Most Deadly Form of Pancreatic Cancer Reveals Potential Therapeutic Targets

Scientists led by the Mayo Clinic and the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, say they have identified specific potential therapeutic targets for the most aggressive and lethal form of pancreatic cancer.

The team identified, in preclinical models, therapeutic targets for adenosquamous cancer of the pancreas (ASCP) and pinpointed already available cancer inhibitors originally designed for other types of cancer, according to a study, “Genomic and Epigenomic Landscaping Defines New Therapeutic Targets for Adenosquamous Carcinoma of the Pancreas,” published in Cancer Research.

“ASCP is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses,” wrote the investigators.

“These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs.

“Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP.

“Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion–positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provides new strategies for targeting this aggressive subtype of pancreatic cancer.”

“The rarity of ASCP, the scarcity of tissue samples suitable for high resolution genomic analyses, and the lack of validated preclinical models, has limited the study of this particularly deadly subtype of pancreatic cancer,” said Daniel Von Hoff, MD, distinguished professor and TGen’s physician-in-chief, and one of the study’s authors. “We need entirely new possible approaches for our patients with ASCP.”

PDAC is the most common form of pancreatic cancer, which this year is projected to kill nearly 57,600 Americans, making it the nation’s third leading cause of cancer-related death, according to the American Cancer Society. Among pancreatic cancer patients, a small percentage (less than 4%) are diagnosed with ASCP, a particularly aggressive form of pancreatic cancer.

“ASCP currently has no effective therapies. Unlike PDAC, ASCP is defined by the presence of more than 30% squamous (skin-like) 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 ASCPs have novel ‘hits’ (mutations and deletions) in genes that regulate tissue development and growth superimposed on the common mutational ‘landscape’ of a typical PDAC. 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 ASCP.”

While this activated aggressive stem-cell-like state is resistant to current therapies for pancreatic cancer, continued Barrett, the study has shown that ASCP 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 Mayo Clinic and TGen research team conducted what is believed to be the most in-depth analysis of ASCP tissue samples.

Researchers identified multiple mutations and genomic variants that are common to both PDAC and the more aggressive ASCP. The team also identified two potential therapeutic targets unique to ASCP genomes: FGFR signaling, including an FGFR1-ERLIN2 gene fusion, and a pancreatic cancer stem cell regulator known as RORC.

These data provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this lethal cancer, the study pointed out.

Using organoids, scientists 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 pharmacological FGFR inhibition,” providing new candidate targets for developing therapies for patients with ASCP.

In addition, the study noted, “To our knowledge, this is the first study to apply DNA content sorting to the genomic analysis of ASCP,” a method that purifies the cancer DNA from other cells and parts of cells, thereby eliminating any biological “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 ASCP.

“Of significant interest will be clinical trials with FGFR and RORC inhibitors that include correlative studies of genomic and epigenomic lesions in both ASCP and PDAC,” according to the research team.

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