genetic, epigenetic and immunologic aberrations found in gliomas that appear rational and promising for therapeutic developments in the presence and future. The current state of the latest therapeutic developments including tumor-specific targeted drug therapies, metabolic targeting, epigenetic modulation and immunotherapy are summarized and suggestions for future directions are offered. Furthermore, they highlight contemporary issues related to the clinical development, such as challenges in clinical trials and toxicities.

Expert opinion: The commitment to understanding the process of gliomagenesis has created a catalogue of aberrations that depict multiple mechanisms underlying this disease, many of which are suitable to therapeutic inhibition and are currently tested in clinical trials. Thus, future treatment endeavors will employ multiple treatment modalities that target disparate tumor characteristics personalized to the patient's individual tumor.

Keywords: DIPG; Glioma; IDH1; RTK inhibitors; epigenetic therapy; glioblastoma; immunotherapy; onco-metabolic targeted drugs; oncolytic virus; vaccine.

Figure 1. Schematic overview of current targeted therapies in HGGs

Aberrant oncogenic RTK pathways including the PI3K-AKT (green) and RAS (pink) oncogenic pathways are targeted with a variety of small molecule inhibitors (grey boxes) and monoclonal antibodies. Oncometabolites produced by IDH1/2-mutated glioma cells can be intracellularly targeted by small molecule inhibitors and a IDH1 mutant specific vaccine, which is currently being tested HGG patients. Epigenetic modifiers targeting on HDAC and histone 3.3/3.1 are shown as well. Notably, various immunotherapeutic strategies that are currently undergoing evaluations in clinical trials are pictured including tumor vaccines, immune checkpoint inhibitors, CAR-T cell therapies, and oncolytic viruses (yellow box). Abbreviations: mut: mutant.

Figure 2. Immune checkpoint interactions on T cells and cancer

Antigens released from tumor cells are taken up by antigen-presenting cells. The T-cell receptor (TCR) interacts with a presented antigen to activate the immune system. PD-1, which is expressed on T-cells, has an inhibitory role (red arrow) through its interaction with PD-L1 on the tumor cells resulting in tolerance and inhibition of tumor destruction. Similarly, CTLA-4, which is also expressed on T-cells, mediates inhibitory signals after binding with its ligands CD80 or CD86 dampening the immune response and preventing activation. Blocking both interactions, with monoclonal antibodies to PD-1, PD-L1 or CTLA-4 (for example, nivolumab, pembrolizumab, ipilimumab) precludes inhibition allowing for T-cell activation (green arrow) with subsequent tumor cell lysis.