UNSW medical researchers have found a way to starve pancreatic cancer cells and “turn off” cells that prevent treatment from working effectively. Their findings in mice and human laboratory models – which were developed 10 years ago and are about to be tested in a human clinical trial – are published today in Research against cancer, a journal of the American Association for Cancer Research.
“Pancreatic cancer has seen minimal improvement in its survival over the past four decades – and without immediate action, it is expected to be the second biggest cancer killer in the world by 2025,” says Associate Professor Phoebe Phillips of UNSW Medicine & Health.
“But thanks to our latest breakthrough, I am the most optimistic and hopeful of my career today.”
Pancreatic cancer is notoriously difficult to treat because of the dense scar tissue surrounding the tumors – the tissue acts like a stronghold that blocks the delivery of chemotherapy.
“This scar tissue is produced by critical ‘helper cells’ – also known as cancer-associated fibroblasts – that cancer cells recruit to support their growth and spread. Yet these helper cells have been ignored in current treatment strategies, ”A / Prof. Phillips said.
“Our approach affects both tumor cells and helper cells, so it is ideal for overcoming the aggressiveness and drug resistance of the disease.”
In today’s article, the team demonstrates their novel way of metabolically rewiring helper cells by targeting a particular protein called SLC7A11, which in turn stops the cells’ tumor-promoting activity and shrinks scar tissue. that they produce.
“We found that disabling SLC7A11 in mice with pancreatic tumors directly killed pancreatic cancer cells, reduced the spread of tumor cells throughout their body, and decreased scar tissue strength,” says researcher Dr. George Sharbeen. postdoctoral at A / Prof. Phillips’ lab who led the experimental work.
Complete models, in-depth study
SLC7A11 has already been studied in pancreatic cancer cells, but this is the first research to show that it also plays an essential role in non-tumor helper cells.
“In other words, we have identified a novel ‘dual cell’ therapeutic target – attacking both tumor cells and their helper – that overcomes the current limitations of standard chemotherapy.” The team used several complementary models to improve the clinical translatability of their findings, including pancreatic cancer cell lines and patient-derived helper cells, bench 3D models including an explant model that holds pieces of human pancreatic tumor tissue and several mice. models of pancreatic cancer.
“We have also used our state-of-the-art nanomedicine that we developed in a multidisciplinary collaboration with engineers – Professor Cyrille Boyer from UNSW and Professor Thomas Davis from the University of Queensland – to provide gene therapy to inhibit SLC7A11. This therapy is advantageous because our nano “The drug is tiny and able to penetrate the scar tissue of pancreatic cancer,” says co-first author, Associate Professor Joshua McCarroll of the Children’s Cancer Institute.
Clinical trial about to begin
The team’s findings laid the groundwork for a clinical trial led by A / Prof. Phillips and Professor David Goldstein, a collaborator at UNSW Medicine, who was funded by a recently awarded translational program grant from the Cancer Institute NSW.
“In this trial, we will reuse an anti-arthritis drug called sulfasalazine – which we know to strongly inhibit SLC7A11 – for the treatment of pancreatic cancer patients with high SLC7A11 tumors, which we have shown. more than half of the patients. It has the potential to improve the response to treatment and ultimately the survival of these patients, “A / Prof. Says Phillips.
The researchers say the ability to reuse an existing drug that is already in the clinic will help them progress faster.
“Using an approved drug allowed us to get that product into the clinic much faster than we would if we were starting from scratch with drug development as well,” says the assistant professor. Phillips.
“We are taking this exciting development all the way from the lab to the clinic with the sole aim of improving outcomes for patients with pancreatic cancer.”
The research team hopes to analyze and publish the first set of trial results within three years.
Improve results that haven’t changed in decades
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 wish to identify the ideal drugs to combine with their therapeutic approach to enhance the anti-tumor effects.
Pancreatic cancer is a highly fatal disease, with only one in 10 patients surviving beyond five years. In 2020, an estimated 4,000 Australians have been diagnosed with pancreatic cancer – around 90% of them will die, often within months of diagnosis.
“We clearly need improved treatments to reverse these dismal statistics, and we hope that the clinical translation of our results will ultimately increase the number of pancreatic cancer survivors,” says the assistant professor. Phillips.
“We will not give up until we improve the quality of life for patients and provide them with effective treatment.”
This work was funded by the NHMRC, the Cancer Institute NSW and PanKind (The Australian Pancreatic Cancer Foundation).