Breakthrough brings potential glioblastoma dr

Glioblastoma, the most common malignant brain tumor in adults, is an aggressive disease – patients survive an average of just 15 months after diagnosis. Despite more than two decades of research into the causes and treatments of glioblastoma, this prognosis has hardly improved.

However, recent work by a team led by the Keck School of Medicine of USC has shown that circadian clock proteins, which help coordinate changes in body functions throughout the day, may play a key role in glioblastoma growth and proliferation, according to current studies standard treatments can play . This discovery has led to a potential breakthrough: the identification of a small molecule drug known as SHP656 that can target clock proteins and could prove effective in treating the disease.

“This is a potent molecule that we are very interested in for its potential for use against glioblastoma,” said Steve Kay, PhD, associate professor and provost professor of neurology, biomedical engineering and life sciences at the Keck School of Medicine USC and director of the USC Michelson Center for Convergent Bioscience.

Kay has assembled a collaboration that brings together academics with expertise in glioblastoma, circadian clock biology and biological chemistry with Synchronicity Pharma, a biotechnology startup he co-founded. The results of their research on the SHP656 molecule have just been published in Proceedings of the National Academy of Sciences.

“We are now beginning to take the clinical drug development journey — transforming this from a science story to a translational story,” said Kay, the study’s senior author, who also co-directs the Rosalie and Harold Rae Brown Center for Cancer Drug Development at USC Norris Comprehensive Cancer Center.

Neutralize rogue cells

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

“In the vast majority of patients, the cancer returns. And when it comes back, it’s resistant to chemotherapy and radiation,” Kay said.

Researchers believe that cancer returns because a small number of “cancer stem cells” remain after surgery, chemotherapy and radiation. 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 found that cancer stem cells hijack the body’s circadian clock machinery, allowing them to spread faster and resist the effects of chemotherapy and radiation treatment.

Armed with this knowledge, Kay and his collaborators have designed and tested thousands of molecules capable of binding to, and potentially neutralizing, the circadian clock proteins in cancer stem cells. They used several advanced techniques, including artificial intelligence (AI), to determine which molecule would be best for fighting glioblastoma. The team’s AI algorithms modeled how each new molecule would bind to the clock proteins, looking for the perfect “lock-and-key” fit. They identified a particularly promising molecule: SHP656.

The next step was to test the effectiveness of SHP656 against real cancer cells. Using glioblastoma stem cells collected from patients, the researchers showed that SHP656 reduced the growth of cancer stem cells but did not damage the body’s normal stem cells.

“We see that the molecule acts differently on healthy brain cells than on tumor cells,” said Kay. “This was a real advance in our understanding of how to design drugs that target clock proteins.”

expand potential

Synchronicity Pharma has now started Phase 1 clinical trials for this class of new molecules. So far, the molecule appears to be safe in healthy subjects. They hope to begin phase 2 trials in glioblastoma patients within two to three years.

In addition to its potential to treat glioblastoma, SHP656 and other molecules that target clock proteins show promise in treating other cancers. Kay and his colleagues are also studying their utility in colon cancer, liver cancer, and acute myeloid leukemia.

“This study shows that academic researchers can be at the forefront of cancer drug discovery when they bring together the right kind of collaboration,” he said.

About this study

In addition to Kay, the other authors of the study are Priscilla Chan of the Department of Biomedical and Biological Sciences, USC’s Keck School of Medicine; Tsuyoshi Hirota, Simon Miller, Manish Kesherwani, Yoshiko Nagai, Moeri Yagi, and Florence Tama from the Institute of Transformative Bio-Molecules, Nagoya University; and Jamie Cope of Synchronicity Pharma LLC.

This work was supported by the Japan Society for the Promotion of Science Grants [18H02402, 20K21269, 21H04766]; the Takeda Science Foundation; the Uehara Memorial Foundation; the Tokyo Biochemical Research Foundation; the Hitachi Global Foundation; the Rosalie and Harold Rae Brown Center for Cancer Drug Development at USC Norris Comprehensive Cancer Center; Synchronicity Pharma LLC; the National Cancer Institute [R01CA238662-01]; the National Institute of Neurological Disorders and Stroke [1F31NS120654-01]; and the Charlie Teo Foundation-More Data Better Tools grant.

Disclosure: Steve Kay is a director of Synchronicity Pharma LLC and receives financial compensation for his role.

About USC’s Keck School of Medicine

Founded in 1885, USC’s Keck School of Medicine is one of the nation’s premier medical institutions, known for innovative patient care, scientific discovery, education and community service. Medical and graduate students work closely with world-renowned faculty and receive hands-on training in one of the most diverse communities in the country. They engage in cutting-edge research as they become the healthcare leaders of tomorrow. The faculty of the Keck School is instrumental in training 1,200 resident physicians in 70 specialty and subspecialty programs and thus plays an important role in the education of physicians practicing in Southern California.