Small-molecule drug could offer breakthrough treatment for cancerous brain tumors

brain tumour
A new type of small-molecule drug, the first to target circadian clock proteins as a way to treat glioblastoma, is currently in phase 1 clinical trials. Credit: Issey Takahashi

Identifying a small-molecule drug that can target circadian clock proteins in the brain could prove effective in treating glioblastoma, the most common cancerous brain tumor in adults, researchers from the Keck School of Medicine at USC.

Glioblastoma is an aggressive disease. Patients survive on average only 15 months once they are diagnosed. Despite more than two decades of research into the causes and treatments of glioblastoma, the prognosis has not improved much.

But recent work by a team at the Keck School of Medicine has shown that circadian clock proteins, which help coordinate changes in body functions over the course of a day, may play a key role. in the growth and proliferation of glioblastomas after current standard treatments, according to research. published in “Proceedings of the National Academy of Sciences”.

According to USC Biological Sciences at the Keck School of Medicine and director of the USC Michelson Center for Convergent Biosciences.

Kay has assembled a collaboration that brings together academics specializing in glioblastoma, circadian clock biology, and biological chemistry with Synchronicity Pharma, a biotech startup he co-founded.

“We are now starting to walk down the path of clinical drug development — turning this from a scientific story to a translational story,” said Kay, the study’s lead author, who also co-leads USC Norris. Brown Center for Cancer Drug Development. .

Early symptoms of glioblastoma can include everything from blurred vision, headaches, and nausea to seizures and personality changes. Patients usually undergo a brain scan, which identifies the tumor, and then receive a combination of surgery, radiation therapy, and chemotherapy. While most tumors shrink significantly after initial treatment, few patients experience prolonged remission.

“In the vast majority of patients, the cancer comes back,” Kay said. “And when he comes back, he’s resisting chemotherapy and radiation.”

Researchers believe the cancer comes back because a small number of ‘cancer stem cells’ are left behind after surgery, chemotherapy and radiation therapy.

These stem cells can multiply and spread very quickly, and research by Kay’s team helps explain why. He and Dr. Jeremy N. Rich of the University of Pittsburgh discovered that cancer stem cells hijack the body’s circadian clock machinery, allowing them to spread faster and resist the effects of chemotherapy and radiotherapy.

Armed with this knowledge, Kay and his collaborators have created and tested thousands of molecules capable of binding to — and potentially neutralizing — rogue circadian clock proteins inside cancer stem cells, according to USC.

Using several advanced techniques, including artificial intelligence, to determine which molecule was best suited to fight glioblastoma, the team studied how each new molecule would bind to clock proteins, looking for the perfect ‘lock and key’ fit, and identified one. particularly promising molecule: SHP656, according to USC.

The next step was to test the effectiveness of SHP656 against real cancer cells. Using glioblastoma stem cells taken from patients, the researchers showed that SHP656 reduced the growth of cancer stem cells, but did not harm normal stem cells in the body, according to the study.

“We find that the molecule acts differently on healthy brain cells compared to tumor cells,” Kay said. “It was a real leap forward in our understanding of how we can develop drugs that target clock proteins.”

City News Service contributed to this article.

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