Discovery of biomarkers that could be drug targets against a deadly form of brain cancer

Researchers at Georgetown Lombardy Comprehensive Cancer Center have identified biomarkers that could be targets for new drugs to treat brain tumors in glioblastoma, raising hopes of a highly lethal cancer.

Currently, the drug most commonly used to treat glioblastoma, temozolomide, is the only drug able to cross the blood-brain barrier to attack the tumor, but resistance develops rapidly and many patients do not live more than a year after diagnosis. This new finding provides preliminary evidence that there may be a benefit in targeting specific modifications in cancer cells with new agents once a patient’s tumor becomes resistant to temozolomide.

The report was published on June 22, 2022 in Scientific progresss.

“As an area, we have struggled to manage the short-term efficacy of temozolomide because many drugs that have been used successfully in other cancers have been disappointing when tested in clinical trials for glioblastoma. We focused on the details of how temozolomide damages DNA,” says Rebecca B. – an author of the study. To help radiation treatments work better. Our team discovered that temozolomide-resistant glioblastomas depend on a protein called CLK2, and that inhibition of CLK2 activity can cause widespread disorientation, leading to cancer cell death. . »

The targets identified by the researchers were modifications to a key structural component of DNA and RNA, specifically guanine, one of the four bases that make up DNA. Guanine changes may ultimately affect CLK2, which has been implicated in tumor aggressiveness. In addition to identifying the weak changes, the researchers were able to identify drugs that help stabilize RNA and can slow or stop resistance that normally develops to temozolomide.

Only about 5% of patients diagnosed with glioblastoma live five years after diagnosis, with median survival of just over a year; Survival rates have not changed significantly since the mid-1970s. Temozolomide (Temodar) has been standard of care since 2005 in combination with surgery and radiotherapy.

Targeting of guanine by temozolomide also affects structures that regulate key cancer-causing genes. If these cancer-causing genes, called oncogenes, can be turned off, the drug may have a longer period of activity. Some of this knowledge has come from studies of a neurological disease, amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig’s disease. The researchers hypothesized that ALS has some features similar to glioblastoma, so they could also offer new treatment strategies for glioblastoma.

“Some of the mechanisms underlying neurodegenerative diseases appear to be relevant to temozolomide resistance in glioblastoma,” says Diana M. author. Tiek was a doctoral student in Riggins’ lab when he began this research. “This work shows that inspiration and insight can come from places we may not have considered, and that it is very important to take risks and experiment and see if you have the right or not.”

The researchers are currently conducting studies in small animal models, where they will test to see if the new CLK2 inhibitor can effectively enter the brain and reduce temozolomide-resistant glioblastoma. “We are also investigating whether other cancer drugs that attack guanine and are commonly used in triple-negative breast cancer and colorectal cancer, for example, alter RNA structures in the same way, which could make CLK2 inhibition more effective in cases of recurrent drug. These cancers are also resistant,” Riggins concludes.

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