A recent study led by Tanya Kalin, MD, PhD, professor of Child Health and Internal Medicine at the University of Arizona College of Medicine — Phoenix, has made a breakthrough discovery with the potential to improve therapeutic outcomes for patients with lung cancer. The study identified a new protein called FOXF1 that stabilizes blood vessels in lung tumors, reduces intertumoral hypoxia, and prevents lung cancer from spreading.the study conducted by the senior author, it was found that lung cancer continues to be the primary cause of cancer-related deaths worldwide. Data from the American Lung Association indicates that in 2021, the disease was responsible for 22% of all cancer-related deaths. The survival rate for patients with advanced non-small cell lung cancers is less than 20% over a five-year period, highlighting the urgent need for effective treatment options.
In an effort to explore new therapeutic approaches, Dr. Kalin’s laboratory developed a nanoparticle delivery system to successfully transport FZD4 to the pulmonary endothelium. This approach resulted in a decrease in lung tumor growth and metastasis in pre-clinical models of lung cancer. As a result, this treatment approach shows promise for addressing the challenges posed by this devastating disease.The potential to increase levels of FOXF1 or FZD4, genetically or through gene therapy, shows promise for improving treatment outcomes in lung cancer patients.
Research from Dr. Kalin’s group suggests that activating FOXF1 or FZD4 could enhance the delivery of chemotherapy drugs or immune checkpoint inhibitors in lung cancer treatment.
<p”The successful targeting of FOXF1/FZD4 signaling with gene therapy has reduced lung cancer progression and normalized tumor blood vessels. Our next step is to develop a pharmacological approach to activate this signaling pathway and move this therapy into clinical trials.”Dr. Kalin spoke about the trials,” Dr. Kalin said.
Dr. Kalin, who is also the vice chair of translational research for Phoenix Children’s Center for Cancer and Blood Disorders, recently published the findings in EMBO Molecular Medicine. The study illustrated that FOXF1 is present in normal lung endothelial cells, but its levels are reduced in the vasculature associated with lung tumors. By using datasets from the Cancer Genome Atlas, they demonstrated that lung cancer patients with higher levels of FOXF1 mRNA had better survival rates compared to those with lower levels of FOXF1.
Dr. Kalin and her team then actively removed the FOXF1 gene from endothelial cells, using developed a gene-editing technology that had a significant impact. When they removed FOXF1 in their models, it caused lung tumor growth and spread, as well as abnormalities in tumor blood vessels, and a lack of frizzled-4 (FZD4) gene activity, which affects the development of cells and tissues through the Wnt/β-catenin signaling pathway. However, when they increased FOXF1 gene expression in endothelial cells using a transgenic model of lung cancer, it successfully stopped the growth and spread of lung tumors and stabilized the blood vessels associated with the tumors.FOXF1 has been found to directly activate FZD4, a receptor involved in the Wnt/β-catenin signaling pathway. The study, titled “FOXF1 promotes tumor vessel normalization and prevents lung cancer progression through FZD4,” was published in EMBO Molecular Medicine in 2024.
