scholarly journals Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia

2020 ◽  
Vol 21 (22) ◽  
pp. 8823
Author(s):  
Justin F. Creeden ◽  
Khaled Alganem ◽  
Ali S. Imami ◽  
Nicholas D. Henkel ◽  
F. Charles Brunicardi ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tyrosine Kinases ◽  
Tumor Development ◽  
Review Literature ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Desmoplastic Stroma ◽  
B Lymphoid ◽  
Therapeutic Research ◽  
Lymphocyte Cell

Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.

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.

scholarly journals Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma

Oncotarget ◽  
2016 ◽  
Vol 7 (27) ◽  
pp. 40992-41004 ◽  
Author(s):  
Angela Diana ◽  
Lai Mun Wang ◽  
Zenobia D’Costa ◽  
Paul Allen ◽  
Abul Azad ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Prognostic Value ◽  
Ductal Adenocarcinoma ◽  
Desmoplastic Stroma

scholarly journals Overexpression of BUB1B, CCNA2, CDC20, and CDK1 in tumor tissues predicts poor survival in pancreatic ductal adenocarcinoma

2019 ◽  
Vol 39 (2) ◽  
Author(s):  
Shu Dong ◽  
Fei Huang ◽  
Hao Zhang ◽  
Qiwen Chen
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Development ◽  
Disease Free Survival ◽  
Tumor Stage ◽  
Gene Expression Omnibus ◽  
Ductal Adenocarcinoma ◽  
Advanced Tumor Stage ◽  
Kaplan Meier ◽  
Advanced Tumor ◽  
Tumor Tissues

AbstractOverexpressed genes in tumors usually contributed to aggressiveness in pancreatic ductal adenocarcinoma (PDAC). Using Gene Expression Omnibus (GEO) profiles including GSE46234, GSE71989, and GSE107610, we detected overexpressed genes in tumors with R program, which were enriched by Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO), and Reactome pathway databases. Then, we performed a survival analysis of enriched genes based on TCGA profile. Our results revealed that high BUB1B, CCNA2, CDC20, and CDK1 expression in tumors was significantly associated with worse overall survival (OS) (Log rank P=0.00338, P=0.0447, P=0.00965, and P=0.00479, respectively), which was validated using a Kaplan–Meier plotter with a median cutoff (Log rank P=0.028, P=0.0035, P=0.039, and P=0.0033, respectively). Moreover, overexpression of BUB1B, CCNA2, CDC20, and CDK1 in tumor tissues was significantly associated with disease-free survival (DFS) in PDAC patients (Log rank P=0.00565, P=0.0357, P=0.00104, and P=0.00121, respectively). BUB1B, CCNA2, CDC20, and CDK1 were significantly overexpressed in deceased PDAC patients (all P<0.01) and in patients with recurrence/disease progression (all P<0.05). In addition, PDAC patients with neoplasms of histologic grade G3-4 had significantly higher BUB1B, CCNA2 and CDC20 levels (all P<0.05). In conclusion, the up-regulation of BUB1B, CCNA2, CDC20, CDK1, and WEE1 in tumor tissues are associated with worse OS and DFS in PDAC and is correlated with advanced tumor stage and tumor development.

scholarly journals From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 21 (11) ◽  
pp. 4067 ◽  
Author(s):  
Christopher Montemagno ◽  
Shamir Cassim ◽  
Jacques Pouyssegur ◽  
Alexis Broisat ◽  
Gilles Pagès
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Poor Prognosis ◽  
Malignant Progression ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Therapeutic Targeting ◽  
Normal Tissues ◽  
Attractive Candidate ◽  
Rising Incidence ◽  
Resistance To Chemotherapy

