Potential New Treatment for Esophageal Squamous Cell Carcinoma

Columbia researchers have found a potential new treatment for metastasized esophageal squamous cell carcinoma (ESCC) targeting colony-stimulating factor-1 receptor (CSF-1R), which plays a key role in cancer. ESCC and other squamous cell carcinomas (SCCs) have a strong tendency to metastasize. Unfortunately, ESCC is usually diagnosed at an advanced stage, when it has an overall survival rate of only about 20 percent.

Anil K. Rustgi, MD, lead author of the study published in Cancer Discovery, is director of Columbia University’s Herbert Irving Comprehensive Cancer Center (HICCC). His interdisciplinary research centers on tumor initiation, the tumor microenvironment, and tumor metastasis in gastrointestinal cancers, including those originating from the esophagus, pancreas, and colon. A point of emphasis is the TP53 gene, which provides instructions for making Tumor protein p53 (or p53). P53 suppresses tumors by keeping cells from proliferating too fast or in an uncontrolled manner. TP53 mutations, which are found in approximately 80 percent of ESCC cases, are associated with higher metastatic rates and poor patient survival.

“TP53 is the most commonly mutated gene in human cancers, present in almost 70 percent of them,” says Rustgi. “Understanding the underlying mechanisms of its role in cancer will help us to unleash new translational therapies.”

Rustgi and his colleagues found that the mutant protein p53-R172H increases the growth factor called colony-stimulating factor-1 (Csf-1) in metastatic ESCC to the lungs. More specifically, they found that co-regulation of Csf-1 signaling through its receptor, Csf-1r, by p53-R172H and Brd4 contributes to lung metastasis. It is this Csf-1/Csf-1r signaling pathway that Rustgi is exploring as a potential target in treating metastatic ESCC. He says that inhibition of Brd4 not only significantly reduces tumor invasion and lung metastasis, but also reduces circulating Csf-1 levels.

“Our work shows that targeting mutant p53-dependent CSF-1/CSF-1R signaling may have merit and open up new therapeutic avenues for patients with metastatic ESCC, as well as other cancers, which could be very impactful considering the frequency of p53 mutations,” says Gizem Efe, PhD student in Dr. Rustgi’s lab and first author on the paper.

“Historically,” says Rustgi, “the p53 protein has been difficult to target. Our current approach—as demonstrated in the work reported in this paper and in wonderful collaboration with an interdisciplinary team of researchers from Columbia and Mt. Sinai (NY)—is to seek to identify downstream factors and then develop new molecular biomarkers and experimental treatment strategies.”