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Researchers Find New Protein That Resists Chemotherapy Drugs

A study led by co-first authors, Dr. Prashant Thakkar and Dr. Katsuhiro Kita, former postdocs at Weill Cornell Medicine has come forward with the knowledge of a new protein variant that is responsible for gastric cancers to resist a generally effective family of chemotherapy drugs.

Published on October 20 in "Development Cell", the results of the study also propose a likely course of treatment that could be adopted for cancer patients. The researchers took into consideration a family of chemotherapy drugs called taxanes that work by interfering with proteins that make up the cell's internal skeleton and showed how they failed in the case of the variant protein, called CLIP-170S. This problem was found to be more common in gastric cancer, leaving the patients with fewer choices in terms of their treatment.

"We identified a novel variant that is clinically prevalent and is expressed in more than 60 percent of patients with gastric cancer and operates with a mechanism that's different from previously discovered ones," said co-senior author Dr. Paraskevi Giannakakou, professor of pharmacology in medicine and director of research in the Division of Hematology and Medical Oncology, and associate director for education in the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

Speaking about the high number of cases of gastric cancer patients (about 80% of the cases) developing taxane-resistant tumors, the co-senior author Dr. Manish Shah, director of the Gastrointestinal Oncology Program and chief of the Solid Tumor Oncology Service in the Division of Hematology and Medical Oncology at Weill Cornell Medicine and New York-Presbyterian/Weill Cornell Medical Center, said, "Most patients with gastric cancer live less than a year, and if we could figure out a way to make the taxanes more effective, we could have a bigger impact on patients."

"In the quest to overcome the newly discovered taxane resistance mechanism, the researchers resorted to computational biologists.

"Starting with a database of approved drugs, we created a computational program that was able to screen through these molecules, in silico, to identify the ones that would essentially make resistant cells look more like cells that are sensitive to taxanes," said co-senior author Dr. Olivier Elemento, director of the Caryl and Israel Englander Institute for Precision Medicine, associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine and a professor of physiology and biophysics at Weill Cornell Medicine.

The algorithm also highlighted Imatinib, sold under the brand name Gleevec, which is completely unrelated in its actions to taxanes.

"That's important because it demonstrates how you can go in without preconceptions and use computational screening to come up with molecules that have an effect," said Dr. Elemento, who is also a co-founder and equity stakeholder of OneThree Biotech, an artificial intelligence-driven drug discovery, and development company.Clinical trials on the combined treatment are expected to begin soon.

According to Dr. Shah, "The whole story is really quite remarkable, and it opens the door for overcoming taxane resistance in other cancers as well."

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