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all pancreatic tumors, is a highly devastating disease with poor prognosis and rising incidence. The lack of available specific diagnostics tests and the limited treatment opportunities contribute to this pejorative issue. Over the last 10 years, a growing interest pointing towards mesothelin (MSLN) as a promising PDAC-associated antigen has emerged. The limited expression of MSLN in normal tissues (peritoneum, pleura and pericardium) and its overexpression in 80 to 90% of PDAC make it an attractive candidate for therapeutic management of PDAC patients. Moreover, its role in malignant progression related to its involvement in tumor cell proliferation and resistance to chemotherapy has highlighted the relevance of its targeting. Hence, several clinical trials are investigating anti-MSLN efficacy in PDAC. In this review, we provide a general overview of the different roles sustained by MSLN during PDAC progression. Finally, we also summarize the different MSLN-targeted therapies that are currently tested in the clinic.

scholarly journals Coming in the Air: Hypoxia Meets Epigenetics in Pancreatic Cancer

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2353
Author(s):  
Claudia Geismann ◽  
Alexander Arlt
Keyword(s):  
Pancreatic Cancer ◽  
Immune Escape ◽  
Treatment Options ◽  
Tumor Development ◽  
Therapy Resistance ◽  
Ductal Adenocarcinoma ◽  
Epigenetic Alterations ◽  
Hypoxic Conditions ◽  
The Us ◽  
Desmoplastic Stroma

With a five-year survival rate under 9%, pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest tumors. Although the treatment options are slightly improving, PDAC is the second leading cause of cancer related death in 2020 in the US. In addition to a pronounced desmoplastic stroma reaction, pancreatic cancer is characterized by one of the lowest levels of oxygen availability within the tumor mass and these hypoxic conditions are known to contribute to tumor development and progression. In this context, the major hypoxia associated transcription factor family, HIF, regulates hundreds of genes involved in angiogenesis, metabolism, migration, invasion, immune escape and therapy resistance. Current research implications show, that hypoxia also modulates diverse areas of epigenetic mechanisms like non-coding RNAs, histone modifications or DNA methylation, which cooperate with the hypoxia-induced transcription factors as well as directly regulate the hypoxic response pathways. In this review, we will focus on hypoxia-mediated epigenetic alterations and their impact on pancreatic cancer.

scholarly journals Tyrosine Phosphoproteomics of Patient-Derived Xenografts Reveals Ephrin Type-B Receptor 4 Tyrosine Kinase as a Therapeutic Target in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3404
Author(s):  
Santosh Renuse ◽  
Vijay S. Madamsetty ◽  
Dong-Gi Mun ◽  
Anil K. Madugundu ◽  
Smrita Singh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Target ◽  
Tyrosine Kinases ◽  
High Resolution Mass Spectrometry ◽  
Human Tumor ◽  
Ductal Adenocarcinoma ◽  
Spectrometric Analysis ◽  
Molecular Heterogeneity ◽  
Type B

Pancreatic ductal adenocarcinoma is a recalcitrant tumor with minimal response to conventional chemotherapeutic approaches. Oncogenic signaling by activated tyrosine kinases has been implicated in cancers resulting in activation of diverse effector signaling pathways. Thus, the discovery of aberrantly activated tyrosine kinases is of great interest in developing novel therapeutic strategies in the treatment and management of pancreatic cancer. Patient-derived tumor xenografts (PDXs) in mice serve as potentially valuable preclinical models as they maintain the histological and molecular heterogeneity of the original human tumor. Here, we employed high-resolution mass spectrometry combined with immunoaffinity purification using anti-phosphotyrosine antibodies to profile tyrosine phosphoproteome across 13 pancreatic ductal adenocarcinoma PDX models. This analysis resulted in the identification of 1199 tyrosine-phosphorylated sites mapping to 704 proteins. The mass spectrometric analysis revealed widespread and heterogeneous activation of both receptor and non-receptor tyrosine kinases. Preclinical studies confirmed ephrin type-B receptor 4 (EphB4) as a potential therapeutic target based on the efficacy of human serum albumin-conjugated soluble EphB4 in mice bearing orthotopic xenografts. Immunohistochemistry-based validation using tissue microarrays from 346 patients with PDAC showed significant expression of EphB4 in >70% of patients. In summary, we present a comprehensive landscape of tyrosine phosphoproteome with EphB4 as a promising therapeutic target in pancreatic ductal adenocarcinoma.

