A groundbreaking study spearheaded by NYU Grossman School of Medicine, the Department of Radiation Oncology, and the Perlmutter Cancer Center has discovered a promising treatment duo that curbs pancreatic cancer growth in mice.

This pivotal research builds upon previous findings from NYU Langone, which highlighted the ability of pancreatic cancer cells to tap into alternate energy sources, a key factor in their lethal nature.

Published today in Nature Cancer, the research delves into the efforts to halt the fuel-switching capabilities of pancreatic ductal adenocarcinoma (PDAC) cells. These cells use the enzyme glutaminase to convert glutamate to a more usable form, glutamine. Although there are drugs that target glutaminase, they inadvertently drive cancer cells to explore other energy alternatives.

Paving a new direction, the researchers turned their focus to DRP-104, an experimental drug developed by Dracen Pharmaceuticals.

It’s a new “prodrug” version of the compound 6-Diazo-5-oxo-L-norleucine (DON) and has been developed to trick and starve cancer cells by impersonating glutamine.

This unique approach, unlike glutaminase inhibitors, restricts all pathways that rely on glutamine. DRP-104, currently in trials against lung cancer, cannot be consumed as fuel but attaches to the same enzymes as glutamine.

The latest experiments showed that using DRP-104 on its own restricted PDAC growth in pancreatic cancer mouse models. Yet, the findings didn’t stop there.

PDAC cells, when deprived of their fuel by DRP-104, ramped up signaling via a protein termed extracellular signal-regulated kinase (ERK).

By combining DRP-104 with an existing ERK pathway inhibitor, trametinib, the research team noticed enhanced survival rates in the mouse models.

Alec Kimmelman, M.D., Ph.D., from NYU Langone Health, emphasizes “Despite a decade of advances in understanding how cancer cells switch fuel sources, we have not yet effectively translated this into clinically relevant therapies.”

According to him, “Broad antagonism of metabolic pathways with glutamine analogs may provide another mode of attack against these highly resistant tumor cells. The fact that such drugs are already being tested in the clinic makes us hopeful that we may finally see patient outcomes improve, if this approach proves to be effective in clinical trials.”

The research path ahead is set on decoding the broader implications of glutamine restriction on pancreatic cancer and exploring potential other targets.

Kimmelman stresses the importance of achieving a therapeutic balance, ensuring that potential side effects on healthy tissues are minimized.

Source: 10.1038/s43018-023-00647-3

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