Gastroenterologists, oncologists, and geneticists from NewYork-Presbyterian/Columbia have identified a genetic mechanism that could hold the key to developing treatments for metastatic esophageal squamous cell carcinoma (ESCC), a deadly form of esophageal cancer in the US and worldwide without effective treatment options.
Using genetic mouse models, the team, including Anil K. Rustgi, MD, Director of Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian/Columbia, and Gizem Efe, a PhD student in Dr. Rustgi’s lab and first author on the study, demonstrated that a loss of Colony Stimulating Factor-1 (CSF-1) reduced tumor cell invasion and metastasis to the lung. The findings, published in Cancer Discovery in December 2023, suggest that the CSF-1/CSF-1R axis could be an important target for the development of therapeutics for metastatic ESCC. This is the first time that CSF-1/CSF-1R has been identified as a potential mechanism for treating ESCC.
Previously, much of the research into treatments for ESCC has focused on ways to target mutant p53, a protein present in roughly 70% of all human cancers. However, those efforts have led to only incremental improvements, explains Dr. Rustgi. “Our notion is that if we can’t target mutant p53 for the most part, let’s see if we can target genes that are downstream from it and that are upregulated,” he says.
Our notion is that if we can’t target mutant p53, let’s see if we can target genes that are downstream from it and that are upregulated.
— Dr. Anil K. Rustgi
Poor Prognosis for Esophageal Cancer
Esophageal cancer is an aggressive form of cancer that includes both ESCC and esophageal adenocarcinoma (EAC). ESCC is the sixth leading cause of cancer-related mortality in men in the world. The number of new cases of ESCC and EAC is expected to grow to nearly 1 million by 2040. When patients with esophageal cancer develop metastases, the prognosis is especially poor.
“The five-year survival rate is less than 20% so that’s amongst the worst. That’s been motivational for us and our collaborators,” Dr. Rustgi says.
Surgery is not an option for patients whose cancer has metastasized, so treatment consists mainly of systemic chemotherapy or, in certain cases, immunotherapy. However, chemotherapy has generally not been effective for patients with metastases and patients receiving immunotherapy often experience relapse or treatment resistance. “Those two gaps are huge in the field,” Dr. Rustgi says.
New Targets for ESCC Treatment
The investigation by Dr. Rustgi and colleagues examined genes that were downstream from mutant p53 but upregulated in ESCC that had metastasized to the lung. They used genetic mouse models to look at various cell lines and identify which genes were upregulated in metastatic lung lesions. From there they used genetic deletion and complementary pharmacologic inhibition studies to test how turning off these upregulated mutant p53 targets impacted lung metastases.
CSF-1 creates an environment that is conducive or permissive for metastasis. If we take it out of our system, the lung metastases essentially go away, sort of like an Achilles heel, even in the face of mutant p53 still being there.
— Dr. Anil K. Rustgi
They found that by removing CSF-1 they significantly reduced tumor cell invasion and lung metastasis. “CSF-1 creates an environment that is conducive or permissive for metastasis. If we take it out of our system, the lung metastases essentially go away, sort of like an Achilles heel, even in the face of mutant p53 still being there,” Dr. Rustgi says.
The CSF-1/CSF-1R axis is a potential target for future therapies to treat metastatic ESCC.
CSF-1 is secreted by the tumor cells and binds to its own receptor (CSF-1R), making the CSF-1/CSF-1R axis an attractive target for therapies. The paper also explores the biochemistry of how mutant p53 works to induce CSF-1, a finding that suggests mutant p53 could be used as a biomarker for upregulation of CSF-1 in metastatic ESCC.
CSF-1 is not the only upregulated gene in the p53 pathway that has potential as a treatment target in ESCC. Mutant p53 has multiple targets, creating several potential avenues for researchers. “You can imagine combinatorial therapy where you can utilize drugs against specific targets induced by mutant p53,” Dr. Rustgi says.
Dr. Rustgi and his colleagues are continuing to explore how different p53 mutations behave in cancer as well as whether the downstream genetic targets of p53 are the same in liver metastases as they are in lung metastases. The team is currently working on an atlas that can be shared with the US and global research communities and spur discoveries.
The research is an important potential advance in the treatment of metastatic ESCC, but it also has implications in other cancers with common genomic properties, including head and neck squamous cell carcinoma and lung squamous cell carcinoma.
“We seek to understand how mutated p53 works in ESCC as a basis for understanding how mutated p53 might work in other cancers as well. We converged on ESCC as a platform to understand p53 and cancer biology in general,” Dr. Rustgi says.
