Biomarker Predicts Cancer Aggressiveness and Drug Susceptibility

Researchers have identified a protein required by some forms of brain cancer (glioblastoma multiforme, GBM) that can be used as a predictive marker for aggressiveness and effective drug response.

Glioblastoma is the most common primary tumor of the central nervous system and is almost always fatal. The aggressive invasion of glioblastoma cells into the surrounding normal brain makes complete surgical removal impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Treatment of glioblastoma usually comprises surgical removal of the tumor followed by radiation treatment and chemotherapy using the drug temozolomide (TMZ). However, the penetration of the tumor into adjacent brain tissue prevents the surgical removal of all tumor cells, which usually develop resistance to TMZ.

Investigators at Mount Sinai School of Medicine (New York, NY, USA) found that the mitotic spindle checkpoint protein BUB1B (serine/threonine-protein kinase BUB1 beta) may serve as a predictive marker for glioblastoma aggressiveness and effective drug response. BUB1B is a kinase involved in spindle checkpoint function and chromosome segregation. The protein has been localized to the kinetochore and plays a role in the inhibition of the anaphase-promoting complex/cyclosome (APC/C), delaying the onset of anaphase and ensuring proper chromosome segregation. Impaired spindle checkpoint function has been found in many forms of cancer.

The investigators used gene expression data from GBM stem-like cells, astrocytes, and neural progenitor cells that were sensitive or resistant to BUB1B inhibition to create a computational framework to predict sensitivity to BUB1B inhibition. Applying this framework to tumor expression data from patients, they stratified tumors into BUB1B-sensitive (BUB1BS) or BUB1B-resistant (BUB1BR) subtypes. Through this effort, they found that BUB1BS patients had a significantly worse prognosis regardless of tumor development subtype (i.e., classical, mesenchymal, neural, proneural). Functional genomic profiling of BUB1BR versus BUB1BS isolates revealed a differential reliance of genes enriched in the BUB1BS classifier, including those involved in mitotic cell cycle, microtubule organization, and chromosome segregation.

By comparing drug sensitivity profiles, the investigators predicted that BUB1BS cells would be more sensitive to type I and II topoisomerase inhibitors, Raf inhibitors, and other drugs, and experimentally validated some of these predictions.

“It was truly remarkable to see our predictive model yield a new set of molecular subtypes, which appear to be far more indicative of prognosis and therapeutic response than existing subtypes,” said senior author Dr. Jun Zhu, professor of genetics and genomic sciences at Mount Sinai Medical School. “For patients who receive the grim diagnosis of glioblastoma, this signals new hope for tailored treatment more likely to be effective against their cancer.”

The study was published in the October 15, 2017, issue of the journal Cancer Research.

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