Cleveland Clinic study finds platelets may drive glioblastoma progression

New Cleveland Clinic research published in Cancer Cell demonstrates that glioblastoma drives overactivity in blood platelets, which suppress cancer-killing T cells and accelerate tumor growth. Led by Anthony Sloan and Justin Lathia, researchers found that blocking the PAR4 receptor on platelets reverses immune suppression and improves survival in female preclinical models, likely mediated by estrogen. The study establishes a novel bridge between cancer biology, blood-clotting conditions, and sex differences.

Overactive platelets suppress T cells

• ▪Cleveland Clinic research published in Cancer Cell shows that people with glioblastoma have overactive platelets that slow cancer-fighting T cell activity, contributing to tumor growth and cancer progression.
• ▪Researchers led by Anthony Sloan and Justin Lathia at Cleveland Clinic found that overactive platelets in glioblastoma act through protease-activated receptor 4 (PAR4) to slow T cells that normally kill cancer cells.

PAR4 receptor role in cancer

• ▪Targeting the PAR4 receptor on platelets may guide new therapeutics by helping the immune system fight glioblastoma, according to Cleveland Clinic researcher Justin Lathia.
• ▪Justin Lathia stated that research highlights the PAR4 receptor as a key element in both cancer biology and blood-clotting biology.

PAR4 targeting shows sex-dependent outcomes

• ▪Cleveland Clinic researchers suggest that hormones, particularly estrogen, regulate the molecular link between platelet PAR4 activation, anti-tumor T cell suppression, and glioblastoma survival.
• ▪In preclinical models of glioblastoma, Cleveland Clinic researchers found that blocking the PAR4 receptor reversed T cell suppression and improved survival in females, but did not improve survival in males.
• ▪Anthony Sloan noted that the study reveals a molecular bridge between the blood clotting system and the hormonal environment that may explain sex differences in cancer response.

Sex differences in glioblastoma

• ▪Glioblastoma is more common in males and is associated with shorter survival in males than in females, according to Cleveland Clinic researchers.
• ▪Both male and female preclinical models of glioblastoma showed increased platelet reactivity, according to Cleveland Clinic researcher Anthony Sloan.

Clotting risks and therapy delays

• ▪Cleveland Clinic researchers examined activity in the tumor microenvironment, including platelets and surrounding cells, to determine why cancer-associated blood-clotting events occur.
• ▪Alok Khorana of Cleveland Clinic stated that clotting events like pulmonary embolism, deep vein thrombosis, stroke, and myocardial infarction can require urgent hospitalization that delays cancer therapy.
• ▪Thrombotic events such as pulmonary embolism and deep vein thrombosis are the second leading cause of death in cancer patients.

Program Project Grant details

• ▪The glioblastoma research at Cleveland Clinic was conducted under a National Institutes of Health Program Project Grant led by Justin Lathia that was renewed for five years.
• ▪The National Institutes of Health Program Project Grant encompasses three separate research projects involving multiple investigators across institutions studying glioblastoma.