Study identifies potential therapeutic targets for most lethal pancreatic cancer

Using pre-clinical models, researchers have identified two promising therapeutic targets for the most aggressive and lethal form of pancreatic cancer, adenosquamous cancer of the pancreas (ASCP).

The team of researchers led by Mayo Clinic and the Translational Genomics Research Institute (TGen), both US, suggested fibroblast growth factor receptor (FGFR) and Retinoic acid–related orphan receptor C (RORC) inhibitors that are already available in clinic could be effective against ASCP.

Dr Daniel Von Hoff, Distinguished Professor and TGen’s Physician-In-Chief, considered one of the nation’s foremost authorities on pancreatic cancer and one of the study’s authors, said: “The rarity of ASCP, the scarcity of tissue samples suitable for high resolution genomic analyses and the lack of validated pre-clinical models, has limited the study of this particularly deadly subtype of pancreatic cancer.”

Where pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and the US’ third leading cause of cancer-related death (according to the American Cancer Society); ASCP is a rare and particularly aggressive form of pancreatic cancer, diagnosed in less than four percent of patients.

“ASCP currently has no effective therapies. Unlike PDAC, ASCP is defined by the presence of more than 30 percent squamous (skin-like) epithelial cells in the tumour. The normal pancreas does not contain squamous cells,” said the study’s senior author, Dr Michael Barrett, who holds a joint research appointment at Mayo Clinic and TGen.

Dr Barrett explained that in their study they discovered ASCPs have novel mutations and deletions in genes that regulate tissue development and growth, alongside those typically evident in PDAC. “As a consequence, cells within the tumour have the ability to revert to a stem-cell-like state that includes changes in cell types and appearance, and the activation of signalling pathways that drive the aggressive nature of ASCP.”

He added that while the aggressive stem-like state is very resistant to current pancreatic cancer therapies, the study indicated ASCP could be targeted by drugs currently in clinical use.

Using multiple analysis methods, the research team conducted “what is believed to be the most in-depth analysis of ASCP tissue samples”.

They identified multiple mutations and genomic variants that are common to both PDAC and ASCP, but highlighted two significant therapeutic targets that were unique to ASCP genomes alone: FGFR signalling, inhibition of FGFR signalling had a significant effect on organoids harbouring the FGFR1-ERLIN2 gene fusion; and a pancreatic cancer stem cell regulator known as RORC.

The team concluded in their study: “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.”

The paper was published in Cancer Research.