HomeWorldNew Research: Cancer drug development influenced by differences in animal biology

New Research: Cancer drug development influenced by differences in animal biology

Weill Cornell Medicine researchers have discovered a small but significant metabolic difference between human and mouse lung tumor cells, which explains a discrepancy in the results of previous studies and points to new strategies for developing cancer treatments.

The work, published in Cancer Discovery, focuses on lung adenocarcinoma, a common but often difficult-to-treat cancer that scientists have long studied in mouse models. However, these models did not fully match human clinical observations in some cases. A new article shows why; a specific gene mutation has opposite effects on tumor growth in mice and humans.

The inspiration for the project dates back more than a decade, when co-author Dr. Benjamin Stein, now an instructor of cancer biology in medicine at Weill Cornell Medicine, studied the role of the tumor suppressor LKB1 in metabolism as a graduate student. In mice, tumors containing mutations in two key genes, KRAS and TP53, can become much more aggressive by acquiring a mutation in a third gene, LKB1.

“However, the clinical data showed that these three mutations did not really occur at high frequency in humans,” Stein said. After starting a postdoctoral appointment in the laboratory of co-author Dr. Lewis Cantley, former director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, with Drs. Stein decided to focus on decoding this difference.

At the time, co-author Dr. John Ferrarone, a medical oncologist who worked in the lab of co-author Dr. Harold Varmus, Lewis Thomas University Professor of Medicine. member of the Meyer Cancer Center. “My main interest in this project was more from a clinical angle, so I wondered if there was a way to potentially use tumors with these common mutations,” said Dr. Ferrarone, who is now an instructor of medicine at Weill Cornell.

Working with Dr. Varmus, Dr. Cantley, who is now at the Dana Farber Cancer Center, and other collaborators from Weill Cornell and other institutions, the researchers took a deep dive into how the products of these three genes behave in mouse models. and cultured human cells. The group used techniques that ranged from state-of-the-art genetic engineering, proteomics, metabolomics and mouse models to classical biochemical and cell biology experiments.

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

A multidisciplinary approach pointed to a fundamental difference in LKB1-driven regulation of glucose metabolism between mice and humans, due to slight differences in the regulation of the metabolic enzyme triosephosphate isomerase (TPI1) in the two species. As a result, mouse tumors that carry mutations in KRAS and TP53 also gain a significant metabolic advantage by mutating LKB1. But in humans, mutation of LKB1 in the same context appears to harm tumor cells because they can no longer regulate TPI1 and glucose metabolism. This explains why these three mutations rarely occur together in human cancers.

These results suggest a new strategy for attacking lung adenocarcinomas: targeting the controls of the LKB1 metabolic pathway. “Knocking out a key regulatory enzyme can have very damaging effects, so the discussion now is more about going downstream and targeting other molecules,” said Dr. Stein.

Nevertheless, he and Dr. Ferrarone are optimistic about the work leading future drug discovery efforts. The new findings also sound a note of caution to investigators who rely heavily on mouse models to screen drug candidates, as compounds that might work well against human cancers might actually be missing from current mouse tumor models.

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