Target In Pancreatic Adenocarcinoma Research Articles

Genetic and immune identification and functional analysis of TRPM8 as a potential biomarker for pancreatic adenocarcinoma proliferation.

Pancreatic adenocarcinoma (PAAD), a member of highly lethal malignant tumors, has a poor outcome and extremely poor prognosis. The transient receptor potential (TRP) superfamily, a group of nonselective cation channels, is capable of influencing cellular functions by regulating calcium homeostasis. In addition, it has been shown that TRP channels can also affect various cellular phenotypes by regulating gene transcription levels and are involved in the development of a variety of malignant tumors. In order to find new therapeutic targets and biomarkers to improve the clinical prognosis of pancreatic cancer, we performed genetic and immunological characterization of TRP channels in PAAD, as well as related functional and prognostic analyses. We investigated the expression, genetic alterations, methylation levels, and immune infiltration levels of TRP channels in PAAD, and further also analyzed the function of TRP channels in PAAD and their prognostic value for PAAD patients. Our results suggest that TRPM8 may contribute to tumor proliferation by controlling the PI3K-AKT-mTOR signaling pathway in PAAD. After careful evaluation of the accumulated data, we concluded that TRPM8 has potential as a prognostic indicator and prospective therapeutic target in PAAD.

Design, Synthesis, Docking Studies and Molecular Dynamics Simulation of New 1,3,5-Triazine Derivatives as Anticancer Agents Selectively Targeting Pancreatic Adenocarcinoma (Capan-1).

On the basis of remarkable anticancer profile of s-triazine nucleus, a new series of 2-methoxy-4-(3-morpholino-5-(arylamino)phenoxy)benzaldehyde derivatives 11 a-u was prepared and evaluated for in vitro antiproliferative activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562 and Z138). Compounds 11 o, 11 r and 11 s were the most potent anticancer agents on pancreatic adenocarcinoma (Capan-1) cell line with IC50 value of 1.4, 5.1 and 5.3 μM, respectively, while compounds 11 f, 11 g, 11 k, 11 l and 11 n displayed selective activity against the pancreatic adenocarcinoma (Capan-1) cell line with IC50 values of 7.3-11.5 μM. These results indicate that derivative 11 o may serve as a promising lead compound for the ongoing development of novel antiproliferative agents. The docking studies were conducted to predict the interactions of derivative 11 o with putative protein targets in pancreatic adenocarcinoma (Capan-1) cell line, specifically the prenyl-binding protein PDEδ. Furthermore, the analysis of the molecular dynamics simulation results demonstrated that complex 11 o promoted a higher stability to the prenyl-binding protein PDEδ.

Integrated analysis identifies cuproptosis-related gene DLAT and its competing endogenous RNAs network to predict the prognosis of pancreatic adenocarcinoma patients.

Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor with poor prognosis. However, the relationship between cuproptosis-related genes (CRGs) and its competing endogenous RNA (ceRNA) network with the prognosis of PAAD patients remains unclear. To investigate this relationship, we calculated the difference in CRGs between PAAD tissues and normal tissues using the 'limma' R package. Additionally, we employed least absolute shrinkage and selection operator (LASSO) Cox regression analysis to construct a prognostic signature for CRGs. Survival analysis of patients with PAAD was performed using Kaplan-Meier analysis. Furthermore, we used bioinformatics tools to screen for CRGs-related MicroRNA (miRNA) and lncRNAs. To validate these findings, we conducted real-time quantitative polymerase chain reaction (RT-qPCR), CCK-8, colony formation, and Transwell assays to assess the effect of DLAT in vitro. Our results revealed a cuproptosis-related prognostic signature consisting of 3 prognostic genes (DLAT, LIAS, and LIPT1). Notably, patients with a high-risk score for the CRGs signature exhibited poor prognosis in terms of overall survival (OS) (P < .05). The receiver operating characteristic (ROC) curve was used to evaluate the prognostic signature of CRGs. The results showed that the 1-year, 3-year, and 5-year area under the curve values for predicting OS were 0.62, 0.66, and 0.79, respectively. Additionally, the CRGs-related ceRNA network revealed the regulatory axis of LINC00857/has-miR-1179/DLAT in PAAD. In vitro experiments demonstrated that knockdown of LINC00857 and DLAT inhibited the growth and invasion of PAAD cells. This study identified a CRG-related prognostic signature consisting of 3 biomarkers (DLAT, LIAS, and LIPT1) for PAAD. Furthermore, ceRNA network analysis suggested the involvement of the LINC00857/has-miR-1179/DLAT axis in the development of PAAD. Overall, this study provides theoretical support for the investigation of diagnostic and prognostic biomarkers as well as potential therapeutic targets in PAAD.

1650P Identification of potential targets in pancreatic adenocarcinoma: The KRAS Wild-Type subset

1650P Identification of potential targets in pancreatic adenocarcinoma: The KRAS Wild-Type subset

The potential use and experimental validation of genomic instability-related lncRNA in pancreatic carcinoma.

