New Agent May Help Combat Glioma Tumors

Researchers are reporting in the journal Cancer Research that they have identified a biomarker enzyme associated with aggressive glioma brain tumors. In addition, they have demonstrated potent efficacy in a mouse model of glioma for a small molecule inhibitor they recently developed.  

The investigators define a FOXD1-ALDH1A3 pathway in controlling the clonogenic and tumorigenic potential of mesenchymal (MES) glioma stem-like cells (GSCs) in glioblastoma tumors. The team has developed a novel small molecule inhibitor of ALDH, which is currently called GA11 and it has demonstrated potent in vivo efficacy when administered systemically in a murine GSC-derived xenograft model of glioblastoma. 

GA11 is able to retain a core structure that resembles natural inhibitors of the biomarker enzyme, according to the researchers. However, the inhibitor has been modified to allow it to pass through the blood-brain barrier. 

Ichiro Nakano, MD, PhD, and colleagues report that these features make GA11 an attractive drug candidate to target GSCs in glioblastoma multiforme tumors. Currently, Dr. Nakano, a professor of neurosurgery and academic neurosurgeon at the University of Alabama at Birmingham, along with colleagues at the University of Pisa, Italy, are conducting a preclinical evaluation of the GA11. They are also investigating analogs of GA11.

There is an acute unmet clinical need with glioblastoma multiforme (GBM). Dr. Nakano said the average survival of this patient population is only 15 or 16 months. He said a GBM tumor is a mix of different cells and so no one approach is the answer. The mesenchymal GSC is a more malignant subtype and the most therapy resistant. Dr. Nakano and colleagues found that one form of the enzyme aldehyde dehydrogenase (ALDH1A3) is a specific marker for mesenchymal GSCs.

Nakano and his team have found that cells with high levels of ALDH1A3 expression were more tumorigenic in vivo compared to cells that are low in ALDH1A3. The team reports that the FOXD1 transcription factor regulates the production of ALDH1A3 in mesenchymal GSCs. The researchers found that the expression levels of both FOXD1 and ALDH1A3 were inversely correlated with disease progression in clinical samples from patients with high-grade gliomas.

The researchers concluded that the FOXD1-ALDH1A3 axis is critical for tumor initiation in mesenchymal GSCs. If this turns out to be the case, it may be possible to develop new molecular targets for the treatment of GBM and other ALDH1-activated cancers, according to the investigators.