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Emerging Therapies for Glioblastoma

Alissa A. Thomas, MD1; Cameron W. Brennan, MD2; Lisa M. DeAngelis, MD1; Antonio M. Omuro, MD1
[+] Author Affiliations
1Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York
2Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York
JAMA Neurol. 2014;71(11):1437-1444. doi:10.1001/jamaneurol.2014.1701.
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Importance  Glioblastoma is the most common primary malignant brain tumor, but despite multimodal treatment with surgery, radiotherapy, and temozolomide chemotherapy, the prognosis is poor, with a median survival of 16 to 19 months and poor quality of life throughout the disease course. New treatments are needed.

Evidence Review  Articles were identified through a search of PubMed references from March 2005 through January 2014, using the terms glioblastoma, glioma, malignant glioma, and brain neoplasm, as well as by search of the authors’ files. Clinical trials were identified in the Clinicaltrials.gov registry.

Findings  Advances in the understanding of the molecular biology of glioblastoma are being rapidly translated into innovative clinical trials, capitalizing on improved genomic, epigenetic, transcriptional, and proteomic characterization of glioblastomas as well as host factors, including the brain microenvironment and immune system interactions. Therapies targeting tumor growth factor receptors and downstream pathways, angiogenesis, modulation of cancer stemlike cells, cell cycle regulation, oncolytic viruses, new radiotherapy techniques, and immunotherapy, including vaccines and modulation of immune checkpoints (eg, programmed cell death 1 and cytotoxic T-lymphocyte antigen 4), are under investigation. In addition to novel agents, techniques to circumvent the blood-brain barrier to facilitate central nervous system drug exposure are being developed.

Conclusions and Relevance  Glioblastoma is an aggressive tumor with heterogeneous molecular features and complex host interactions, many of which are amenable to therapeutic intervention. Meaningful treatment advances will depend on identifying agents that target mechanistic vulnerabilities that are relevant to specific subgroups of patients; increasing patient enrollment into clinical trials is essential to accelerate the development of patient-tailored treatments.

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Figure 1.
Summary of Major Cancer Pathways Altered by Mutation and DNA Copy Number Aberration in Untreated Primary Glioblastoma From The Cancer Genome Atlas

Primary glioblastoma shows a high prevalence of mutations, focal DNA amplifications, and deletions targeting genes within the PI3 kinase/mitogen-activated protein kinase (MAPK) pathway (A) and the p53 and retinoblastoma protein tumor suppressor pathways (B). Adapted with permission from Brennan et al.18

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Figure 2.
Emerging Treatment Strategies in Glioblastoma

A, Treatment strategies in glioblastoma may target the tumor's growth pathways. B, Treatment strategies also may alter the microenvironment. The light green and gray cells represent tumor cells; orange, glioma stemlike cells; purple, immune effector cells; dark green, immune regulatory cells; and the red line, a blood vessel. C, Treatment must gain access to the tumor by overcoming the blood-brain barrier. The green mass represents a glioblastoma. BAD indicates Bcl-2–associated death promoter; ERK, extracellular signal-regulated kinase; Grb2, growth factor receptor-bound protein 2; GTP, guanosine triphosphate; MDM2, mouse double minute 2 homolog; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; NF1, neurofibromatosis type 1; NFκB, nuclear factor κ-light-chain-enhancer of activated B cells; PDK1, pyruvate dehydrogenase lipoamide kinase isozyme 1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α; PIK3R1, phosphatidylinositol 3-kinase regulatory subunit α; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog; Raf-1, RAF proto-oncogene serine/threonine-protein kinase; RTK, receptor tyrosine kinase; and SOS, son of sevenless.

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