Die Barbacid-Gruppe im CNIO eliminiert Pankreastumoren bei Mäusen vollständig und ohne das Auftreten von Resistenzen

Translated version of the above article:

Current drugs against pancreatic cancer lose effectiveness in months because the tumor becomes resistant. The group of the National Cancer Research Center (CNIO) manages to avoid these resistances in animal models with a triple combined therapy.

These results „open a way to the design of combined therapies that can improve survival,“ the authors indicate, although this will not happen in the short term. The results are published in ‚PNAS‘.

Mariano Barbacid, head of the CNIO’s Experimental Oncology Group, emphasizes that „we are not yet in a position to carry out clinical trials with triple therapy.“

In Spain, more than 10,300 cases of pancreatic cancer, one of the most aggressive tumors, are diagnosed every year. Its detection in advanced phases, and the lack of effective therapies, means that the survival five years after diagnosis is less than 10%. But research is taking off, and beginning to change the paradigm after decades of very little progress.

Mariano Barbacid, head of the Experimental Oncology Group of the National Cancer Research Center (CNIO), has designed a therapy that manages to eliminate pancreatic tumors in mice completely and permanently, and without notable side effects. The study is published in the journal PNAS (Proceedings of the National Academy of Sciences), with Carmen Guerra as main co-author and Vasiliki Liaki and Sara Barrambana as first authors.

„These studies open a way to design new combined therapies that can improve the survival of patients with pancreatic ductal adenocarcinoma [the most common pancreatic cancer],“ say the authors in PNAS. „These results set the course for developing new clinical trials.“

Eliminate resistance to treatment

The first drugs aimed at molecular targets for pancreatic cancer were approved in 2021, after half a century without improvements compared to conventional chemotherapy. These new drugs block the action of KRAS, a mutated gene in 90% of people with pancreatic cancer; its effectiveness, however, is modest, because after a few months the tumor becomes resistant.

This problem of resistance to KRAS inhibitor drugs is addressed by the new study by Barbacid, a pioneer in both KRAS research and in the development of animal models for pancreatic cancer.

The strategy of the CNIO group has been to block the action of the KRAS oncogene at three points, instead of just one – it is more difficult for a beam to break if it is fixed to the ceiling in three places, rather than only in one point. And, indeed, after genetically removing three molecules from the KRAS signaling pathway in mouse models, the tumors disappeared permanently.

Against three links in the chain

Applying the same strategy in patients implies looking for drugs that block the KRAS molecular pathway at the same three points. The team employed triple therapy, which combined a KRAS inhibitor available for experimental studies (daraxonrasib); a drug approved for certain lung adenocarcinomas (afatinib); and a protein degrader (SD36).

The treatment was applied to three mouse models of pancreatic ductal adenocarcinoma, and in all of them „a significant and lasting regression of these experimental tumors without causing significant toxicities,“ the authors write.

„This study describes a triple combined therapy (…) that induces the robust regression of experimental models of pancreatic ductal adenocarcinoma, and prevents the appearance of resistance. This triple combination is well tolerated in mice,“ they say in PNAS.

Towards a clinical trial, but not yet

Regarding the following steps, Barbacid explains that „it is important to understand that, although experimental results such as those described here had never been obtained, we are still not in a position to carry out clinical trials with triple therapy.“

„The path to optimize the triple combination therapy described here for use in a clinical scenario will not be easy,“ says PNAS. „(..) 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.

Financing

This study has been funded by the CRIS Foundation Against Cancer; the European Research Council (ERC); the State Agency for Research in co-financing with the European Regional Development Fund; Next Generation funds of the European Union; the Center for Biomedical Research in Network (CIBERONC); and the Carlos III Institute of Health.

About the National Cancer Research Center (CNIO)

The National Cancer Research Center (CNIO) is a public research center under the Ministry of Science, Innovation and Universities. It is the largest cancer research center in Spain and one of the most important in Europe. It includes half a thousand scientists, plus support staff, who work to improve cancer prevention, diagnosis and treatment.