Breakthrough Discovery: Targeting a New Hope for Aggressive Brain Cancer Treatment

A research project co-directed by scientists at UCLA has identified that focusing on a protein known as endocan and its associated signaling pathway may serve as a promising novel strategy for combating glioblastoma, a fierce and deadly form of brain cancer.

The research team revealed that endocan, which is generated by endothelial cells that line the blood vessels within the tumor, activates PDGFRA, a receptor on glioblastoma cells that stimulates tumor expansion and contributes to the cancer’s resistance to conventional therapies like radiation.

This revelation, featured in Nature Communications, indicates a potential pathway to the creation of treatments that specifically hinder this interaction, not only decelerating tumor growth but also rendering glioblastoma more susceptible to current therapies.

“By aiming at the communication between glioblastoma and vascular endothelial cells, we can devise treatments that prevent the tumor from adapting and thriving. This could also enhance the effectiveness of therapies, particularly radiation, making them more effective in combating this aggressive cancer,” stated Dr. Harley Kornblum, director of the UCLA Intellectual and Developmental Research Center, professor of psychiatry, pediatrics, and molecular and medical pharmacology at the David Geffen School of Medicine at UCLA and co-senior author of the research.

Enhancing the efficacy of treatments for glioblastoma is crucial. On average, those diagnosed with this brain tumor live only 12 to 15 months, with a mere 5% survival rate at five years post-diagnosis.

A significant obstacle in treating glioblastoma is its intricate nature. Brain tumors frequently depend on blood vessel cells, known as vascular endothelial cells, to facilitate their growth. These tumor blood vessels not only provide oxygen and nutrients but also release molecules that aid in the tumor’s survival. Understanding these interactions is essential for discovering new treatments and halting glioblastoma’s advancement, according to Kornblum.

To investigate how glioblastoma engages with nearby blood vessel cells to promote its growth, the research team initially utilized a database developed in a prior study to identify what molecules are produced within the tumor blood vessels and their functions. Via this platform, the team pinpointed endocan as a significant candidate molecule driving tumor expansion.

To examine the functional role of endocan in brain tumors, the scientists employed a mix of experimental models, including analysis of glioblastoma cells and blood vessel cells sourced from patients, trials with genetically modified mice devoid of endocan, and observations of tumor behavior in laboratory settings.

From these experiments, the team discovered that various regions of the tumor fulfill distinct functional roles, and that endocan not only supports tumor growth but also delineates the tumor’s geography, especially the aggressive edge areas that frequently persist post-surgery. Essentially, endocan helps to shape the molecular traits of this edge region.

“Understanding how tumors organize themselves is a critical challenge,” remarked Kornblum, who is also affiliated with the UCLA Health Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

While surgery can eliminate a substantial part of the tumor core, the invasive edge typically remains after removal, leading to recurrence. Our findings indicate that endocan plays a pivotal role in this mechanism, coordinating both tumor cell behavior and the formation of blood vessels that sustain tumor growth.”

Dr. Harley Kornblum, Director, Intellectual and Developmental Research Center, University of California – Los Angeles Health Sciences

Simultaneously, the research team made the unexpected discovery that endocan interacts with a receptor on glioblastoma cells, known as PDGFRA, activating pathways that encourage tumor growth and resistance to conventional treatments. They identified that tumors exhibiting high levels of endocan are more resistant to radiation therapy, one of the primary treatments for glioblastoma.

The investigators then demonstrated that obstructing endocan’s interaction with PDGFRA through the targeted therapy drug ponatinib prolonged survival in preclinical models and enhanced the response to radiation therapy. These results propose that directly targeting endocan or disrupting its signaling pathways could pave the way for innovative therapeutic strategies for glioblastoma.

Notably, the study also links endocan’s actions to cMyc, a protein crucial in numerous cancers yet challenging to target directly. “Inhibiting the endocan-PDGFRA axis may offer an indirect method to undermine cMyc’s function in glioblastoma,” Kornblum stated.

Future investigations will target validation of these findings in human tumors, particularly the cells located at the infiltrative edge of glioblastomas. Furthermore, the team aims to explore whether targeting endocan could augment responses to radiation therapy.

Dr. Ichiro Nakano from Harada Hospital in Japan is the other senior author of the study. The co-first authors are Soniya Bastola and Marat Pavlyukov from UCLA. A complete author list is included with the article.

The research received partial support through grants from the National Institutes of Health, the UCLA SPORE in Brain Cancer, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.