Researchers led by a team at Sanford Burnham Prebys Medical Discovery Institute have identified a combination of two already approved anticancer compounds that can significantly shrink pancreatic tumors and melanoma tumors in mice. The researchers say the findings support immediate evaluation of the drugs in a clinical trial.

“The sad reality is that at present, pancreatic cancer therapy is lagging since there is no effective treatment for these tumors,” noted Ze’ev Ronai, PhD, professor in Sanford Burnham Prebys’ Tumor Initiation and Maintenance Program and senior author of the team’s published paper, in Nature Cell Biology. “Our study identifies a potential treatment combination that can immediately be tested against these aggressive tumors. We are already meeting with oncologists at Oregon Health & Science University to discuss how to advance this discovery into clinical evaluation.” The researchers reported their results in a paper titled, “Translational reprogramming marks adaptation to asparagine restriction in cancer.”

Pancreatic cancer is one of the deadliest cancers, and the five-year survival rate is less than 10%. This is partly because pancreatic cancer can be difficult to diagnose, as typical symptoms may not occur until the disease is advanced. It’s expected that more than 56,000 people in the United States are expected to receive a pancreatic cancer diagnosis in 2019.

Rapidly proliferating tumors have an increased need for nutrients to fuel their growth, so cutting off their supply of macromolecules could feasibly help to halt tumor growth, the researchers explained. “… limiting nutrient supply is widely recognized as a potential therapeutic strategy.” However, cancer cells are masters at enduring nutrient-restricted environments by rewiring some metabolic pathways. The ability of cancer cells to synthesize nonessential amino acids from scratch allows them to survive nutrient limitation as an anticancer approach. But there are some potential chinks in the armor. Cancer cells can, for example, maintain glutamine-dependent processes even when there is no glutamine supply, because they can carry out glutamine biosynthesis de novo, but with the notable exception of asparagine biosynthesis. Asparagine is a key amino acid that is required for protein synthesis. “Since the inability to maintain cellular asparagine levels underlies the tumor growth suppression seen on glutamine restriction, curtailing cellular asparagine levels is an appealing alternative to limit tumor growth,” the team noted. An enzyme, asparagine synthetase (ASNS), catalyzes the conversion of aspartate to asparagine, and the lack of ASNS in acute lymphoblastic leukemia renders cells sensitive to asparagine restriction. However, this approach doesn’t work in solid tumors that have low levels of ASNS.

Ze’ev Ronai, PhD, a professor in Sanford Burnham Prebys’ Tumor Initiation and Maintenance Program and senior author of the study. [Sanford Burnham Prebys]

For their study, the scientists first used a drug called L-asparaginase (L-Aase) to starve pancreatic tumors of asparagine (L-Asn). However, they found that instead of dying, the tumor turned on the MAPK stress response pathway that allowed the cancer cells to produce asparagine from scratch. The scientists then treated mice with a second drug, an MEK inhibitor (MEKi), which blocked the stress response pathway. This dual approach effectively shrank the pancreatic tumors. L-asparaginase is already approved by the FDA to treat certain leukemias, and the MEK inhibitor is approved for the treatment of solid tumors, including melanoma. As part of their studies, the scientists also showed that the two treatments combined shrank melanoma tumors in mice. Due to the large unmet clinical need in pancreatic cancer, the scientists have decided to focus on this type of cancer first.

“Notably, combined L-Aase and MEKi treatment effectively suppressed tumor growth in a dose-dependent manner, compared with either treatment alone,” the researchers noted. “Importantly, whereas MEKi showed some degree of anti-metastatic activity, when combined with L-Aase, there was marked suppression of lung metastasis compared with either treatment alone … These findings substantiate the effectiveness of combined L-Aase and MEK inhibition in suppressing melanoma and pancreatic cancer growth and melanoma metastasis.”

Encouragingly, the team’s analysis of tumors from human patients showed that low ASNS and MAPK activity correlated with favorable outcomes following anticancer treatment. “ … we analyzed RNA-sequencing (RNA-seq) data that were obtained from 15 patients with melanoma before they were treated with BRAFi or combined BRAFi and MEKi,” they wrote. “A significantly lower level of ASNS expression was identified in responders (>30% reduction in tumor size) versus nonresponders (<30% reduction in tumor size). Furthermore, ASNS was among the top seven genes whose expression was the strongest predictor of response to MAPK signaling inhibitors.”

“This research lays the basis for the inhibition of pancreatic tumor growth by a combined synergistic attack based on asparagine restriction and MAPK signaling inhibition,” said Eytan Ruppin, MD, PhD, a study author and chief of the Cancer Data Science Library at the National Cancer Institute, part of the National Institutes of Health (NIH). “Our lab was able to further support these findings through a computational analysis of patient data.”

Rosalie C. Sears, PhD, a professor at Oregon Health & Science University, added: “It’s clear we’re not going to find a single magic bullet that cures cancer but will instead need several drugs that target multiple vulnerabilities. This study identifies a promising dual treatment for pancreatic cancer—one of the deadliest cancers—and I look forward to seeing these drugs tested in patients.”