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A New Method To Shrink Temozolomide-resistant Glioblastoma – Early Study Shows

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Researchers at Georgetown Lombardi Comprehensive Cancer Center have discovered biomarkers that could be targeted for innovative drugs to treat glioblastoma brain tumors, bringing hope for an extremely fatal cancer.

Temozolomide, the drug 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 early evidence that, once a patient’s tumor develops temozolomide resistance, it may be helpful to target particular mutations in cancer cells with newer treatments.

The discovery was published in Science Advances today.

Since many of the treatments that have been used successfully in treating other malignancies turn out to be ineffective when evaluated in human trials for glioblastoma, the field has struggled to deal with temozolomide’s short-term effectiveness. Being able to target markers that aid drug-resistant glioblastoma survival is one method to address this issue, according to Rebecca B. Riggins, co-corresponding author.

“To make radiation treatments more effective, We focused on the details of how temozolomide damages DNA.”

They “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 targets discovered by the researchers were modifications in a crucial structural component of both DNA and RNA, especially guanine, one of the four DNA bases. Guanine modifications may eventually have an effect on CLK2, which has been linked to tumor aggressiveness.

Aside from discovering susceptible alterations, the researchers were able to identify medicines that assist stabilize RNA and could potentially slow or stop the development of temozolomide resistance.

Only around 5% of glioblastoma patients survive five years following diagnosis, with a median survival of just over a year; survival statistics haven’t moved much since the mid-1970s. In conjunction with surgery and radiation, temozolomide (Temodar) has been the standard treatment since 2005.

The targeting of guanine by temozolomide also affects structures that regulate important cancer-causing genes.

If these cancer-causing genes, known as oncogenes, could be switched off, the medicine may be active for a longer period of time. A portion of this understanding was gained through research on Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease.

The researchers hypothesized that since glioblastoma and ALS share several characteristics, these characteristics may help develop new treatment plans for glioblastoma.

According to Deanna M. Tiek, co-corresponding author, “some of the mechanisms underlying neurodegenerative diseases appear to be relevant to temozolomide resistance in glioblastoma.”

“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.”

In order to determine if the novel CLK2 inhibitor can effectively enter the brain and reduce temozolomide-resistant glioblastoma, the researchers are currently conducting tests in small animal models.

Riggins continues, “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.”

Source: 10.1126/sciadv.abn3471

Image Credit: Getty

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