To fight pancreatic cancer more effectively, we should do more than attack cancer cells. We should also attack their collaborators, cancer-associated fibroblasts (CAFs). By widening the fight to encompass CAFs—cells that create fibrotic fortresses around pancreatic tumors—we may finally overcome a disease that has been known to withstand the most determined sieges.
The castle keep and outer walls of a pancreatic tumor were fired upon simultaneously in research conducted by scientists at the University of New South Wales (UNSW). The scientists’ weapon of choice? A drug that inhibits SLC7A11, a cystine transporter.
The researchers confirmed that SLC7A11 was a suitable target in experiments with human cells and transgenic mice. These experiments with transgenic mice included stable knockdown of SLC7A11, in the tumor compartment only, and then in the tumor and stromal compartments. Next, the scientists demonstrated the effectiveness of a nanoparticle SLC7A11-silencing drug in experiments with transgenic mice.
Detailed findings appeared March 12 in Cancer Research, in an article titled, “Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition.”
“In an orthotopic pancreatic ductal adenocarcinoma (PDAC) mouse model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments,” the article’s authors wrote. “Finally, treatment with a nanoparticle SLC7A11-silencing drug developed by our laboratory reduced PDAC tumor growth, metastasis, CAF activation, and fibrosis in orthotopic PDAC tumors.”
In this article, which reflects 10 years of effort, the authors noted that while SLC7A11 has been studied in pancreatic cancer cells before, it had not previously been shown to play a critical role in CAFs. Now that the authors have demonstrated the value of inhibiting SLC7A11 in PDAC-derived CAFs, they are looking forward to seeing their approach evaluated in an upcoming human clinical trial.
“Pancreatic cancer has seen minimal improvement in survival for the last four decades—and without immediate action, it is predicted to be the world’s second biggest cancer killer by 2025,” said Phoebe Phillips, PhD, the article’s senior author and an associate professor at UNSW Medicine & Health. “But our latest advance means today I am the most optimistic and hopeful I have been in my career.”
Phillips and colleagues used several complementary models to improve the clinical translatability of their findings, including patient-derived PDACs and CAFs, 3D at-the-bench models including an explant model that maintains pieces of human pancreatic tumor tissue, and multiple mouse models of pancreatic cancer.
“We also used our cutting-edge nanomedicine we developed in a multidisciplinary collaboration with engineers—UNSW professor Cyrille Boyer, PhD, and University of Queensland professor Thomas Davis, PhD—to deliver a gene therapy to inhibit SLC7A11. This therapy is advantageous because our nanodrug is tiny and able to penetrate the scar tissue in pancreatic cancer,” said Joshua McCarroll, PhD, co-first author and associate professor from the Children’s Cancer Institute.
The team’s findings have formed the foundation for a clinical trial led by Phillips and UNSW Medicine collaborator professor David Goldstein, PhD. “In this trial,” Phillips noted, “we will repurpose an anti-arthritis drug called sulfasalazine—which we know potently inhibits SLC7A11—for the treatment of pancreatic cancer patients with tumors that have high SLC7A11 levels, which we’ve shown to be the case in more than half of patients. It has the potential to improve treatment response and ultimately survival of these patients.”
The researchers say the opportunity to repurpose an existing drug that’s already in the clinic will help them make progress more quickly. The research team hopes to analyze and publish the first set of results of the trial within three years.
In addition to the clinical trial, the team now hopes to assess how their approach interferes with the exchange of nutrients between tumor cells and helper cells. They also want to identify the ideal drugs to combine with their therapeutic approach to enhance antitumor effects.