New drug target identified for common brain cancer

By Samantha Black, Ph.D.

August 21, 2019 -- Research led by the Cleveland Clinic has identified a potential new therapy in the treatment of glioblastoma. An article published in Cancer Discovery on August 21, identifies FGF2 (fibroblast growth factor 2), as a novel drug target for glioblastoma, the most common primary malignant brain tumor.

According to the American Brain Tumor Association, Glioblastomas represent about 15% of all primary brain tumors. They are malignant grade IV tumors which infiltrate the brain. New treatments are needed because current treatments only have a survival rate between 11 and 15 months and recurrence is very common.

Activation of FGF2 contributes to glioma stem cell self-renewal and tumor growth. Researchers at the Cleveland Clinic led by Justin Lathia, PhD, identified that FGF2 is an important intermediary in a novel pro-cancer signaling loop. Moreover, they suggest that deactivation of FGF2 may stop the growth and spread of glioblastoma. In this positive feedback loop, metalloproteinase domain-like protein decysin 1 (ADAMDEC1) expression, in which FGF2 solubilization is critical, enables glioblastomas cancer stem cells (GSC) stemness.

ADAMEC1 is secreted by GSCs resulting in a breakdown of the extracellular matrix in the brain, which gives GSCs nutrients to support their spread. Moreover, this production of ADAMDEC1 further stimulates the positive feedback loop involved with GSC growth.

FGF receptor 1 (FGFR1) is activated by the solubilization of FGF2 and mediated through a few additional signaling cascades. FGFR1 signaling ultimately induces the expression of ADAMDEC1, which sends this whole cellular feedback loop into motion again. By blocking FGF2’s ability to activate FGFR1 (and prevent ADAMDEC1 expression), the pathway can be blocked and halt the spread of GSCs.

The FGF cell signaling proteins are involved in a variety of biological processes including embryonic development, cell growth, tissue growth, and tumor growth. Understanding the specific function of these proteins and how they contribute to tumor growth will provide novel therapeutic avenues for researchers and medical professionals.

"These findings are exciting because they put forth a new paradigm for glioma stem cell regulation," said Dr. Lathia. "This pathway shows that glioma stem cells' ability to access key nutrients in their surrounding microenvironment, by way of ADAMDEC1, is integral for their maintenance and spread. Finding a way to interrupt this feedback loop will be important for treating glioblastoma."



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