UCLA researchers in the Department of Molecular and Medical Pharmacology have discovered that irradiation therapy can be combined with an antibody drug conjugate to form a novel therapeutic strategy to treat and extend survival of glioblastoma patients.
BACKGROUND:
Glioblastoma (GBM) is a fast-growing and aggressive brain tumor. The National Brain Tumor Society estimated that over 14,000 people in the United States received a GBM diagnosis in 2023. GBM’s account for an estimated 50% of all primary malignant brain tumors and survival is poor, with only a 40% survival rate after the first year of diagnosis and 17% in the second year. GBMs are difficult to treat due to the localization of the tumors within the brain and the limited capacity of the brain to repair itself and malignant cells migrating to adjacent brain tissue, among other factors. Current treatments include the chemotherapy agent temozolomide (TMZ) or the use of irradiation (IR). These treatment options transiently halt tumor growth but do not induce cell death. Research has shown that certain GBM cells have an increased expression for BCL-xL, which prevents cancer cell death. UCLA researchers have previously shown that combining TMZ/IR with BCL-xL inhibitions leads to increased GBM cell death in a laboratory setting but work remains to show the clinical efficacy of targeting BCL-xL.
INNOVATION:
UCLA researchers led by Dr. David Nathanson aimed to successfully target BCL-xL. Platelets have a high dependency on BCL-xL for survival and treatment with BH3, a BCL-xL inhibitor, leads to thrombocytopenia. UCLA researchers circumvented these issues by using ABBV-155, an antibody drug conjugate, to deliver a potent BCL-xL inhibitor to GBM cells. ABBv-155 delivers a drug through an antibody specific for the B7H3 protein, which is highly expressed in GBM and other cancers. Research showed that combining ABV-155 with IR effectively induces cell death in glioblastoma cells and is a promising therapeutic strategy.
POTENTIAL APPLICATIONS:
- Treatment for glioblastomas that can decrease number of GBM cells by causing cell death.
- Treatment for other cancers with high BCL-xL expression.
ADVANTAGES:
- Target GBM cells without inducing thrombocytopenia.
- Combination of ABV-155 with IR decreased tumor growth and extended survival
DEVELOPMENT-TO-DATE:
B7H3 was shown to be highly expressed in GBM autopsy samples. The response of tumors was shown through in several patient-derived orthotopic GBM xenografts.