Investigators at Georgetown Lombardi Comprehensive Cancer Center, providing hope for a cancer that is highly lethal, have identified biomarkers that could be targets for novel drugs to treat glioblastoma brain tumors.
Temozolomide, the medicine currently used most frequently to treat glioblastoma, has the unusual ability to penetrate the blood-brain barrier and attack the tumor, but resistance quickly develops, and many patients do not live for more than a year following diagnosis.
This novel discovery offers preliminary evidence that, once a patient’s tumor develops temozolomide resistance, it may be advantageous to target particular mutations in cancer cells with newer treatments.
The finding appeared June 22, 2022, in Science Advances.
“As a field, we have struggled to deal with the short-term effectiveness of temozolomide, as many of the drugs used successfully in other cancers are disappointing when they are subsequently tested in glioblastoma clinical trials. One way to deal with this problem is to learn enough about how we can target features that help drug-resistant glioblastoma survive,” says Rebecca B. Riggins, PhD, Associate Professor and Associate Director of Education and Training at Georgetown Lombardi and co-corresponding author of the study.
“We focused on the details of how temozolomide damages DNA to help radiation treatments work better. Our team found that temozolomide-resistant glioblastoma relies on a protein called CLK2, and that inhibiting the activity of CLK2 could cause widespread confusion, leading to cancer cell death.”
The modifications to guanine, one of the four bases that make up DNA, one of the main structural elements of both DNA and RNA, were the targets the researchers found. Guanine modifications may ultimately have an effect on CLK2, which has been connected to the tumor’s aggressiveness.
As a field, we have struggled to deal with the short-term effectiveness of temozolomide, as many of the drugs used successfully in other cancers are disappointing when they are subsequently tested in glioblastoma clinical trials. One way to deal with this problem is to learn enough about how we can target features that help drug-resistant glioblastoma survive.Rebecca B. Riggins
Beyond finding susceptible alterations, the researchers discovered medications that aid in RNA stabilization and may be able to slow down or prevent the development of temozolomide resistance.
The median survival for those with glioblastoma is little over a year, and only around 5% of patients with the disease survive five years following diagnosis; survival statistics haven’t moved significantly since the middle of the 1970s. Since 2005, temozolomide (Temodar) in conjunction with surgery and radiation therapy has been the standard of care.
Guanine-targeting drugs like temozolomide also affect the regulatory systems for important cancer-causing genes. The medicine may be active for a longer amount of time if these oncogenes, which cause cancer, could be kept inactive. Studies on the neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS), sometimes known as Lou Gehrig’s illness, provided some of the information for this study.
The researchers hypothesized that since glioblastoma and ALS share several characteristics, these characteristics may help develop new treatment plans for glioblastoma.
“Some of the mechanisms underlying neurodegenerative diseases appear to be relevant to temozolomide resistance in glioblastoma,” says Deanna M. Tiek, PhD, a F99/K00 fellow at the Northwestern University Feinberg School of Medicine and The Robert H. Lurie Comprehensive Cancer Center and co-corresponding author.
Tiek was a PhD student in Riggins’ lab when this research began. “This work demonstrates that inspiration and insight can come from places we might not have considered, and that it’s so important to take a risk, do the experiment, and see if you were right or not.”
Currently, researchers are testing whether the new CLK2 inhibitor can effectively reach the brain and reduce temozolomide-resistant glioblastoma in small animal models of disease.
“We are also investigating whether other anti-cancer drugs that attack guanine and are commonly used in triple-negative breast cancer and colorectal cancer, for example, change RNA structures in a similar way, which could make CLK2 inhibition more effective in recurrent, drug-resistant forms of those cancers as well,” concludes Riggins.