Drug Candidate Shows Efficacy in Aggressive Brain Cancer

A recent study was able to identify a biomarker enzyme linked to aggressive glioma brain tumors, revealing the disease’s underlying mechanisms. The investigators were also able to create an investigational small molecule inhibitor that has been particularly effective in mouse models of glioma.

The inhibitor, GA11, was created to have a structure similar to the natural inhibitor of the biomarker, but the drug was altered to allow it to pass through the blood-brain barrier, according to the study published by Cancer Research.

"In principle, both these features make GA11 an attractive drug candidate to target glioma stem-like cells in glioblastoma multiforme tumors," said researcher Ichiro Nakano, MD, PhD.

Currently, there have only been 2 treatments for glioblastoma multiforme discovered over the past 30 years. These treatments have extended survival from 5 months to between 15 and 16 months, according to the study.

A glioblastoma multiforme tumor is composed of multiple different cells that each respond to drugs differently. However, glioma stem-like cells drive the progression of the disease, and make a prime target for treatments.

In particular, mesenchymal glioma stem-like cells are more aggressive and the most resistant to treatment, so the researchers decided that uncovering the underlying mechanisms of these cells may lead to novel treatments, according to the study.

The researchers discovered that ALDH1A3, a form of the enzyme aldehyde dehydrogenase, is a biomarker for mesenchymal glioma stem-like cells. These researchers were also the first to discover that cells with high levels of ALDH1A3 were more tumorigenic compared with cells with low expression.

Additionally, the FOXD1 transcription factor was found to regulate the production of this enzyme in mesenchymal glioma stem-like cells. Gliomas with high levels of FOXD1 and ALDH1A3 were discovered to be deadlier compared with gliomas with low levels, according to the study.

The researchers found that the mechanism that drives mesenchymal glioma stem-like cell tumorigenicity in humans is also applicable to fruit flies. By removing the expression of the FOXD1 gene or ALDH1A3 in fruit fly models of glioma, brain tumor formation was avoided.

Activity in the FOXD1 gene is typically only active during fetal formation, and is not active after birth. However, the researchers suggest that mesenchymal glioma stem-like cells may take over the mechanisms of embryonic development to promote cancer growth, according to the study.

In preclinical testing, GA11 was able to inhibit ALDH in yeast and reduced ALDH1 activity in laboratory cultured mesenchymal glioma stem-like cells. GA11 also showed the ability to inhibit the proliferation of glioma cells in vitro, and inhibited xenograft growth in mouse brains.

"In conclusion, the FOXD1-ALDH1A3 axis is critical for tumor initiation in mesenchymal GSCs, therefore providing possible new molecular targets for the treatment of GBM and other ALDH1-activated cancers,” the authors wrote.

The researchers said that the role of glioma stem-like cells are just 1 method of discovering new methods to treat glioma. Other scientists are exploring immunotherapy (check-point inhibitors), vaccination, and increasing sensitivity to radiotherapy as other potential options.

Dr Nakano believes that combination treatments are the most promising strategies to treat glioma, and that 1 treatment may not be effective.

The researchers plan to conduct another clinical trial for glioblastoma in 2017 in conjunction with scientists at the University of Alabama at Birmingham (UAB). They are currently working on creating treatment options for brain metastases, which are highly lethal, and have few treatment options. Dr Nakano believes that pathways are shared between glioma and metastatic brain tumors, according to the study.

"If so the molecular targets identified for gliomas are most likely essential in brain metastases. Studies are underway, and similar to the glioma therapy development, I am working to develop clinical trials for brain metastasis, together with medical oncologists Mansoor Saleh, MD, Andres Forero, MD, and others at UAB,” Dr Nakano concluded.

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