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Brain Tumor Research Highlights: July 2017

Cover photo courtesy of the National Cancer Institute (NCI)

Over the years, NBTS has given more than $35 million to brain tumor research projects. We’re very proud of the impact this funding has made in advancing the neuro-oncology field closer to better treatments and ultimately a cure. And while NBTS is currently focused on driving our flagship research projects – like the Defeat GBM Research Collaborative – forward, there also continues to be great scientific research efforts happening in the neuro-oncology field, en masse.

This is critical, as no one researcher, one lab, or one institution can cure this disease alone. Below are highlights of some newly published research from the brain tumor scientific and medical community, compiled by NBTS Director of Research & Scientific Policy, Ann Kingston, PhD and NBTS Research Programs Manager, Amanda Bates:

Preclinical Research News

APOBEC3G acts as a therapeutic target in mesenchymal gliomas by sensitizing cells to radiation-induced cell death
Wang Y, Wu, S, Zheng S, Wang S, Arjun W, Ezhilarasan R, Sulman EP, Koul D, Yung, WKA. (2017) Oncotarget. doi 10.18632/oncotarget.17348.[ Epub ahead of print]
> View the paper

The Cancer Genome Atlas (TCGA) divided glioblastoma (GBM) into four proposed subtypes: classical, mesenchymal, proneural, and neural. In this study, researchers screened glioma initiating cells (GICs) and TCGA data and found that apolipoprotein B mRNA editing catalytic polypeptide-like 3G (APOBEC3G), was highly and preferentially expressed in mesenchymal GBM. APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family of proteins are a group of DNA-editing enzymes that play an important role in the innate immune response to retroviruses and retrotransposons. APOBEC3G was also associated with significantly decreased survival time in GBM patients, suggesting that it is a tumor-promoting factor. The study identified APOBEC3G as a survivor factor of mesenchymal GBM after radiation and showed that the TGFβ signaling pathway regulated by APOBEC3G was associated with enhanced tumor invasion in GBM. Targeting APOBEC3G, by gene knockdown, sensitizes GBM cell lines to radiation by attenuating activation of the DNA repair pathway. This work suggests that APOBEC3G represents a potential molecular target for novel therapeutics that may improve the treatment outcome of glioma patients.

This study was supported by funding from National Brain Tumor Society’s Defeat GBM Collaborative.

mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT
Gu Y, Albuqurque CP, Braas D, Zhang W, Villa GR, Bi J, Ikegami S, Masui K, Gini B, Yang H, Gahman TC, Shiau A, Cloughesy TF, Christofk HR, Zhou H, Guan K-L, Mischel, PS. (2017). Molecular Cell 67, 128-138;

Dysregulated amino acid metabolism is an emerging hallmark of cancer. Tumor cells may regulate amino acid uptake by modulating the level or activity of specific amino acid transporters but the molecular mechanisms underlying such a regulation are not well studied. In this research study, researchers found that the protein complex mTORC2 regulates amino acid metabolism in cancer cells including glioblastoma (GBM) by the phosphorylation of serine 26 on the cystine-glutamate antiporter (or exchanger) xCT. When this phosphorylation occurs, the activity of xCT is inhibited. The results demonstrate that mTORC2 controls cystine uptake and glutathione metabolism by directly phosphorylating xCT, linking altered growth factor receptor signaling with amino acid metabolism and reactive oxygen species buffering in cancer. Such a mechanism enables tumor cells to adapt to changing nutrient levels by connecting proliferative and survival signals to environmental conditions. Taken together, these results provide further evidence supporting a critical role for mTORC2 in linking growth factor receptor signaling with glucose, amino acid, and glutathione metabolism in cancer, including GBM.

This study was supported by funding from National Brain Tumor Society’s Defeat GBM Collaborative

Clinical Research News

A Study of the Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers
(clinical identifier NCT02034110)

The B-Raf proto-oncogene serine/threonine kinase (B-Raf) is a member of the Raf kinase family. BRAF V600E mutation can constitutively activate the mitogen-activated protein kinase (MAPK) pathway signaling, promoting tumor growth and progression. BRAF mutation is frequent in melanoma, papillary thyroid cancer, colorectal cancer, and ovarian cancer but also in certain rare cancers such as anaplastic thyroid cancer as well as low- and high- grade gliomas. Combined inhibition of both BRAF and MEK (another member of the MAPK signaling cascade) provides more complete inhibition of the MAPK pathway, and has been shown to produce more potent tumor growth inhibition and delayed onset of treatment drug resistance.

