Researchers fight to tackle pancreatic cancer’s resistance to personalized medicine

A research team from the University of Arizona (AZ, USA) is attempting to develop patient-specific, personalized treatments for pancreatic cancer by creating and sequencing cell lines from a patient’s own tissue.

“Currently there are no targeted therapies directly against the hallmark mutations common in pancreatic cancer, and each patient derived model we tested had its own unique therapeutic sensitivities,” commented author Erik Knudsen (University of Arizona Cancer Center). “I’d say that’s why many pancreatic cancer clinical trials fail; it’s that expectation that most tumors will respond in the same way to a drug.”

As part of the study, recently published in Cell Reports, the team tested a wide range of drugs currently available to pancreatic cancer patients on both conventional cell lines used most often by researchers and the pharmaceutical industry, and cell lines developed by the team directly from patients.

The team observed that while conventional cell lines were more sensitive to standard drugs used in treating pancreatic cancer, only a small number of lines derived from patients were responsive to any of the single-agent treatments.

Personalized medicine normally relies on sequencing patient tumor DNA, which elucidates the mutations that can then be targeted by appropriate drugs. Nevertheless, these mutations are complex thus making single mutations more difficult to target. Although combination therapy may be able to provide a solution, determining which drugs to use and at what doses to use them requires in vitro models with genetics identical to the individual’s tumor.

Developing such cell lines directly from patients is time consuming, with the lines also requiring appropriate authentication to the original cell line from which they were derived. The most commonly used cell lines, however, have not been monitored over time and the original patient’s tumor from which they were derived was never fully characterized genetically.

“There’s a bit of frustration with the current personalized medicine approach,” added Knudsen. “If you sequence a hundred tumors from patients in the clinic, you might be able to treat one or two patients with the resulting information, because of the nature of pancreatic cancer genetics. Using new, patient-derived models fills in the gap for us and lets us guide our therapies with functional sensitivities to drugs, not with preconceived notions.”

Corresponding author Agnieszka Witkiewicz (University of Arizona Cancer Center) further commented: “Pancreatic cancer is particularly challenging to treat. Since there are no early detection tests, the majority of patients present with advanced disease. By that time, the tumor has accumulated multiple genetic changes selecting for resistance to many therapies.”

Knudesn and Witkiewicz emphasized that advancing research in pancreatic cancer treatment requires these vital cell lines from a large number of patients. Models that are developed from a single patient with the individual’s specific mutations are also required to test therapeutics derived following initial genome sequencing. Both also agreed that clinical trials incorporating a drug-screened patient model will be vital for improving patient outcomes.

“The path forward in studying pancreatic cancer is one that marries genetic analysis while also functionally analyzing drug sensitivities,” commented Knudsen. “This isn’t a part of any conventional trial design in pancreatic cancer today.”

“All of our work is about the patients at the end of the day – it’s about a disease where standard approaches repeatedly have failed and patients really need hope,” concluded Witkiewicz. “I think this work seeds new ideas for changing the paradigm for the treatment of pancreatic cancer– especially when there are so many failed trials. It will take a concerted effort from all of us, in academia, in pharma, in the clinic – everywhere.”

Source: Cell Press press release via EurekAlert!