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Animal biology variations may impact development of cancer drugs

Researchers from Weill Cornell Medicine have identified a metabolic difference between human and mouse lung tumor cells that explains discrepancies in previous studies and suggests new strategies for developing cancer treatments. Published in Cancer Discovery, the study focused on lung adenocarcinoma, a common but challenging cancer to treat.

Although researchers have long studied this cancer in mouse models, these models did not always match human clinical observations. The study revealed that a specific gene mutation had opposite effects on tumor growth in mice and humans, highlighting the need to explore such differences for more accurate drug screening.

More than 10 years ago, Dr. Benjamin Stein, now an instructor of cancer biology in medicine at Weill Cornell Medicine, was studying the role of LKB1 in metabolism as a graduate student. He discovered that in mice, tumors containing mutations in two genes, KRAS and TP53, can become much more aggressive by acquiring a mutation in LKB1. However, Dr. Stein noticed that the three mutations didn’t occur frequently in human clinical data. Upon starting his post-doctoral appointment at Weill Cornell Medicine, Dr. Stein decided to decode this difference, and focused on the project with co-senior author Dr. Lewis Cantley, the former director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

More than 10 years ago, Dr. Benjamin Stein, now an instructor of cancer biology in medicine at Weill Cornell Medicine, was studying the role of LKB1 in metabolism as a graduate student. He discovered that in mice, tumors containing mutations in two genes, KRAS and TP53, can become much more aggressive by acquiring a mutation in LKB1. However, Dr. Stein noticed that the three mutations didn’t occur frequently in human clinical data. Upon starting his post-doctoral appointment at Weill Cornell Medicine, Dr. Stein decided to decode this difference, and focused on the project with co-senior author Dr. Lewis Cantley, the former director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

Dr. John Ferrarone, a co-lead author of the study, was also exploring the same issue in human clinical data next door as a medical oncology fellow at the Meyer Cancer Center, under the guidance of co-senior author Dr. Harold Varmus, the Lewis Thomas University Professor of Medicine.

“My primary focus on this project was from a clinical standpoint, as I wanted to determine if there was a possibility of exploiting tumors with these prevalent mutations,” stated Dr. Ferrarone, who presently serves as an instructor in medicine at Weill Cornell.

The researchers at Weill Cornell Medicine, along with collaborators from other institutions, joined forces with Dr. Varmus and Dr. Cantley, who is currently affiliated with the Dana Farber Cancer Center, to investigate the behavior of the gene products in mouse models and cultured human cells. Their research involved a range of cutting-edge techniques, including genetic engineering, proteomics, metabolomics, and mouse models, as well as traditional biochemical and cell biological experiments.

“Using multiple approaches at the genetic, protein and metabolite level allowed us to obtain a more comprehensive understanding of what was going on within each species, and then try to cross-correlate and dissect where the disparities were between the two,” said Dr. Stein.

By employing a multi-disciplinary approach, the team identified a critical difference in glucose metabolism regulation between humans and mice, driven by LKB1 and caused by slight variations in the regulation of the metabolic enzyme TPI1. In mice, tumors carrying mutations in KRAS and TP53 acquire a substantial metabolic edge by mutating LKB1 as well. However, in humans, mutating LKB1 in the same scenario appears to hinder the tumor cells since they can no longer regulate TPI1 and glucose metabolism. This is the reason why the three mutations rarely coexist in human cancers.

Those results suggest a new strategy for attacking lung adenocarcinomas: targeting the metabolic pathway LKB1 controls.

“Taking out a master regulator enzyme can have very detrimental effects, so the discussions now are more about going downstream and targeting other molecules,” said Dr. Stein.

Despite the discrepancies observed between mouse and human models, Dr. Stein and Dr. Ferrarone are hopeful that the insights from their research will help inform the development of novel cancer treatments. At the same time, their findings serve as a warning to researchers who rely solely on mouse models for drug discovery, as potential drugs that may be effective in humans could be overlooked in current mouse tumor models.

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