Development of Pancreatic Cancer: Targets for Early Detection and Treatment

2016 ◽  
Vol 34 (5) ◽  
pp. 525-531 ◽  
Author(s):  
Markus M. Lerch ◽  
Julia Mayerle ◽  
Ujjwal Mahajan ◽  
Matthias Sendler ◽  
F. Ulrich Weiss ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Chronic Pancreatitis ◽  
Early Detection ◽  
Tyrosine Kinases ◽  
Histone Deacetylases ◽  
Hedgehog Signaling ◽  
Pharmaceutical Preparations ◽  
Chemotherapeutic Agents ◽  
Ductal Adenocarcinoma ◽  
Diagnostic Tools

Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death worldwide and compared to other malignancies its share in cancer mortality is expected to rise further. This is due to a lack of sensitive diagnostic tools that would permit earlier detection in a potentially curable stage and the very slow progress in finding effective drug treatments for pancreatic cancer. Key Messages: Aside from genetic predispositions and environmental agents, chronic pancreatitis is by far the greatest risk factor for PDAC. It also shares several etiological factors with pancreatic cancer and represents its most challenging differential diagnosis. Biomarkers that can distinguish between chronic pancreatitis and PDAC may therefore be suitable for the latter's early detection. Moreover, targeting the natural history of chronic pancreatitis would be one approach to prevent PDAC. Targeting tumor-cell signaling directly by interfering with receptor tyrosine kinases has shown some efficacy, although the results in clinical trials were less encouraging than for other cancers. Other compounds developed have targeted the formation of extracellular matrix around the tumor, the proteolytic activity in the tumor environment, histone deacetylases, hedgehog signaling and heat shock proteins, but none has yet found its way into routine patient care. Attempts to individualize treatment according to the tumor's somatic mutation profile are novel but so far impractical. Conclusions: Progress in the treatment of pancreatic cancer has been exceedingly slow and mostly dependent on improved pharmaceutical preparations or combinations of established chemotherapeutic agents. The promise of major breakthroughs implied in targeting tumor signal transduction events has so far not materialized.

scholarly journals The Screening and Early Detection of Pancreatic Cancer: Who, When, and How?

2020 ◽  
Vol 25 (2) ◽  
pp. 65-71
Author(s):  
Jae Hyuck Chang
Keyword(s):  
Pancreatic Cancer ◽  
Chronic Pancreatitis ◽  
General Population ◽  
Early Detection ◽  
Imaging Modality ◽  
Ductal Adenocarcinoma ◽  
Average Risk ◽  
Cystic Lesions ◽  
Low Prevalence ◽  
New Onset

More than 80% of patients with pancreatic ductal adenocarcinoma (PDA) present with symptomatic, surgically unresectable disease. If a “stage shift” from the current 20% resectable proportion to greater by early detection can be achieved, it will unequivocally lead to improved survival in this otherwise dismal disease. Although the goal of early detection of PDA is laudable, the relatively low prevalence PDA renders general population screening infeasible. To avoid the perils of overdiagnosis and to focus early detection efforts on individuals deemed to be at higher-than-average risk, we need to define those subsets of individuals, such as familial kindred and patients with precursor cystic lesions, chronic pancreatitis, and new-onset diabetes. The next step is to determine when and how often to conduct surveillance in the atrisk individuals and the modalities (biomarkers and imaging) that will be used in the surveillance and diagnostic settings, respectively. Nonetheless, vast challenges still remain in terms of validated blood-based biomarkers, imaging modality, and when and how often the surveillance.

scholarly journals Advances in Early Detection of Pancreatic Cancer

2019 ◽  
Author(s):  
Atsushi Kanno ◽  
Atsushi Masamune ◽  
Keiji Hanada ◽  
Masataka Kikuyama ◽  
Masayuki Kitano
Keyword(s):  
Risk Factors ◽  
Pancreatic Cancer ◽  
Chronic Pancreatitis ◽  
Early Detection ◽  
Early Diagnosis ◽  
Clinicopathological Features ◽  
Ductal Adenocarcinoma ◽  
Study Group ◽  
Intraductal Papillary Mucinous Neoplasms ◽  
Mucinous Neoplasms

Early detection of pancreatic ductal adenocarcinoma (PDAC) requires further examination after selecting cases with risk factors for the condition, such as family history, hereditary pancreatic carcinoma syndrome, intraductal papillary mucinous neoplasms, or chronic pancreatitis. The Japan Study Group on the Early Detection of Pancreatic Cancer has investigated and clarified the clinicopathological features for the early diagnosis of PDAC. Further approaches for the early diagnosis of PDAC are warranted.

