UCLA researchers in the Department of Molecular and Medical Pharmacology identified the mechanisms of apoptotic resistance in glioblastoma multiforme (GBM) and developed a novel therapy to treat GBM.
BACKGROUND:
Glioblastoma (GBM) is the most aggressive form of brain tumor. Therapeutic options for GBM are limited and suboptimal. Treatment usually involves invasive surgery, after which chemotherapy (temozolomide [TMZ]) and radiation therapy are used. Survival and mortality rates for GBM are extremely poor; five year survival rate is 5.6% and the median overall survival (mOS) is 12-14 months.
Conventional therapies (e.g., temozolomide (TMZ), Irradiation (IR)) transiently halt tumor growth of GBM but fail to induce cell death through apoptosis. Consequently, the inability to kill GBM tumor cells ultimately leads to disease progression and a poor patient survival. The intrinsic apoptotic pathway is governed by the interactions of the BCL2 family of proteins which regulate the release of cytochrome C from the mitochondria. The precise molecular mechanisms of apoptotic resistance in GBM remain ambiguous. A therapy that targets the apoptotic resistance in GBM is urgently needed.
INNOVATION:
Dr. David Nathanson and colleagues performed BH3 profiling, a functional assay to measure the state of apoptosis pathway in a cell. This assay involves treating live cells with peptides against BCL2 family of proteins (anti-apoptotic) within the mitochondria to measure the release of cytochrome C, an indirect determinant of apoptotic response. They identified two anti-apoptotic molecular blocks which prevent the release of cytochrome C.
To further assess the role of these molecular blocks in GBM, patient-derived GBM organoids were treated with a panel of anti-apoptotic inhibitors. They found that only a combination of certain anti-apoptotic inhibitors against these molecular blocks can synergistically induce cell death in GBM. . Additionally, the researchers also found that patient-derived GBM organoids that did not respond to treatment all had p53 mutations. In summary, the researchers discovered that TMZ-IR can be combined with anti-apoptotic inhibitors to significantly increase cancer cell death in p53 wild type (WT) GBM.
POTENTIAL APPLICATIONS:
- Treatment for glioblastoma (recurrent and/or newly diagnosed)
- Treatment of glioblastoma that are resistant to current standard of care (SOC)
ADVANTAGES:
- Identified novel anti-apoptotic mechanism of GBM
- Developed treatments to target apoptotic resistance
- Can be used in combination with TMZ-IR to increase cell death
DEVELOPMENT-TO-DATE:
The study has been validated in vitro in patient-derived GBM organoids and in vivo (patient-derived) orthgonic xenograft) model.