Lerner Research Institute News
Read about the latest advances from Lerner Research Institute scientists, including new findings, grant awards, innovations and collaborations.
New Cleveland Clinic research suggests that Ibrutinib, a drug recently approved by the FDA to treat lymphoma and leukemia, may also help treat glioblastoma (GBM)—the most common and lethal type of brain cancer. The promising study findings, published in Science Translational Medicine, offer hope that Ibrutinib may one day help improve GBM patient outcomes and survival, which currently are exceptionally poor.
The team of researchers, led by Shideng Bao, PhD, Lerner Research Institute Department of Stem Cell Biology & Regenerative Medicine, found that Ibrutinib suppressed tumor growth and increased survival in a preclinical model of GBM. Ibrutinib was significantly more effective in slowing tumor growth than the current standard-of-care GBM chemotherapy drug, Temozolomide, and extended average survival rate by more than 10-fold.
Targeting a Dangerous Subset of Cancer Cells
Dr. Bao's team found that Ibrutinib works by inhibiting glioma stem cells (GSCs)—a particularly aggressive type of cancer cell, which can self-renew, spread and resist conventional treatments. This is what makes them so dangerous and of great interest to researchers as a potential therapeutic target.
In both a preclinical model and cultured human GBM cells, the team found that Ibrutinib effectively suppressed GSC-driven tumor growth and potently induced GSC death.
Harnessing Ibrutinib to Overcome Resistance
A key characteristic of GBM tumor cells is their ability to evade treatment. Traditional therapies, including chemotherapy and radiation, often work for a while, but the cancer cells eventually stop responding. The highly resistant GSCs enable GBM tumors to rapidly recur. Thus, targeting GSCs is critical for improving GBM treatment.
The researchers discovered in a preclinical model that combining radiation therapy with GSC-targeting Ibrutinib helped overcome this deadly resistance. Combination therapy overcame therapeutic resistance and extended lifespan more effectively than either radiation or Ibrutinib treatment alone.
Building on Earlier Work
Dr. Bao's earlier work demonstrated that GSCs promote GBM resistance to radiation therapy. He and colleagues then went on to find that GSCs have high levels of a protein called BMX (bone marrow and X-linked non-receptor tyrosine kinase). They showed that BMX activates a molecule called STAT3 (signal transducer and activator of transcription 3), and that "turning on" STAT3 enables GSCs to replicate, spread and promote GSC-driven tumor growth.
In the present study, the researchers found that Ibrutinib effectively inhibited BMX activity and thus interfered in the activation of STAT3. Fewer active BMX molecules resulted in fewer active or "turned on" STAT3 molecules and, therefore, reduced tumor growth and GSC-driven resistance.
Translating Discovery to a Cure
While additional research is critical to understand Ibrutinib's effects in patients with GBM, these preclinical findings are very promising. Since Ibrutinib is already FDA-approved for use in humans, Dr. Bao says clinical trials to use Ibrutinib as a treatment for GBM, either alone or in combination with current therapies, are not far.
The study was supported by grants from the National Cancer Institute (NIH) and National Institute of Neurological Disorders and Stroke (NIH) to Dr. Bao, and grants from the National Key Research and Development Program of China to Dr. Bao's collaborator, Dr. Bian.