Pancreatic Cancer: Mayo Clinic Led Study Identifies Potential Therapeutic Targets For Deadly Pancreatic Cancer

Pancreatic Cancer: Oncologist and genomic scientists led by Mayo Clinic and the Translational Genomics Research Institute (TGen),along with teams from University of California-San Diego,  Sloan Kettering Institute, Salk Institute for Biological Studies and  University of Nebraska in a new study have  identified specific potential therapeutic targets for the most aggressive and lethal form of pancreatic cancer.


 
The study involved in what could be termed the most comprehensive analysis of adenosquamous cancer of the pancreas (ASCP) ever done.  T
 
The Mayo Clinic and TGen team identified, in preclinical models, therapeutic targets for this extremely fast-moving and deadly form of pancreatic cancer, and identified already available cancer inhibitors originally designed for other types of cancer.
 
The study findings were published in the journal: Cancer Research, a journal of the American Association for Cancer Research (AACR). https://cancerres.aacrjournals.org/content/early/2020/09/12/0008-5472.CAN-20-0078
 
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 research's authors told Thailand Medical News, “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 .We need entirely new possible approaches for our patients with ASCP."
 
To date, pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, which this year is projected to kill nearly 58,000 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.
 
The study's senior author, Dr Michael Barrett, Ph.D., who holds a joint research appointment at Mayo Clinic and TGEN added, "Adenosquamous cancer of the pancreas or 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,"
 
He added, "Our study has shown that ASCPs have novel 'hits' ie 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.”
 
Dr Barrett further added, “While this activated aggressive stem-cell-like state is very resistant to current therapies for pancreatic cancer, the research has shown that ASCP can be targeted by drugs currently in clinical use for other cancers as well as non-cancer related conditions.”
 
To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, the team applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX).
 
Utilizing 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 ever of ASCP tissue samples.
 
The study team identified multiple mutations and genomic variants that are common to both PDAC and the more aggressive ASCP.
 
Most significantly, the study team 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.
 
The study findings provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this lethal cancer.
 
Utilizing organoids, which are laboratory cultures derived from samples of patient tumors, researchers tested the activity and functional significance of candidate therapeutic targets.
 
From the study findings, 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.
 
The study team also says, "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.”
 
Also by using an interrogation tool known as ATAC-seq, the study team also identified RORC as another distinguishing feature of ASCP.
 
The team further commented, "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.”
 
 In summary, the study data provide the basis for the development of novel approaches to treat ASCP. The team proposes that ASCP evolve from the same lineage as PDACs yet consist of enriched levels of RORC-positive cancer stem cells, a feature that may drive other tumors with mixed adenosquamous and adenocarcinoma features.
 
Furthermore, in addition to an epigenome that may promote stem cell features, the team reports that a subset of ASCP has activated FGFR signaling that can be targeted with current inhibitors. Although currently limited in numbers, the availability of PDXs and organoids that recapitulate the genomic and epigenomic lesions found in patient samples provides initial preclinical models to interrogate therapeutic targets in this lethal chemoresistant cancer.
 
The team further commented, "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.”
 
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