Pancreatic Cancer Fail to resist "Dual Cell" Approach

We should do more than attack cancer cells to combat pancreatic cancer more effectively. We must also target their accomplices, cancer-associated fibroblasts (CAFs). By expanding the fight to include CAFs—cells that form fibrotic fortifications around pancreatic tumors—we may be able to eventually defeat a disease that has been known to survive even the most ferocious assaults.

In a study performed by scientists at the University of New South Wales, the castle keep and the outer walls of a pancreatic tumor were both shot at at the same time (UNSW). The tool of choice for scientists  SLC7A11, a cystine transporter, is inhibited by this drug.

In experiments with human cells and transgenic mice, the researchers confirmed that SLC7A11 was a viable target. Stable knockdown of SLC7A11 in the tumor compartment only, then in the tumor and stromal compartments, was tested in transgenic mice. The scientists then used transgenic mice to show the efficacy of a nanoparticle SLC7A11-silencing compound.

The results were published in Cancer Research in an article titled, “Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition.”

“Stable knockdown of SLC7A11 was needed in both cell types to reduce tumor development, metastatic spread, and intratumoral fibrosis in an orthotopic pancreatic ductal adenocarcinoma (PDAC) mouse model using human PDAC cells and CAFs, demonstrating the importance of targeting SLC7A11 in both compartments,” the authors wrote. “Finally, in orthotopic PDAC tumors, treatment with a nanoparticle SLC7A11-silencing drug produced by our lab reduced PDAC tumor formation, metastasis, CAF activation, and fibrosis.”

Although SLC7A11 had previously been studied in pancreatic cancer cells, it had not previously been shown to play a critical role in CAFs, according to the authors of this study, which represents ten years of work. The authors are eager to see their method tested in a human clinical trial now that they have demonstrated the value of inhibiting SLC7A11 in PDAC-derived CAFs.

The article's senior author, Phoebe Phillips, PhD, an associate professor at UNSW Medicine & Health, said, "Pancreatic cancer has seen little progress in survival over the last four decades—and without urgent intervention, it is expected to be the world's second biggest cancer killer by 2025."“However, our most recent breakthrough has me feeling more confident and hopeful than I have in my entire career.”

Phillips and colleagues used patient-derived PDACs and CAFs, 3D at-the-bench models, including an explant model that preserves pieces of human pancreatic tumor tissue, and several mouse models of pancreatic cancer to enhance the clinical translatability of their results.

“We have used our cutting-edge nanomedicine, which we established in a multidisciplinary partnership with engineers, UNSW professor Cyrille Boyer, PhD, and University of Queensland professor Thomas Davis, PhD, to deliver a gene therapy to inhibit SLC7A11,” says Dr. Davis. Since our nanodrug is small and can penetrate scar tissue in pancreatic cancer, this therapy is advantageous,” said Joshua McCarroll, PhD, co-first author and associate professor at the Children's Cancer Institute.

Phillips and UNSW Medicine partner professor David Goldstein, PhD, are leading a clinical trial based on the team's results. “We can repurpose an anti-arthritis medication named sulfasalazine—which we know potently inhibits SLC7A11—for the treatment of pancreatic cancer patients with tumors that have elevated SLC7A11 levels, which we've shown to be the case in more than half of patients,” Phillips said. It has the ability to increase these patients' clinical response and, eventually, survival.”

The ability to repurpose an approved medication that is already in the clinic, according to the researchers, would help them move forward more rapidly. Within three years, the study team expects to review and report the trial's first collection of findings.

Aside from the clinical trial, the researchers want to see how their method affects the exchange of nutrients between tumor cells and helper cells. They also want to find the best medications to pair with their treatment plan to improve antitumor efficacy.