Investigators at Georgetown Lombardi Comprehensive Cancer Center have identified biomarkers that could be targeted for novel drugs to treat glioblastoma brain tumors, providing hope for a highly lethal cancer.
Currently, the most commonly used glioblastoma treatment, temozolomide, is uniquely able to cross the blood/brain barrier to attack the tumor, but resistance develops quickly, and many patients do not survive more than a year after diagnosis. This new discovery provides preliminary evidence that targeting specific alterations in cancer cells with newer agents may be beneficial once a patient's tumor becomes resistant to temozolomide.
The discovery was published in Science Advances on June 22, 2022.
"We have struggled as a field to deal with temozolomide's short-term effectiveness, as many drugs used successfully in other cancers are disappointing when tested in glioblastoma clinical trials. One solution is to learn enough about how to target features that help drug-resistant glioblastoma survive "Rebecca B. Riggins, PhD, Associate Professor and Associate Director of Education and Training at Georgetown Lombardi, and study co-corresponding author, says "We concentrated on the specifics of how temozolomide damages DNA in order to improve the efficacy of radiation treatments. Our research team discovered that temozolomide-resistant glioblastoma is dependent on a protein called CLK2, and that inhibiting CLK2 activity could cause widespread confusion, ultimately leading to cancer cell death."
The researchers identified changes in guanine, one of the four bases that comprise DNA, as a key structural component of both DNA and RNA. Guanine modifications may eventually have an effect on CLK2, which has been linked to tumor aggressiveness. Aside from identifying vulnerable modifications, the researchers were able to identify drugs that help stabilize RNA and could potentially slow or stop the development of temozolomide resistance.
Only about 5% of glioblastoma patients survive five years after diagnosis, with a median survival of just over a year; survival rates haven't changed much since the mid-1970s. Temozolomide (Temodar) has been the standard of care in conjunction with surgery and radiation since 2005.
Temozolomide's guanine targeting affects structures that regulate key cancer-causing genes. If these cancer-causing genes, known as oncogenes, could be turned off, the drug could be active for a longer period of time. Some of this information came from research into the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease. Because ALS shares some characteristics with glioblastoma, the researchers hypothesized that it could help develop new glioblastoma treatment strategies.
"Some of the mechanisms underlying neurodegenerative diseases appear to be relevant to temozolomide resistance in glioblastoma," says Deanna M. Tiek, PhD, an F99/K00 fellow and co-corresponding author at Northwestern University Feinberg School of Medicine and The Robert H. Lurie Comprehensive Cancer Center. When this research began, Tiek was a PhD student in Riggins' lab. "This work demonstrates that inspiration and insight can come from unexpected places, and that it's critical to take a risk, do the experiment, and see if you were correct or not."
The researchers are now conducting studies in small animal models to see if the novel CLK2 inhibitor can enter the brain and shrink temozolomide-resistant glioblastoma. "We're also looking into whether other anti-cancer drugs that target guanine and are commonly used in triple-negative breast cancer and colorectal cancer, for example, alter RNA structures in a similar way, which could make CLK2 inhibition more effective in recurrent, drug-resistant forms of those cancers as well," Riggins concludes.