Pancreatic cancer may succumb to a “dual cell” approach

To fight pancreatic cancer more effectively, you have to do more than attack the cancer cells. They also need to attack their collaborators, cancer-related fibroblasts (CAFs). By expanding the battle to include CAF (cells that create fibrous fortresses around pancreatic tumors), we may eventually overcome diseases known to withstand the most decisive siege. Maybe.

In a study conducted by scientists at the University of New South Wales (UNSW), the fort of the castle and the outer wall of the pancreatic tumor were fired at the same time. What weapon did scientists choose? A drug that inhibits the cystine transporter SLC7A11.

Researchers have confirmed that SLC7A11 is a suitable target in experiments with human cells and transgenic mice. These experiments with transgenic mice included a stable knockdown of SLC7A11, performed in the tumor compartment only, followed by the tumor and stromal compartments. Scientists then demonstrated the effectiveness of the nanoparticle SLC7A11 silencing drug in experiments with transgenic mice.

Detailed findings appeared on March 12th Cancer research, “Cancer-related fibroblasts of pancreatic ductal adenocarcinoma determine the response to SLC7A11 inhibition.. “

“In a mouse model of sympathetic pancreatic ductal adenocarcinoma (PDAC) utilizing human PDAC cells and CAF, stable knockdown of SLC7A11 in both cell types to reduce tumor growth, metastatic diffusion, and intratumoral fibrosis. It is necessary and demonstrates the importance of targeting SLC7A11 in both compartments, “the author of the article writes. “Finally, treatment with the nanoparticle SLC7A11 silencing drug developed in our laboratory reduced PDAC tumor growth, metastasis, CAF activation, and fibrosis in orthotopic PDAC tumors.”

In this article, which reflects a decade of effort, the author states that although SLC7A11 has previously been studied in pancreatic cancer cells, it has not previously been shown to play an important role in CAFS. The authors have demonstrated the value of inhibiting SLC7A11 with PDAC-derived CAF and look forward to evaluating their approach in future human clinical trials.

“Pancreatic cancer has had minimal improvement in survival over the last 40 years. Without immediate action, it is predicted to be the second largest cancer murderer in the world by 2025.” Said Phoebe Phillips, lead author and associate professor of UNSW Medicine. &health. “But our latest advances mean that I am the most optimistic and hopeful of my career today.”

Phillips et al. Used several complementary models, including patient-derived PDAC and CAF, a 3D bench model including an explant model that maintains fragments of human pancreatic tumor tissue, and multiple mouse models of the pancreas. Improved the clinical translatability of findings. cancer.

“We also provided gene therapy that inhibits SLC7A11 using state-of-the-art nanomedicine developed in an interdisciplinary collaboration with engineers (Professor Cyrille Boyer of UNSW and Professor Thomas Davis of the University of Queensland). This treatment is advantageous because the nanodrugs are small and can penetrate the scar tissue of pancreatic cancer, “said Joshua McCarroll, co-lead author and associate professor at the Institute for Pediatric Cancer.

The team’s findings laid the foundation for clinical trials led by Philips and UNSW medical collaborator Professor David Goldstein. “This study reuses an anti-arthritis drug called sulfasalazine, which has been shown to strongly inhibit SLC7A11, for the treatment of patients with pancreatic cancer who have tumors with high levels of SLC7A11. More than half of the patients It may improve treatment response and ultimately improve the survival of these patients. “

Researchers say the opportunity to reuse existing drugs already in the clinic will help them progress faster. The research team hopes to analyze and publish the first set of results for the trial within three years.

In addition to clinical trials, the team now wants to evaluate how their approach interferes with the exchange of nutrients between tumor cells and helper cells. They also want to identify the ideal drug to combine with their therapeutic approach to enhance antitumor effects.