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New Treatment Targets Chemotherapy-Resistant Brain Cancer

Cerebral glioblastoma. Credit: KGH

Researchers have demonstrated the efficacy of a new treatment targeting genetic mutations in patients with chemotherapy-resistant secondary glioblastoma (sGBM), a rare and deadly form of brain cancer.

Low-grade gliomas progress into sGBM, which has limited treatment options and a 5-year survival rate under 10%. Secondary glioblastoma is treated with temozolomide (TMZ), a chemotherapy drug. Upon relapse, which happens in most patients, genetic mutations enable sGBM tumors to resist the drug's effects when it is administered a second time.

"Precision cancer medicine promises to tailor treatments according to personal cancer mutations, but it is complicated by the dynamic changes during cancer evolution. sGBM tumors are high on the list of toughest tumors to treat," remarked Jiguang Wang, PhD, Assistant Professor in the Division of Life Science at Hong Kong University of Science and Technology and co-senior author of the study, which was published in Cell. "This clinical trial and its results are quite significant in furthering the knowledge about sGBM treatment."

In analyzing the mutational landscape of 188 sGBM cases, the researchers found enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. They reported that METex14 often co-occurred with ZM fusion. Present in around 14% of cases, METex14 was associated with significantly poorer prognosis. The researchers found that METex14 enables progression of glioma by prolonging the activity of the MET oncogene.

They also identified a potential solution to this problem: PLB-1001, a MET kinase inhibitor that was highly effective at selectively inhibiting MET-altered tumor cells in preclinical models. In addition, PLB-1001 was able to permeate the blood-brain barrier, an essential factor for effective treatment. In a phase 1 clinical trial enrolling patients with MET-altered, chemotherapy-resistant glioma, PLB-1001 achieved partial response in at least two patients with advanced sGBM over the course of two months.

"Developing computational models on cancer evolution helps to predict cancer cells' future behavior and prioritize treatment options," commented Dr. Wang. "In this study, MET is one of the running targets we have identified. By using PLB-1001 as a standalone drug, our collaborators were able to see shrinkage of the tumors over a two-month period in selected patients. More studies need to be done to see if PLB-1001 can be used in conjunction with other drugs to have longer-lasting results."

For More Information

Hu H, Mu Q, Bao Z, et al (2018). Mutational landscape of secondary glioblastoma guides MET-targeted trial in brain tumor. Cell. [Epub ahead of print] PII:S0092-8674(18)31250-9. DOI:10.1016/j.cell.2018.09.038

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