scholarly journals A Circulating Exosome RNA Signature Is a Potential Diagnostic Marker for Pancreatic Cancer, a Systematic Study

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2565
Author(s):  
Yixing Wu ◽  
Hongmei Zeng ◽  
Qing Yu ◽  
Huatian Huang ◽  
Beatrice Fervers ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Chronic Pancreatitis ◽  
Early Detection ◽  
Validation Dataset ◽  
Healthy Controls ◽  
Rna Seq ◽  
Healthy Individuals ◽  
Kras Mutations ◽  
Significant Difference ◽  
Rna Signature

Several exosome proteins, miRNAs and KRAS mutations have been investigated in the hope of carrying out the early detection of pancreatic cancer with high sensitivity and specificity, but they have proven to be insufficient. Exosome RNAs, however, have not been extensively evaluated in the diagnosis of pancreatic cancer. The purpose of this study was to investigate the potential of circulating exosome RNAs in pancreatic cancer detection. By retrieving RNA-seq data from publicly accessed databases, differential expression and random-effects meta-analyses were performed. The results showed that pancreatic cancer had a distinct circulating exosome RNA signature in healthy individuals, and that the top 10 candidate exosome RNAs could distinguish patients from healthy individuals with an area under the curve (AUC) of 1.0. Three (HIST2H2AA3, LUZP6 and HLA-DRA) of the 10 genes in exosomes had similar differential patterns to those in tumor tissues based on RNA-seq data. In the validation dataset, the levels of these three genes in exosomes displayed good performance in distinguishing cancer from both chronic pancreatitis (AUC = 0.815) and healthy controls (AUC = 0.8558), whereas a slight difference existed between chronic pancreatitis and healthy controls (AUC = 0.586). Of the three genes, the level of HIST2H2AA3 was positively associated with KRAS status. However, there was no significant difference in the levels of the three genes across the disease stages (stages I–IV). These findings indicate that circulating exosome RNAs have a potential early detection value in pancreatic cancer, and that a distinct exosome RNA signature exists in distinguishing pancreatic cancer from healthy individuals.

scholarly journals Soluble AXL is a novel blood marker for early detection of pancreatic ductal adenocarcinoma and differential diagnosis from chronic pancreatitis

EBioMedicine ◽  
2022 ◽  
Vol 75 ◽  
pp. 103797
Author(s):  
Neus Martínez-Bosch ◽  
Helena Cristóbal ◽  
Mar Iglesias ◽  
Meritxell Gironella ◽  
Luis Barranco ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Chronic Pancreatitis ◽  
Early Detection ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Blood Marker

scholarly journals BRM270 Inhibits the Proliferation of CD44 Positive Pancreatic Ductal Adenocarcinoma Cells via Downregulation of Sonic Hedgehog Signaling

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Do Luong Huynh ◽  
Hyebin Koh ◽  
Nisansala Chandimali ◽  
Jiao Jiao Zhang ◽  
Nameun Kim ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Ductal Adenocarcinoma ◽  
Cell Phenotype ◽  
Sonic Hedgehog Signaling ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells ◽  
Adenocarcinoma Cells

Pancreatic cancer has a poor survival rate as compared to other types of cancer. Surface marker CD44 plays important role in epithelial-mesenchymal transition and cancer stem cell phenotype. Therefore, targeting CD44 positive pancreatic cancer cells might enhance therapies effectiveness. Our previous studies indicated the antitumorigenesis effect of BRM270 in osteosarcoma, lung cancer, and glioblastoma; however there is no evidence on BRM270 impacts on pancreatic cancer growth. In this study, we investigated the effect of BRM270 on the isolated CD44 positive pancreatic ductal adenocarcinoma cells (CD44+PDAC). Results showed that CD44 positive cells undergo apoptosis induced by BRM270. Moreover, BRM270 also inhibits stemness and metastasis traits in CD44+PDAC via Sonic hedgehog signaling pathway and SALL4 expression.In vivostudy indicated that tumor growth derived from CD44+PDAC was suppressed as daily uptake by BRM270 5 mg/kg. These data suggest the alternative approach in antipancreatic tumorigenesis via herbal plants extract and selectively targeting CD44+PDAC cells in tumor.

scholarly journals Feasibility and safety of electrochemotherapy (ECT) in the pancreas: a pre-clinical investigation

2015 ◽  
Vol 49 (2) ◽  
pp. 147-154 ◽  
Author(s):  
Roberto Girelli ◽  
Simona Prejanò ◽  
Ivana Cataldo ◽  
Vincenzo Corbo ◽  
Lucia Martini ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Clinical Investigation ◽  
Tumour Response ◽  
Chemotherapeutic Agents ◽  
Ductal Adenocarcinoma ◽  
Safe Procedure ◽  
Reversible Electroporation

