Possible New Pathway Can Overcome Glioblastoma Resistance
- A20 E3 ubiquitin ligase could be a therapeutic target.
- Targeting this ligase may overcome TRAIL resistance.
- No current therapy available for glioblastoma.
PHILADELPHIA — Glioblastoma, a lethal brain cancer, is one of the most resistant to available therapies and patients typically live approximately 15 months.
Previous research has focused on the activation of the apoptosis, or cell death, pathway using therapeutic agents such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); however, the vast majority of these experiments have been stymied by resistance.
“Scientists in this field have been hoping to treat this cancer with this new type of apoptosis pathway-targeted therapeutic drug, and this new information may provide a path forward,” said Chunhai “Charlie” Hao, M.D., Ph.D., a neuropathologist at Emory University.
Using human glioblastoma samples and tumor-initiating cells or cancer stem cells, Hao and colleagues identified a possible new pathway for targeted therapies. Results of their work are published in Cancer Discovery, the newest journal of the American Association for Cancer Research.
TRAIL treatment often leads to caspase-8-mediated apoptosis. However, study results showed that the A20 E3 ligase is highly expressed in glioblastomas and together with receptor interacting protein 1 (RIP1) and caspase-8, forms a signaling complex. Upon TRAIL interaction with this complex, the A20 E3 ligase triggers ubiquitination of RIP1, interferes with activation of caspase-8 and prevents caspase-8-initiated apoptosis.
“Previous research in this area has been unable to overcome the obstacle created by resistance. This research shows one of the mechanisms for how we can manipulate the ubiquitination process to overcome the resistance to the apoptosis-targeted cancer therapies,” said Hao.
Understanding the mechanisms of resistance is vital to developing therapies going forward, according to Hao.
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, the AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes 33,000 laboratory, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants, research fellowships and career development awards to young investigators, and it also funds cutting-edge research projects conducted by senior researchers. The AACR has numerous fruitful collaborations with organizations and foundations in the U.S. and abroad, and functions as the Scientific Partner of Stand Up To Cancer, a charitable initiative that supports groundbreaking research aimed at getting new cancer treatments to patients in an accelerated time frame. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care, and Educational Workshops are held for the training of young cancer investigators. The AACR publishes seven major peer-reviewed journals: Cancer Discovery; Cancer Research; Clinical Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Prevention Research. In 2010, AACR journals received 20 percent of the total number of citations given to oncology journals. The AACR also publishes Cancer Today, a magazine for cancer patients, survivors and their caregivers, which provides practical knowledge and new hope for cancer survivors. A major goal of the AACR is to educate the general public and policymakers about the value of cancer research in improving public health, the vital importance of increases in sustained funding for cancer research and biomedical science, and the need for national policies that foster innovation and the acceleration of progress against the 200 diseases we call cancer.