Greek Scientists at NYU on “Hijacked” Stress Response Mechanism, Promising Drug Targets for Blood Cancer 

Dr. Iannis Aifantis and Dr. Nikos Kourtis in the lab. (Photo: Courtesy of Nikos Kourtis)

NEW YORK – Greek scientists at New York University (NYU) School of Medicine are among the leaders of the team whose research has revealed promising drug targets in the fight against blood cancer. The study first and corresponding author, Nikos Kourtis, PhD, a postdoctoral fellow at NYU Langone, shared the findings with The National Herald.

A protein that participates in normal cell development, and in a type of leukemia in pathological conditions, promotes cancer by taking control of a pathway better known for its role in protection against unfavorable conditions.

The discovery that the NOTCH1 pathway takes control of Heat Shock Transcription factor 1 (HSF1) signaling in T cell acute lymphoblastic leukemia (T-ALL) and that T-ALL is “addicted” to HSF1 function for survival, uncovers new therapeutic targets, researchers say.

Moreover, the NYU School of Medicine scientists who led the latest research efforts say that because an experimental anticancer drug is already in development against one of these targets, heat shock protein 90 (HSP90), the new study identifies the subset of T-ALL patients most likely to benefit from the new therapy.

Reporting in the journal Nature Medicine online, researchers say their study is the first to elucidate the transcriptional regulation of the stress factor HSF1, in any type of cancer.

“Our study shows how NOTCH1 pathway hijacks the heat shock transcription factor 1-orchestred pathway, which typically maintains protein homeostasis, to instead promote tumor growth,” said Dr. Kourtis.

“The cancer cells are sending into overdrive a system that helps healthy cells respond to stress,” said senior and corresponding investigator Iannis Aifantis, PhD, Professor and Chair of the Department of Pathology at NYU Langone Health and its Perlmutter Cancer Center. According to Aifantis, a drug blocking HSP90 is already in early clinical trials at Memorial Sloan Kettering Cancer Center in New York as a treatment for breast cancer. He says if further testing proves successful, the experimental drug, could be quickly adapted for trials in T-ALL patients.

And because early experiments with the drug in animals and human cells show that blocking the gene that produces HSP90 kills only cancer cells, Kourtis says its use is likely to have fewer side effects compared to current T-ALL treatments such as chemotherapy that kills both normal and cancer cells. According to Kourtis “Having a targeted therapy that kills only cancer cells could really boost our efforts to treat T cell acute lymphoblastic leukemia, a common type of childhood cancer.” Kourtis says currently one in five children treated for the disease relapse within a decade and therefore new therapeutic targets are needed in T- ALL. Attempts at blocking NOTCH1 directly have failed, he notes, because of adverse effects on healthy cells connected to the pathway.

As part of the study, researchers genetically blocked HSF1 in T-ALL mouse models, killing all cancer cells without affecting normal cells. This evidence, researchers say, showed that HSF1 was essential to the survival of T-ALL cancer cells.

Further laboratory experiments in T-ALL mice and human cells showed that cancer cells expressing high levels of NOTCH1 are particularly sensitive to HSP90 inhibition. According to Kourtis and Aifantis these results will be powerful for the design of clinical trials targeting the stress response machinery of the cell.

The team’s next plans are to evaluate whether targeting other “druggable” effectors of the HSF1 pathway shows promising anticancer activity in T-ALL.

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