New triple-drug treatment halts pancreatic cancer progression, mouse study reveals

Triple-drug therapy for pancreatic cancer has shown promise in early animal studies, offering a potential new treatment for a disease with notoriously low survival rates.

Pancreatic cancer is considered one of the most deadly common cancers, with a 5-year relative survival rate of approximately 13%. This means that approximately 87% of cancer patients are expected to die within five years of diagnosis. Survival rates for people diagnosed at a very late stage of the disease can be as low as 1%.

In a study published Dec. 2 in PNAS, researchers tested a new combination therapy that simultaneously blocks three cancer growth pathways and showed promising results in mice.

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“These studies pave the way for the design of new combination therapies that can improve survival for patients with pancreatic ductal adenocarcinoma.” [the most common pancreatic cancer]”These results point the way to the development of new clinical trials,” the study authors said in a statement.

In its early stages, pancreatic cancer grows silently within the abdomen without any obvious symptoms. By the time the disease is discovered, it has often already spread to other organs, making it difficult to remove surgically.

Standard treatments such as chemotherapy attack all rapidly dividing cells in the body and often cause a lot of collateral damage in the process of controlling tumor growth. And even then, tumors usually find other ways to grow and become resistant to treatment.

The new treatment not only prevented the cancer from coming back in the rodents, it was also non-toxic to the mice as a whole and showed no debilitating side effects.

Almost all pancreatic cancers are usually associated with mutations in a gene called “KRAS,” which controls and suppresses cell division and growth. However, when the gene mutates, it becomes stuck in the “on” position, causing abnormal cell division rates and cancer.

Prior to the study, lead study author Carmen Guerra, a cancer biologist in the Experimental Oncology Group at Spain’s National Cancer Research Center (CNIO), developed a mouse model to investigate how KRAS mutations and other related pathways benefit pancreatic tumor survival. Blocking specific KRAS-related pathways can stop small tumors from growing, but larger tumors often adapt to “open another door” for survival, she told Live Science.

In the latest study, Guerra and her team analyzed these resistant tumors and found that a protein called STAT3 becomes highly active when other growth pathways are blocked. This suggests that it may function as an emergency backup pathway for tumor growth.

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The research team tried to genetically block this pathway, along with other key tumor growth factors, in mouse tumor cells. They then observed that the tumors regressed, confirming that STAT3 was indeed an important “mechanism of resistance,” Guerra said.

At that time, researchers had determined that tumors could be eliminated by genetically blocking three pathways: KRAS, the KRAS-related pathway, and STAT3. So they set out to test drug-based strategies.

This three-pronged approach includes two existing drugs: afatinib, which is approved by the Food and Drug Administration for certain lung cancers, and daraxonelasib, which is currently in clinical trials. The third drug is a new compound designed to disable STAT3.

The research team evaluated this triple combination therapy in three different mouse models. One involves transplanting mouse tumor cells directly into the mouse pancreas. One involves mice genetically engineered to develop pancreatic cancer. The other uses human tumor samples grown in immunodeficient mice to prevent the mice’s immune systems from attacking foreign tissue. In all three models, the combination treatment completely eliminated the tumor.

“We didn’t even know where the tumor was,” Guerra told LiveScience. “My pancreas was perfectly healthy.”

The treatment also prevented resistance, as the researchers reported that the tumors did not recur for at least 200 days after treatment (or nearly seven months). This is a longer period of time than most monotherapy can achieve in similar mouse models.

Importantly, this triple combination therapy did not cause any toxic or severe side effects in the mice. Treated rodents had similar body weights, blood cell counts, metabolic markers, and organ health compared to tumor-bearing mice that received placebo treatment.

However, given that this new study was conducted in mice, there may be some differences in human pancreatic cancer patients. Guerra noted that mice may be “more resistant to this type of toxicity” than humans. Although the treatment showed no side effects in mice, some of the drugs they used, such as afatinib, have already been tested in humans and are known to have side effects, such as skin and gastrointestinal problems.

So researchers are now working to find alternatives and “develop better drugs” that reach the same pathway, she told LiveScience.

Professor Guerra also stressed that pancreatic tumors are genetically diverse and there is a “huge amount of variation” in patients, making each case different from the next. In that regard, the research team also plans to study additional mouse models with other common KRAS mutations and changes in other cancer-related genes to test the effectiveness of the treatment in different tumors, she told Live Science.