Researchers at the University of Texas MD Anderson Cancer Center published two studies this week on a new approach that could improve treatment for patients with pancreatic cancer — a disease that an estimated 64,050 U.S. adults will be diagnosed with in 2023.
The preclinical studies showed that combining immunotherapy with a KRAS inhibitor can lead to long-lasting tumor elimination in pancreatic cancer.
The research explored the functional role of KRAS mutations in pancreatic cancer. KRAS belongs to a family of genes that encode proteins that participate in cell signaling, activating or deactivating to regulate the growth of cells. When KRAS are mutated, they cause the uncontrolled cell growth that occurs in cancer. The oncology community has known “for a while now” that KRAS mutations drive pancreatic cancer, but it has had a hard time figuring out a way to effectively drug these mutated genes, explained Dr. Raghu Kalluri, an author for both studies.
In the study published in Developmental Cell, the research team tested the functional role of KRAS by generating mouse models with a variety of genetic alterations known to go along with KRAS mutations. By thoroughly examining KRAS’ functional role, the research team gained key insights about how to prepare the tumor microenvironment in advanced pancreatic cancer, Dr. Kalluri pointed out.
The research team then genetically suppressed KRAS in the mice, which led to cancer cell death. In some cases, the number of myeloid cells in the tumor decreased significantly, and in others, the tumor was completely eradicated, Dr. Kalluri said.
In his view, prior models didn’t do a great job of replicating the constantly changing tumor microenvironment found in advanced pancreatic cancer. However, the models generated by his team more accurately reflected the tumor microenvironment present in patients with metastatic pancreatic cancer, and this helped them identify immune activation as a vital element for sustained tumor suppression and elimination, he declared.
In the study published in Cancer Cell, the researchers tested the effects of a KRAS G12D inhibitor known as MRTX1133 in 16 different lab models. They found that the drug reversed both early- and late-stage tumor growth — but not for good. The tumors grew back after some time, letting the research team know that KRAS G12D inhibition will only be successful in the long term if immune cells are activated.
In other words, KRAS inhibitors do a good job of suppressing pancreatic tumors, but these drugs cannot sustain those effects over a long period of time unless they are combined with various immune checkpoint inhibitors, Dr. Kalluri explained.
These preclinical studies have already led to a Phase I clinical trial at MD Anderson, which is testing the use of MRTX1133 in combination with immune checkpoint inhibitors in patients with pancreatic cancer.
Photo: The National Cancer Institute