Therapeutic Targets for Pancreatic Cancer

Specific potential therapeutic targets for the most lethal and aggressive type of pancreatic cancer have been identified by scientists from Translational Genomics Research Institute (TGen) and the Mayo Clinic.

In preclinical models, the researchers identified therapeutic targets for adenosquamous cancer of the pancreas (ASCP) and suggested few cancer inhibitors already used for other types of cancer.

Compared to the common pancreatic ductal adenocarcinoma (PDAC) subtype, ASCP is one of the most deadly pancreatic cancers with greater metastatic potential and worse prognosis. The researchers applied DNA content flow cytometry to a series of 15 tumor samples, including five patient-derived xenografts (PDX), to distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer. Using whole-genome copy-number variant (CNV), assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses, and whole-exome sequencing, the researchers interrogated purified sorted tumor fractions from these samples.

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 KRAS (73%) and TP53 (87%), homozygous deletion of CDKN2A (40%), and amplification of MYC (47%) that are common in PDACs.

Furthermore, genes with accessible chromatin unique to the ASCP genomes were identified during the comparison

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

Finally, the researchers demonstrated that pan FGFR inhibitor has significant activity against organoids derived from the FGFR1-ERLIN2 fusion-positive ASCP PDX model. Their results suggested that the epigenomic and genomic landscape of ASCP leads to new strategies for this deadly type of pancreatic cancer.

Daniel Von Hoff, one of the study authors and TGen’s physician-in-chief, said the study of this particularly deadly type of pancreatic cancer is limited by lack of validated preclinical models and scarcity of tissue samples suitable for high-resolution genomic analyses. He also added that an entirely new approach is needed for patients with ASCP.

The pancreas normally does not contain squamous cells, but ASCP is defined by the presence of more than 30% squamous epithelial cells in the tumor.

Besides the common mutational ‘landscape’ of a typical PDAC, ASCPs have deletions and mutations that regulate tissue growth and development, reports the study. As a result, cells within the tumor have the ability to revert to stem cell properties, including the activation of signaling pathways that drive the aggressive nature of ASCP and changes in cell appearance and types.

The Mayo Clinic and TGen research team conducted what is believed to be the most in-depth analysis of ASCP tissue samples using multiple cancer analysis platforms and methods, including copy number analysis, flow cytometry, variant calling and annotation, whole-exome sequencing, immunohistochemistry, immunofluorescence,  ATAC-seq, single-cell sequencing, and organoid cultures and treatments.

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

The study pointed out that the data can identify candidate therapeutic targets for this deadly cancer. Researchers tested the functional significance and activity of candidate therapeutic targets using organoids. They found that a significant response to pharmacological FGFR inhibition is shown by organoids carrying the FGFR1-ERLIN2 fusion. This provided new targets for developing treatments for ASCP.