scholarly journals Pentraxin 3 is a stromally-derived biomarker for detection of pancreatic ductal adenocarcinoma

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Michelle R. Goulart ◽  
Jennifer Watt ◽  
Imran Siddiqui ◽  
Rita T. Lawlor ◽  
Ahmet Imrali ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ex Vivo ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Diagnostic Biomarkers ◽  
All Trans Retinoic Acid ◽  
Desmoplastic Stroma ◽  
Predictive Role

AbstractPancreatic ductal adenocarcinoma (PDAC), characterized by dense desmoplastic stroma laid down by pancreatic stellate cells (PSC), has no reliable diagnostic biomarkers for timely detection. A multi-center cohort of PDAC patients and controls (chronic pancreatitis, intra-ductal papillary neoplasms, gallstones and otherwise healthy) donated serum in an ethically approved manner. Serum PTX3 above 4.34 ng/mL has a higher sensitivity (86%, 95% confidence interval (CI): 65–97%) and specificity (86%, 95% CI: 79–91%), positive predictive value (97%) and likelihood ratio (6.05), and is superior when compared to serum CA19-9 and CEA for detection of PDAC. In vitro and ex vivo analyses of PTX3, in human PDAC samples, PSCs, cell lines and transgenic mouse model for PDAC, suggest that PTX3 originates from stromal cells, mainly PSC. In activated PSC, PTX3 secretion could be downregulated by rendering PSC quiescent using all-trans-retinoic acid (ATRA). PTX3 organizes hyaluronan in conjunction with tumor necrosis factor-stimulated gene 6 (TSG-6) and facilitates stellate and cancer cell invasion. In SCALOP clinical trial (ISRCTN96169987) testing chemo-radiotherapy without stromal targeting, PTX3 had no prognostic or predictive role. However, in STARPAC clinical trial (NCT03307148), stromal modulation by ATRA even at first dose is accompanied with serum PTX3 response in patients who later go on to demonstrate disease control but not those in whom the disease progresses. PTX3 is a putative stromally-derived biomarker for PDAC which warrants further testing in prospective, larger, multi-center cohorts and within clinical trials targeting stroma.

scholarly journals Prognostic role and correlation of CA9, CD31, CD68 and CD20 with the desmoplastic stroma in pancreatic ductal adenocarcinoma

Oncotarget ◽  
2016 ◽  
Vol 7 (45) ◽  
pp. 72819-72832 ◽  
Author(s):  
Angela Diana ◽  
Lai Mun Wang ◽  
Zenobia D’Costa ◽  
Abul Azad ◽  
Michael A. Silva ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Prognostic Role ◽  
Desmoplastic Stroma

scholarly journals Metastatic pancreatic ductal adenocarcinoma in a teenage girl: A rare disease

2020 ◽  
Vol 60 (6) ◽  
pp. 341-4
Author(s):  
Sutaryo Sutaryo ◽  
Scolastika Dita Kristian
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Acinar Cell Carcinoma ◽  
Abdominal Discomfort ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Solid Pseudopapillary Tumor ◽  
Teenage Girl ◽  
Pancreatic Endocrine Neoplasm ◽  
Pancreatic Cells ◽  
Tumor Types

Pancreatic ductal adenocarcinoma (PDAC) is highly uncommon in patients < 20 years of age, at less than 0.1% of population.1 Pancreatic tumors in children and adolescents can develop from endocrine or exocrine cells. The tumor types include solid pseudopapillary tumor, ductal adenocarcinoma, pancreatoblastoma, acinar cell carcinoma, and pancreatic endocrine neoplasm (malignant and benign).2 Other types of tumors may be attached to it or secondarily engage the gland or emerge from other kinds of non-pancreatic cells inside the pancreas. The prevalent type of classic PDAC in adults is highly uncommon in children.  We report here on a fifteen-year old girl with metastatic pancreatic ductal adenocarcinoma (mPDAC), who presented with abdominal discomfort and jaundice.

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