Pancreatic cancer: an innovative drug slows disease progression

In the summer of 1518, a woman went out into the streets of Strasbourg and began to dance. She danced for hours, and then for days without stopping. Within a short time, dozens of other people joined her. According to accounts from the period, some of them continued to dance until they collapsed. The phenomenon, which later became known as the "dancing plague," sounds almost imaginary today, but it describes a particularly disturbing situation: a movement that is supposed to be voluntary, controlled, and rhythmic, and goes out of control. The article was originally published on the Davidson Institute of Science Education website.

Even inside our body, there are mechanisms that are supposed to work exactly like this: to turn on and off at the right time. Cells receive signals that tell them when to divide, when to stop, and when to die. One of the central switches in this system is a protein called RAS. In a normal state, when it is activated, it transmits growth instructions to the cell for a short time and then turns off. But in various types of cancer, genetic changes can cause this switch to get stuck in the "on" position. The result is a non-stop molecular dance: the cell continues to divide and the tumor continues to develop, without the system being able to stop it.

For decades, researchers have tried to stop this dance, but RAS has been considered one of the most difficult targets for which to develop drugs. A new study published in the New England Journal of Medicine suggests a change: an innovative drug has managed to slow the progression of the disease and extend the lives of patients with metastatic pancreatic cancer who had already received previous treatment.

The role of the RAS protein

The importance of RAS in pancreatic cancer is particularly great. In more than 90 percent of pancreatic tumors, mutations are found that cause abnormal activation of the protein, and therefore it is considered one of the main growth engines of the disease. Precisely because of its central role, RAS has for years been an especially tempting target for drug development, but also the most frustrating. Its structure made it difficult to develop a drug that would be able to attach to it accurately and stop its activity.

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A creative approach: daraxonrasib

The drug tested in the study, daraxonrasib, tries to overcome this obstacle in a creative way. Instead of binding to RAS alone, the drug uses a natural protein found inside the cell, called cyclophilin A. First, the drug binds to cyclophilin A, and the resulting combination is able to hold onto RAS when it is in an active state. This creates a structure that allows for inhibiting the signals that continue to order the cancer cell to divide.

This is a different approach from that of the treatments accepted today. Until now, most patients with metastatic pancreatic cancer were treated mainly with chemotherapy — drugs that usually act against rapidly dividing cells by disrupting DNA replication or the cell division process. But since some healthy cells also divide rapidly, such as in the digestive system, bone marrow, and hair follicles, chemotherapy can cause significant side effects. The new drug offers a more targeted approach: instead of indiscriminately damaging all dividing cells, it tries to inhibit one of the central signals that orders the cancer cell to continue growing and dividing, and thus slow the progression of the disease.

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Study results

The study involved 500 patients whose disease continued to progress despite previous chemotherapy. Daraxonrasib was tested as a new option for patients with metastatic pancreatic cancer of the PDAC type who had already exhausted the first line of treatment. The participants were randomly divided into two groups: 248 patients received the new drug, and 252 patients received chemotherapy according to the choice of the attending physician.

To understand the significance of the results, it is important to remember that at this stage of the disease, treatment options are limited. In patients with metastatic pancreatic cancer whose disease progressed after previous treatment, additional chemotherapy usually manages to inhibit the disease for only a few months, and the expected survival duration at this stage is usually six to seven months. Against this background, the results were particularly striking:

• One year after the start of treatment, in about 53 percent of the patients who received daraxonrasib, the disease was under control, compared to only about 17 percent of the patients who received chemotherapy.

• After half a year, in about 56 percent of the patients who received the experimental treatment, the disease was still under control, compared to only about 33 percent among those receiving chemotherapy.

In other words, the drug did not cure pancreatic cancer, but it managed to slow the progression of the disease and almost doubled the patients' life duration compared to the accepted treatment: patients who received daraxonrasib survived about 13.2 months, compared to 6.7 months for patients who received chemotherapy.

Side effects and future outlook

Alongside the encouraging results, the new treatment was not without side effects. About 98 percent of the patients who received daraxonrasib experienced side effects that were considered related to the treatment, the most common of which were rash, diarrhea, mouth sores, nausea, and vomiting. However, compared to chemotherapy, fewer serious side effects were recorded in the daraxonrasib group, and fewer patients were forced to stop treatment because of them.

When it comes to an aggressive cancer like pancreatic cancer, even extending life by a few months can be a whole world. Usually, the disease is discovered at an advanced stage, when the tumor has already sent metastases, which leads to five-year survival rates being very low — around a few percent. Therefore, a treatment that slows the progression of the disease and extends the patients' lives may be essential for patients whose therapeutic options are very limited.

The excitement in the medical community upon hearing the results was indeed noticeable: when the study was presented at the annual conference of the American Society of Clinical Oncology (ASCO), the audience responded with prolonged standing applause. "After more than a decade without significant progress in the treatment of pancreatic cancer, this study is truly exciting," noted Dr. Yekaterina Dumbrava, an oncologist at the MD Anderson Cancer Center in Texas.

In the future, it will be necessary to check if the drug can also be beneficial in earlier stages of treatment, for example as a first line, and not only after previous treatment has already stopped having an effect. The study also has significance beyond pancreatic cancer itself. It fits into a broader trend of precision medicine, where treatment is chosen according to the biological characteristics of the tumor and its mechanisms. The fact that the RAS pathway is involved in other tumors does not mean that the same drug will work on them to the same extent — this possibility will need to be tested in dedicated studies.