A recent study highlights the potential of targeting a protein known as endocan and its related signaling pathway as a promising strategy for treating glioblastoma, a highly aggressive and deadly form of brain cancer.
A research effort co-led by scientists at UCLA indicates that focusing on a protein named endocan and its associated signaling pathway might offer a viable new method for addressing glioblastoma, a particularly aggressive and fatal type of brain cancer.
The research team found that endocan, produced by endothelial cells that line the blood vessels within the tumor, activates PDGFRA—a receptor on glioblastoma cells that is responsible for promoting tumor growth and contributing to the cancer’s resistance to conventional treatments like radiation therapy.
The findings, detailed in Nature Communications, open avenues for developing treatments that specifically block this interaction, which could not only hinder tumor growth but also enhance the effectiveness of existing therapies against glioblastoma.
“By focusing on the interactions between glioblastoma and the vascular endothelial cells, we can create therapies that inhibit the tumor’s adaptability and survival. This may enhance the success rate of treatments, particularly radiation, in combating this aggressive cancer,” explained Dr. Harley Kornblum, director of the UCLA Intellectual and Developmental Research Center and co-senior author of the study.
Improving treatment outcomes for glioblastoma patients is critical, as those diagnosed typically have a life expectancy of only 12 to 15 months, with merely 5% surviving five years post-diagnosis.
An inherent difficulty in treating glioblastoma is its intricate nature. These brain tumors frequently depend on blood vessel cells, or vascular endothelial cells, for growth. These tumor-associated blood vessels not only supply oxygen and nutrients but also release molecules that aid in the tumor’s survival. Understanding these interactions is vital in identifying new therapeutic strategies to halt glioblastoma’s progression, according to Kornblum.
To investigate how glioblastoma interacts with adjacent blood vessel cells to foster its growth, the researchers first leveraged a database developed in a prior study to identify the molecules produced in the tumor-associated blood vessels and their functions. This approach led to the identification of endocan as a crucial molecule in stimulating tumor growth.
To examine the specific role of endocan in brain tumors, the scientists employed various experimental models, including analyses of glioblastoma and blood vessel cells taken from patients, experiments on genetically modified mice lacking endocan, and assessments of tumor behavior in lab settings.
The results indicated that different areas of the tumor fulfill unique roles, with endocan not only promoting tumor growth but also influencing its spatial arrangement, especially in aggressive edge regions that often remain following surgical intervention. In essence, endocan plays a role in shaping the molecular properties of these edge areas.
“Understanding how tumors organize is a significant challenge,” remarked Kornblum, who is 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. “Although surgery can remove a substantial portion of the tumor core, it often leaves behind the infiltrative edge, resulting in recurrence. Our research shows that endocan is a crucial factor in this dynamic, orchestrating both tumor cell activity and the formation of blood vessels that support tumor growth.”
Additionally, the team made an unexpected discovery that endocan interacts with the PDGFRA receptor on glioblastoma cells, activating pathways that foster tumor growth and contribute to resistance against standard treatments. They observed that tumors with elevated endocan levels displayed greater resistance to radiation therapy, a primary treatment for glioblastoma.
Further investigations revealed that blocking the interaction between endocan and PDGFRA through the targeted therapy drug ponatinib resulted in extended survival in preclinical models and improved responses to radiation treatment. These results imply that directly targeting endocan or disrupting its signaling pathways could pave the way for new therapeutic approaches for glioblastoma.
Importantly, the study also links the actions of endocan to cMyc, a protein involved in numerous cancers that is challenging to target directly. “Targeting the endocan-PDGFRA axis may indirectly disrupt cMyc’s influence in glioblastoma,” noted Kornblum.
Future investigations will aim to confirm these findings in human tumors, particularly within the infiltrative edge of glioblastomas. The team also intends to explore whether targeting endocan could enhance responses to radiation treatment.
Dr. Ichiro Nakano from Harada Hospital in Japan is another senior author of the study, and the co-first authors are Soniya Bastola and Marat Pavlyukov from UCLA. The full list of authors can be found with the published article.
This research received partial support from grants provided by the National Institutes of Health, the UCLA SPORE in Brain Cancer, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.
