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Advances in Pancreatic Cancer: A Multi-Omics Driven Approach

Nov 11, 2021 11:00:00 AM / by Champions Oncology


Pancreatic ductal adenocarcinoma (PDAC) is one of the most common and aggressive forms of pancreatic cancer that has remained difficult to diagnose early and treat successfully. PDAC has a five-year survival rate below 10% and is one of the leading causes of cancer death. Complete surgical resection is one of the few curative treatment modalities, and chemotherapy protocols have limited efficacy[1]. Unfortunately, most existing immunotherapy-based treatments are also associated with poor response rates[2]. Recent analyses of PDAC samples have provided critical insights into genetic alterations that drive tumorigenesis and have identified potential therapeutic targets. Here we highlight several of these key findings and how they may lead to advances in PDAC treatment.


PDAC arises in the epithelial cells of pancreatic duct, or ductules, and is thought to progress in a manner like other carcinomas, in which the normal epithelial cells transition into pre-invasive pancreatic intraepithelial neoplasia lesions that eventually form invasive PDAC[3]. Most PDAC tumors carry somatic mutations in oncogenes, particularly KRAS, TP53, CDKN2A, and SMAD4[4]. KRAS is the most frequently occurring mutation in PDAC but is currently considered an undruggable target based on extensive drug and biologic screens that show in vitro inhibition but limited or no efficacy in animal models[5]. The lack of druggable targets or biomarkers for PDAC has led to more innovative approaches to identify unique molecule attributes.


A recent comprehensive proteogenomic characterization of PDAC pancreatic ductal tissues compared against paired normal adjacent tissue, and the findings validated known mutations in oncogenes[6]. This study also defined previously unknown genomic alterations and analyzed differences in protein expression and protein phosphorylation status between tissues. This comprehensive analysis identified a panel of proteins linked to early stage PDAC, and phosphoproteomic analysis identified several signaling pathways downstream of KRAS, including PI3K/AKT/mTOR and MAPK/ERK, that may be targeted by existing kinase inhibitors. The PAK1/PAK2 kinases were also identified as dysregulated in PDAC tissues and have the potential to be targeted therapeutically.


Recent studies have also better characterized the tumor microenvironment (TME) of PDAC and how this may limit treatment efficacy[7]. PDAC tumors tend to be highly heterogenous with a dense stroma and disorganized blood vessels, which impair drug penetration. The TME is enriched for myeloid derived suppressor cells and regulatory T cells and displays a low mutational burden, thus making this a “cold” tumor immunophenotype that is resistant to existing immunotherapies. Current studies are examining immunotherapy or drug-based strategies to turn “cold” PDAC tumors into “hot” tumors that would be receptive to immune checkpoint blockade.


Further advances in PDAC research will require similar extensive proteogenomic studies that better define dysregulated pathways that trigger early events in tumor formation and may function as early biomarkers for disease. The search for novel therapeutic targets or combinations of targets is also essential to improving the currently dismal array of treatment options for PDAC patients.


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[3] Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin. Cancer Res. 2000 Aug;6(8):2969-72. 

[4] Thompson ED, Roberts NJ, Wood LD, Eshleman JR, Goggins MG, Kern SE, Klein AP, Hruban RH. The genetics of ductal adenocarcinoma of the pancreas in the year 2020: dramatic progress, but far to go. Mod. Pathol. 2020 Dec;33(12):2544-2563.

[5] Janes MR, Zhang J, Li LS, et al. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell. 2018 Jan 25;172(3):578-589.e17.

[6] Cao L, Huang C, Cui Zhou D, et al. Clinical Proteomic Tumor Analysis Consortium. Proteogenomic characterization of pancreatic ductal adenocarcinoma. Cell. 2021 Sep 16;184(19):5031-5052.e26.

[7] Kabacaoglu D, Ciecielski KJ, Ruess DA, Algül H. Immune Checkpoint Inhibition for Pancreatic Ductal Adenocarcinoma: Current Limitations and Future Options. Front. Immunol. 2018 Aug 15;9:1878.


Tags: Solid Tumor Oncology