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:

• Glioma
• glioblastoma
• DIPG
• immunotherapy
• oncolytic virus
• vaccine
• RTK inhibitors
• epigenetic therapy
• IDH1
• onco-metabolic targeted drugs

Article highlights

• Pediatric and adult high-grade gliomas (HGG) carry a uniformly fatal diagnosis due to high recurrence rates and the absence of effective treatments.

• Progress in brain cancer genomics and epigenomics have identified multiple oncogenic drivers targetable by therapeutic inhibition, many of which are currently undergoing evaluations in clinical trial but have yet to show improvements in survival.

• Promising new developments focusing on immunotherapies such as immune-checkpoint inhibitors or oncolytic viruses are underway to overcome the genetic drift and could lead to durable anti-tumor immune responses against a theoretically unlimited number of tumor-associated antigens.

• Future successful therapies will concurrently use multiple modalities that target disparate tumor characteristics personalized to the particular tumor of a given patient.

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Declaration of interests

V Staedtke is supported by the Francis S Collins Scholars Program and RY Bai is supported by National Cancer Institute grant 1R03CA178118-01A1. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.