New Directions in the Treatment of Glioblastoma

Zachary J. Reitman, MD, PhD; Frank Winkler, MD, PhD; Andrew E. H. Elia, MD, PhD

Disclosures

Semin Neurol. 2018;38(1):50-61. 

In This Article

Future Directions

Future advances in GBM treatment will be facilitated by increased understanding of GBM pathogenesis and innovative approaches to exploiting tumor vulnerabilities. Given problems with intratumoral heterogeneity, the most promising targets may be genes whose alterations serve as clonal initiating events. EGFR inhibitors have had limited success in clinical trials possibly because EGFR alterations represent late events that occur in only a fraction of tumor cells.[82,83,91] Numerous therapeutic approaches have been proposed to exploit dependencies in IDH-mutant tumors.[59,92,93] One interesting strategy involves depletion of NAD+ by NAMPT inhibitors, as IDH-mutant tumors have downregulated NAD+ salvage pathways, making them sensitive to reductions in NAD+ levels.[94] Data are also emerging from early-phase trials for the treatment of IDH-mutant tumors with IDH inhibitors.[59] The discovery of hotspot mutations in the TERT promoter and in histone tails raises the question as to whether dependencies in tumors with these alterations can be therapeutically exploited as well. For example, tumors with TERT promoter mutations may develop addictions to pathways regulating transcription factors aberrantly recruited to mutated TERT promoters. Promising therapeutic approaches for histone H3 K27M tumors may involve agents that regulate epigenetic pathways as described above.[74,75]

In addition to intratumoral heterogeneity, escape mechanisms are likely responsible for the failure of targeted agents in clinical trials. Such mechanisms allow continued flux through a pathway and can include the activation of downstream effectors by alternative inputs or the loss of pathway inhibitors such as PTEN.[95] An additional reason for the limited efficacy of targeted approaches may be inadequate target suppression as observed for EGFR inhibitors.[95] This finding highlights the importance of assessing pharmacodynamic end points in clinical trials and continued research on strategies to penetrate the blood–brain barrier. Ultimately, difficulties with intratumoral heterogeneity and tumor evolution will likely require combination treatments that target multiple pathways simultaneously and that counter anticipated escape mechanisms. Such combination strategies will benefit from sequential biopsies to assist with therapy selection upon tumor evolution.

Immunotherapeutic approaches represent an additional line of promising investigation. GBMs are immunosuppressive due to numerous mechanisms, including decreased MHC expression, increased PD-L1 expression, secretion of anti-inflammatory IL-10, and restriction of immune cell infiltration by the blood–brain barrier.[61,96] Multiple strategies to enhance immune targeting of GBMs are under investigation, including immune checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, and vaccines. For example, the checkpoint inhibitors nivolumab and pembrolizumab are currently being tested in newly diagnosed and recurrent GBM patients in at least 15 clinical trials.[96] CAR T cells targeting the tumor antigens EGFR vIII and HER2 are also in early clinical trials.[61,96] While newly diagnosed GBMs have generally low mutational loads,[97] recurrent tumors exposed to temozolomide are often highly mutated[5,54] and may represent attractive targets for immunotherapeutic agents. Immunotherapy for gliomas is comprehensively reviewed in another article in this issue.

Translating molecular advances into clinical progress will depend on recognizing limitations in preclinical models and clinical trial design. Using patient-derived preclinical models rather than artificial cell culture systems may improve the identification and validation of therapeutic targets.[98] Molecular stratification in clinical trials is important for targeting therapies to patients with appropriate molecular alterations. Additionally, innovative approaches to clinical trial design may accelerate the testing of new agents. Such approaches include umbrella trials, which assign agents to patients based on molecular alterations,[61] and platform trials, which can adaptively add or remove treatment arms.[99] Together these new approaches may help to translate new therapies targeted at telomere biology, histone regulatory networks, tumor metabolism, immunotherapy, and TM functionality to the clinic.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....