Abstract Background. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease generally refractory to standard chemotherapeutic agents; therefore improvements in anticancer therapies are mandatory. A major determinant of therapeutic resistance in PDAC is the poor drug delivery to neoplastic cells, mainly due to an extensive fibrotic reaction. Electroporation can be used in vivo to increase cancer cells’ local uptake of chemotherapeutics (electrochemotherapy, ECT), thus leading to an enhanced tumour response rate. In the present study, we evaluated the in vivo effects of reversible electroporation in normal pancreas in a rabbit experimental model. We also tested the effect of electroporation on pancreatic cancer cell lines in order to evaluate their increased sensitivity to chemotherapeutic agents. Materials and methods. The application in vivo of the European Standard Operating Procedure of Electrochemotherapy (ESOPE) pulse protocol (1000 V/cm, 8 pulses, 100 μs, 5 KHz) was tested on the pancreas of normal New Zealand White Rabbits and short and long-term toxicity were assessed. PANC1 and MiaPaCa2 cell lines were tested for in vitro electrochemotherapy experiments with and without electroporation. Levels of cell permeabilization were determined by flow cytometry, whereas cell viability and drug (cisplatin and bleomycin) sensitivity of pulsed cells were measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Results. In healthy rabbits, neither systemic nor local toxic effects due to the electroporation procedure were observed, demonstrating the safety of the optimized electric parameters in the treatment of the pancreas in vivo. In parallel, we established an optimized protocol for ECT in vitro that determined an enhanced anti-cancer effect of bleomycin and cisplatin with respect to treatment without electroporation. Conclusions. Our data suggest that electroporation is a safe procedure in the treatment of PDAC because it does not affect normal pancreatic parenchyma, but has a potentiating effect on cytotoxicity of bleomycin in pancreatic tumour cell lines. Therefore, ECT could be considered as a valid alternative for the local control of non-resectable pancreatic cancer.

scholarly journals Microbial Dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer

2018 ◽  
Author(s):  
Roberto Mendez ◽  
Kousik Kesh ◽  
Nivedita Arora ◽  
Leá Di Martino ◽  
Florencia McAllister ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Survival Rate ◽  
Early Detection ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Ductal Adenocarcinoma ◽  
Metabolic Reconstruction ◽  
Microbiome Analysis ◽  
Early Stages ◽  
Kpc Mice

AbstractPurposeThe lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated to the abysmal survival rate in patients. In addition to several potential detection tools under active investigation, we tested the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high-risk for PDAC.Experimental DesignA combination of 16s pyrosequencing and whole-genome sequencing of gut microbiota was used in a spontaneous genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC). Metabolic reconstruction of microbiome was done using the HUmanN2 pipeline. Serum polyamine levels were measured from murine and patient samples using standard methods.ResultsResults showed a progressive Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentration. Therefore, at the early stages of tumorigenesis, the gut microbial composition changes in a way to release metabolites that foster host tumorigenesis, thereby fulfilling the ‘vicious cycle hypothesis’ of the role of the microbiome in health and disease states.ConclusionsOur results provide a potential, precise, non-invasive tool for early detection of PDAC, which will result in improved outcomes.SynopsisGut microbiota changes during early stages of pancreatic ductal adenocarcinoma (PDAC) progression and contributes towards host polyamine pool. Both changes can be used as an early predictive marker for PDAC.Translational RelevancePancreatic carcinogenesis progresses through pre-cancerous PanIN lesions to invasive cancer. Even though these morphological changes are histologically distinct, imaging techniques are not able to distinguish the pre-invasive PanINs from normal pancreas, making detection of a tumor at a precancerous stage impossible. Thus, majority of cases (85–90%) present with advanced pancreatic cancer at the time of diagnosis. This contributes to the dismal survival rate in this disease. Our study of gut microbiome analysis on KPC mice during tumor progression followed by metabolic reconstruction and experimental validation in human samples indicate that gut-microbiome analysis along with an analysis of the microbial metabolites can be developed as potential biomarkers for detection of PDAC at early stages when histological changes are not yet grossly apparent.

scholarly journals Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases

2020 ◽  
Vol 21 (22) ◽  
pp. 8679 ◽  
Author(s):  
Justin F. Creeden ◽  
Khaled Alganem ◽  
Ali S. Imami ◽  
F. Charles Brunicardi ◽  
Shi-He Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Protein Tyrosine Kinases ◽  
Ductal Adenocarcinoma ◽  
Active Protein ◽  
Protein Tyrosine

Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.

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