In a comprehensive analysis of adenosquamous cancer of the pancreas in preclinical models, researchers identified potential therapeutic targets for this aggressive form of pancreatic cancer. They also identified already-available agents—designed to treat other types of cancer—that may be useful in this setting, according to a study published by Lenkiewicz et al in Cancer Research.
“The rarity of adenosquamous cancer of the pancreas, the scarcity of tissue samples suitable for high resolution genomic analyses, and the lack of validated preclinical models have limited the study of this particularly deadly subtype of pancreatic cancer,” said study author Daniel D. Von Hoff, MD, Distinguished Professor and TGen's Physician-In-Chief, in a statement. “We need entirely new possible approaches for our patients with adenosquamous cancer of the pancreas.”
Daniel D. Von Hoff, MD
Pancreatic ductal adenocarcinoma is the most common form of pancreatic cancer. Among patients with pancreatic cancer, a small percentage—less than 4%—are diagnosed with adenosquamous cancer of the pancreas, a particularly aggressive form of the disease.
“Adenosquamous cancer of the pancreas currently has no effective therapies. Unlike pancreatic ductal adenocarcinoma, adenosquamous cancer of the pancreas is defined by the presence of more than 30% squamous epithelial cells in the tumor. The normal pancreas does not contain squamous cells,” said the study's senior author, Michael Barrett, PhD, who holds a joint research appointment at the Mayo Clinic and TGen.
“Our study has shown that adenosquamous cancers of the pancreas have novel ‘hits’ (mutations and deletions) in genes that regulate tissue development and growth superimposed on the common mutational ‘landscape’ of a typical pancreatic ductal adenocarcinoma,” he continued. “As a consequence, cells within the tumor have the ability to revert to a stem cell–like state that includes changes in cell types and appearance, and the activation of signaling pathways that drive the aggressive nature of adenosquamous cancer of the pancreas.”
Analysis Findings
While this activated aggressive stem cell–like state is resistant to current therapies for pancreatic cancer, Dr. Barrett said, the study has shown that adenosquamous cancer of the pancreas can be targeted by drugs currently in clinical use for other cancers, as well as non–cancer-related conditions.
Using multiple cancer analysis methods and platforms, including flow cytometry, copy number analysis, whole-exome sequencing, variant calling and annotation, ATAC-seq, immunofluorescence, immunohistochemistry, single-cell sequencing, and organoid cultures and treatments, the research team conducted what is believed to be the most in-depth analysis of adenosquamous cancer of the pancreas tissue samples.
The researchers identified multiple mutations and genomic variants that are common to both pancreatic ductal adenocarcinoma and the more aggressive adenosquamous cancer of the pancreas. The team also identified two potential therapeutic targets unique to adenosquamous cancer of the pancreas genomes: FGFR signaling, including an FGFR1-ERLIN2 gene fusion; and a pancreatic cancer stem cell regulator known as RORC.
Using organoids, which are laboratory cultures derived from samples of patient tumors, researchers tested the activity and functional significance of candidate therapeutic targets. According to the study, “Specifically, organoids carrying the FGFR1-ERLIN2 fusion show a significant response to pharmacologic FGFR inhibition,” providing new candidate targets for developing therapies for patients with adenosquamous cancer of the pancreas.
In addition, the study authors said, “To our knowledge, this is the first study to apply DNA content sorting to the genomic analysis of adenosquamous cancer of the pancreas,” a method that purifies the cancer DNA from other cells and parts of cells, thereby eliminating any biologic ‘noise’ that might impede the precision of the analysis.
Using an interrogation tool known as ATAC-seq, researchers also identified RORC as another distinguishing feature of adenosquamous cancer of the pancreas.
“Of significant interest will be clinical trials with FGFR and RORC inhibitors that include correlative studies of genomic and epigenomic lesions in both adenosquamous cancer of the pancreas and pancreatic ductal adenocarcinoma,” concluded the authors.
Disclosure: For full disclosures of the study authors, visit cancerres.aacrjournals.org.