At the recent 2017 ASCO meeting in June, data were presented from a trial involving BRAF V600E-mutated anaplastic thyroid cancer patients that showed significant clinical efficacy and safety of dabrafenib and trametinib (a BRAF V600 inhibitor and a MEK inhibitor respectively) in these patients. These data have now incentivized researchers to assess the safety and efficacy of the same two combined targeted enzyme inhibitors in grade 1 – 4 glioma patients with the BRAF V600E mutation as part of a phase 2 open-label, non-randomized multi-center clinical trial that is currently recruiting.
> View the trial information

A Phase I Study of the Treatment of Recurrent Malignant Glioma with rQNestin34.5v.2, a Genetically Engineered HSV-1 Virus, and Immunomodulation with Cyclophosphamide
(clinical identifier NCT03152318)

A novel therapeutic strategy being investigated for high grade gliomas involves the engineering of herpes viruses that can directly kill tumor cells by a direct lytic effect of the virus on the cancer cells. In this phase I clinical trial in recurrent malignant glioma patients, the safety and effect of an oncolytic herpes virus rQNestin34.5v.2, where expression of a viral gene needed for robust replication is under control of the nestin promoter (rQNestin34.5v.2), will be investigated. This study will also investigate combining rQNestin34.5v.2 with the immunomodulating agent, cyclophosphamide.

rQNestin34.5v.2 is a genetically engineered herpes simplex virus type 1 (HSV-1) and was engineered with deletions/inactivation of both copies of the endogenous genes that encode the viral protein, ICP34.5, needed for robust replication in infected cells. One copy of the ICP34.5 gene was then re-inserted into a different locus under transcriptional control of mammalian nestin promoter/enhancer element. This promoter is active in gliomas but not in normal brain cells. As a result, the virus infects, preferentially replicates in and lyses tumor cells because tumor cells selectively complement engineered mutations in rQNestin34.5v.2 that render it unable to replicate in and lyse normal cells.  This trial is currently recruiting patients.
> View the trial information

Regulatory News

FDA approves Aminolevulinic acid hydrochloride, known as ALA HCl (Gleolan, NX Development Corp.) as an optical imaging agent indicated in patients with gliomas
> Learn more

The U.S. Food and Drug Administration (FDA) has approved Gleolan (aminolevulinic acid hydrochloride, ALA HCl) for use as an optical imaging agent to enhance the visualization of malignant tissue during surgery for high grade glioma patients (suspected World Health Organization Grades III or IV on preoperative imaging). The extent of resection of high grade gliomas has been shown to correlate with patient prognosis.

ALA was evaluated in three clinical trials involving 484 patients 18 to 75 years old who had a preoperative MRI compatible with high-grade (WHO Grade III or IV) glioma and were undergoing surgical resection. Histopathology of biopsied fluorescent tissue showed that the agent has high predictive value for visualization of malignant tissue. The third study was a randomized, multi-center study in 415 patients with a preoperative diagnosis of high-grade glioma by MRI. Patients were randomized to ALA fluorescence arm or to white light control arm. The extent of resection among patients with confirmed high-grade glioma in the ALA fluorescence arm was compared to that among patients in the control arm, with the “completeness” of resection being determined by a central blinded read of early post-surgical MRI. Percentage of patients who had “completeness” of resection was 64% in the ALA arm and 38% in the control arm, with the difference of 26% (95% CI: 16%, 36%).

5 clinical studies, involving 527 patients with glioma, support the safety of Gleolan, The agent was reported to incur risks such as phototoxic reactions, hypersensitivity reactions, and interpretation errors (false negatives and false positives).  An escalation in the extent of resection might escalate the chance of severe short-term neurologic deficits, and adverse reactions that occurred in > 1% of patients in the week following surgery were pyrexia, hypotension, nausea, and vomiting. Other adverse reactions occurring in < 1% of patients in the first 6 weeks after surgery were chills, abnormal liver function test, and diarrhea.

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