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In gastric cancer, there is a protein variant that makes chemotherapy ineffective.

A study conducted by a multidisciplinary team at Weill Cornell Medicine has identified a new protein variant that is responsible for the ability of gastric cancers to resist a class of chemotherapy drugs that was previously considered effective.

The findings point to a treatment strategy that could improve the prognosis of many patients, according to the .

It was published in the journal ‘Developmental Cell’ that the researchers shared their findings.

It took clinical observations, laboratory experiments, and sophisticated computational analysis to figure out why some tumor cells are resistant to a class of chemotherapy drugs known as taxanes, according to the researchers. Taxane treatment by interfering with proteins that form the internal skeleton of the cell, but the variant protein, known as CLIP-170S, allows cells to avoid this interference.

“We discovered a novel variant that is clinically prevalent and expressed in more than 60% of patients with gastric cancer, and it operates through a mechanism that is distinct from previously discovered variants,” said co-senior author Dr Paraskevi Giannakakou, professor of pharmacology in medicine and director of research in the Division of Hematology and Oncology at Weill Cornell Medicine, as well as associate director for in the Sandra and Edward Meyer Center at Weill Cornell Medicine.

Taxanes, which are derived from compounds discovered in yew trees, are first- treatments for a wide range of cancers. Due to the high frequency with which taxane-resistant cells arise and survive treatment, patients are left with few treatment options and prognoses. The situation is particularly dire in the case of gastric cancer.

Doctor Manish Shah, director of the Gastrointestinal Oncology Program at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Center and the Bartlett Family Professor of Gastrointestinal Oncology, said, “Most patients with gastric live less than a year. If we could figure out a way to make taxanes more effective, we could have a bigger impact on patients.” According to him, approximately 80% of gastric cancer patients develop tumors that are resistant to taxanes.

Despite the fact that of research have revealed a variety of mechanisms by which cells can resist taxane-mediated killing, the findings have had little impact on clinical outcomes.

In spite of the fact that everyone is attempting to understand the mechanisms of taxane resistance, “nothing is helping patients clinically, and none of the resistance mechanisms identified in the lab has had a clinical impact,” Dr Giannakakou said in a statement.

Dr Shah approached Dr Giannakakou with a reanalysis he’d done on from the clinical trial that resulted in the FDA’s approval of taxanes for the treatment of patients with gastric cancer. Dr Shah was eager to take another stab at the problem and presented Dr Giannakakou with his findings. The study discovered a subset of gastric patients who did not benefit at all from taxane treatment, indicating that their tumors were already drug-resistant before being exposed to the compound, according to the researchers.

The researchers, who worked with a multi-institutional team of collaborators, compared cells derived from taxane-resistant tumors to cells derived from taxane-sensitive tumors in order to determine which was more effective. In their research, they discovered that the taxane-resistant cells carried a variant form of a protein called CLIP-170, which is normally involved in maintaining the integrity of the cell’s cytoskeleton.

Following that, the team enlisted the assistance of computational biologists in order to investigate potential solutions to the newly discovered taxane resistance mechanism.

The researchers used a database of approved drugs to develop 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, according to co-senior author Dr Olivier Elemento, director of the Caryl and Israel Englander Institute for Precision Medicine and associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computable Medicine.

One was identified by the algorithm that was unexpected: imatinib, a leukemia drug sold under the brand name Gleevec. Taxanes and imatinib have completely different mechanisms of action, and imatinib is not used to gastric cancer, which is one of the clinical indications for the drug. But the researchers were able to confirm that a combination of the two drugs was effective in killing taxane-resistant tumors in laboratory dishes.

OneThree Biotech, an artificial intelligence-driven drug discovery and development , was founded by Dr Elemento, who is also a co-founder and equity stakeholder in the research. “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,” he said.

Because imatinib is already an FDA-approved drug, the investigators hope to begin clinical trials on the combined treatment as soon as possible after receiving FDA approval. CLIP-170 variants may also have the potential to serve as biomarkers for taxane resistance in a variety of solid tumor types.

In addition to being co-director of the Center for Advanced Digestive Care at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, Dr. Shah is also the author of the study.

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