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Ornithine aminotransferase is a new target for pancreatic cancer treatment with fewer side effects

Pancreatic cancer (PC), a highly malignant tumor of the gastrointestinal tract, is difficult to diagnose and treat, with pancreatic ductal adenocarcinoma (PDAC) accounting for more than 95% of all pancreatic cancers. In recent years, the incidence of pancreatic cancer has increased significantly. It is often diagnosed at an advanced stage due to its low early diagnosis rate. With its low survival rate and poor prognosis, pancreatic cancer is known as the "king of cancers".

Over the past two decades, much of the research into new cancer treatments and drugs has focused on genetic targets that promote cancer growth and spread by altering cellular signaling or turning off tumor suppressors. However, there is growing evidence that unique features of cancer cell metabolism may offer new opportunities for developing therapies that target tumors directly without affecting healthy cells.

Recently, researchers at Harvard Medical School published a study in Nature entitled "Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer". The study found that PDAC uses a unique metabolic pathway rarely used by normal cells to obtain and produce the nutrients it needs to survive. This pathway relies on ornithine aminotransferase (OAT), providing a new target for developing therapies specifically targeting PDAC with fewer side effects.

PDAC is a highly lethal malignancy with increasing incidence and poor prognosis, creating an urgent need for the development of effective therapies. Although targeting tumor metabolism has been a hot topic in cancer research for more than a decade, the plasticity of tumor metabolism and the high risk of toxicity limit this anticancer strategy.

To support tumor growth, pancreatic tumors must produce large amounts of polyamine compounds. Most cells use an arginine-dependent process to make the polyamines they need. However, the microenvironment of pancreatic tumors is typically deficient in spermidine.

In this new study, the team found in vitro and in vivo models in humans and mice that PDAC has a significant dependence on glutamine for the de novo synthesis of ornithine. This dependence is associated with arginine depletion in the PDAC tumor microenvironment and is driven by mutant KRAS, which is mutationally activated to induce the expression of OAT and polyamine synthase, leading to changes in the transcriptome and open chromatin landscape of PDAC cells.

That is, pancreatic tumors switch to the OAT pathway, which uses glutamine instead of arginine to produce polyamines, a pathway that is primarily active in the intestine of infants and fasting adults. By using the OAT pathway to produce polyamines, tumors can overcome the challenging arginine-deficient tumor microenvironment. This provides a new target—targeted inhibition of OAT—that promises to inhibit tumor growth.

To test this idea, the team suppressed OAT expression by knocking out the OAT gene or using inhibitors to block OAT in cells and mouse models. Metabolic and cell growth experiments showed that both approaches significantly inhibited tumor cell growth in both cells and mouse models.

"We wanted to develop a compound that would target an enzyme used primarily by cancer cells so that it could attack tumors with fewer side effects without affecting other normal cells," according to the research team. This study found that pancreatic cancer cells use OAT to produce polyamines, a metabolite required for growth. Normal adult cells do not normally use this pathway, so OAT could be a potential therapeutic target for pancreatic cancer.

Faced with the lack of spermidine in the tumor microenvironment, cancer has found a solution to the problem by producing polyamines needed for growth through the OAT pathway, and this study shows that targeting this pathway, which cancer cells cannot bypass, is a new option for pancreatic cancer treatment with strong clinical translational value.