Pancreatic Cancer Treatment Kills Tumors

Often, existing pancreatic cancer treatments stop working after a few months because tumors quickly develop drug resistance. Researchers at the National Cancer Research Centre (CNIO) in Spain have resolved this problem in animal studies using a three-drug combination therapy.

Pancreatic Cancer Research Findings

Researchers say their findings “pave the way for the design of combined therapies that may improve survival,” although they caution that this progress will not immediately translate into new treatments for patients.

Head of the Experimental Oncology Group at CNIA Mariano Barbacid says, “We are not yet in a position to carry out clinical trials with this triple therapy.”

Pancreatic cancer is one of the most aggressive forms of cancer, as it is usually detected in the advanced stages, and effective treatments are limited. Fewer than 10 percent of patients survive five years after diagnosis. Just in Spain, more than 10,300 people are diagnosed with the illness every year.

Barbacid developed a treatment that eliminates pancreatic cancer tumors in mice without major side effects. The study was co-authored by Carmen Guerra, and first authors, Vasiliki Liaki and Sara Barrambana. It was published in PNAS (Proceedings of the National Academy of Sciences).

“These studies open the road to design novel combination therapies that may improve the survival of PDAC patients [pancreatic ductal adenocarcinoma – the most common type of pancreatic cancer]. These results set the course for developing new clinical trials,” say the authors in PNAS.

Eliminating Drug Resistance

In 2021, drugs designed to target specific molecular drivers of pancreatic cancer were approved after 50 years without major improvements beyond chemotherapy.

These treatments focus on KRAS, a gene mutated in approximately 90 percent of cases. Although these drugs represent a big step forward, the benefits are limited due to the frequency with which tumors adapt and become resistant.

Barbacid has dedicated decades to studying KRAS and developing experimental models of pancreatic cancer, and his team focused on overcoming the resistance problem.

The goal of the approach is to shut down the KRAS oncogene at three different points along the signaling pathway. When only one point is blocked, cancer cells can bypass the blockage. Interrupting multiple points at once makes it more difficult for a tumor to reactivate. In mouse models, this caused pancreatic tumors to disappear permanently.

Translating this concept into treatment involves drugs capable of blocking the same three points. To test the strategy, researchers combined three agents into a single therapy. The treatment regimen included the experimental KRAS inhibitor daraxonrasib, the approved lung cancer drug afatinib, and a protein degrader SD36.

This three-drug combination was tested on three mouse models of pancreatic ductal adenocarcinoma. In all three models, the treatment triggered “strong and long-lasting tumor regression without significant toxicity,” according to the published results.

“This study describes a triple combination therapy … that induces the robust regression of experimental PDACs and avoids the onset of tumor resistance. This triple combination is well tolerated in mice.”

What Is Next?

Barbacid says there is more work required before the treatment can be tested on people. “It is important to understand that, although experimental results like those described here have never been obtained before, we are still not in a position to carry out clinical trials with the triple therapy.”

He notes that adapting the three-drug combination for clinical use requires more refinement and development. “Despite the current limitations, these results could open the door to new therapeutic options to improve the clinical outcome of patients with pancreatic ductal adenocarcinoma in the not-too-distant future.”

Sources:

SciTechDaily: New Pancreatic Cancer Treatment Wipes Out Tumors and Blocks Drug Resistance
Medical Xpress: New strategy intercepts pancreatic cancer by eliminating microscopic lesions before they become cancer
bioengineer.org: Breakthrough Snolytic Therapy Offers New Hope for Pancreatic Cancer (PDAC)

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