This study explored the potential role of long noncoding RNA (lncRNAs) associated with genomic instability in the diagnosis and treatment of pancreatic adenocarcinoma (PAAD). Transcriptome and single-nucleotide variation data of PAAD samples were downloaded from the cancer genome atlas database to explore genomic instability-associated lncRNAs. We constructed a genomic instability-associated lncRNA prognostic signature. Then gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses were used to explore the physiological role of lncRNAs involved in genomic instability. Tumor microenvironments, immunotherapy response, immune cell infiltration, immune checkpoint, and drug sensitivity were compared between high-risk and low-risk groups. In vitro experiments were performed for external validation. Six lncRNAs associated with genomic instability were identified, capable of predicting the prognosis of PAAD. Patients were assigned to low-risk or high-risk groups using these biomarkers, with better or worse prognosis, respectively. The tumor immune score, immune cell infiltration, and efficacy of immunotherapy were worse in the high-risk group. A drug sensitivity analysis revealed the high- and low-risk groups had different half-maximal inhibitory concentrations. The expression of cancer susceptibility candidate 8 was significantly higher in tumor tissues than in normal tissues, while the expression of LYPLAL1-AS1 exhibited an opposite pattern. They may be potential diagnostic or prognostic biomarkers for patients with pancreatic cancer. Genomic instability-associated lncRNAs were explored in this study and predicted the prognosis of PAAD and stratified patients risk in PAAD. These lncRNAs also predicted the efficacy of immunotherapy and potential therapeutic targets in PAAD.

Long Non-Coding RNAs and Metabolic Rewiring in Pancreatic Cancer.

Pancreatic adenocarcinoma is a highly aggressive disease with a poor prognosis. The reprogramming of energetic metabolism has long been implicated in pancreatic tumorigenesis and/or resistance to treatment. Considering that long non-coding RNA dysregulation has been described both in cancerogenesis and in the altered homeostasis of several metabolic pathways, metabolism-associated lncRNAs can contribute to pancreatic cancer evolution. The objective of this review is to assess the burden of lncRNA dysregulation in pancreatic cancer metabolic reprogramming, and its effect on this tumor's natural course and response to treatment. Therefore, we reviewed the available literature to assess whether metabolism-associated lncRNAs have been found to be differentially expressed in pancreatic cancer, as well as whether experimental evidence of their role in such pathways can be demonstrated. Specifically, we provide a comprehensive overview of lncRNAs that are implicated in hypoxia-related pathways, as well as in the reprogramming of autophagy, lipid metabolism, and amino acid metabolism. Our review gathers background material for further research on possible applications of metabolism-associated lncRNAs as diagnostic/prognostic biomarkers and/or as potential therapeutic targets in pancreatic adenocarcinoma.

Abstract 2512: TMEM doorways are an actionable target in pancreatic adenocarcinoma

Abstract Introduction: Pancreatic adenocarcinoma (PDAC) is highly lethal due to overwhelming metastatic burden [1]. The mechanisms underpinning metastasis in PDAC have not been identified. The TMEM doorway is the sole portal of intravasation in breast cancer [2, 3]. Importantly, intravasation and dissemination via TMEM doorways is inhibited by Tie2 blockade in breast cancer [4]. We evaluated whether TMEM Doorways are a common targetable mechanism of dissemination in PDAC. Methods: Tumor samples from treatment-naïve patients who underwent curative-intent resection of PDAC were stained for TMEM doorways using a triple immunohistochemistry (IHC) stain (tumor cells expressing the actin regulatory protein Mena, macrophages expressing CD68, and endothelial cells expressing CD31). TMEM doorways were manually counted in the highest TMEM doorway-bearing 400x field (hotspot) identified at 100x scanning magnification for each case. TMEM doorway function was assessed in a murine model of PDAC treated with or without rebastinib (an investigational oral Tie2 inhibitor [4]) by analyzing; (1) TMEM doorway mediated opening using high-molecular weight dextran (155kD-TMR dextran); (2) circulating tumor cells and (3) disseminated tumor cells in murine livers. The Wilcoxon Test was used for the human TMEM doorway scoring comparisons. A student t-test was used for the murine analyses. Results: TMEM doorways were observed in all PDAC tumors from 50 unique treatment-naïve patients. The TMEM doorway score was ≈6x higher than observed in published breast cancer patient samples. Mean TMEM doorway score in “hotspots” from resected human PDAC was 19 and 34 in low- and high-grade tumors, respectively (p-value &amp;lt; 0.01). TMEM doorway mediated opening was decreased by rebastinib treatment (159.8 µm2 ± sd26.5 vs 22.6 µm2 ± sd3.5, p&amp;lt;0.01). PDAC tumor bearing mice treated with rebastinib had a 6.5-fold decrease in the number of circulating tumor cells compared to control (5554 ± sd1017 vs 852 ± sd412 cells/mL blood, p&amp;lt;0.01). PDAC tumor bearing mice treated with rebastinib had fewer disseminated tumor cells compared to untreated mice (11.6 vs 7.0 DTCs/mm2). Conclusions: TMEM doorways appear to be a common mechanism of dissemination in PDAC and breast cancer. TMEM doorway concentration is significantly associated with PDAC tumor grade. Inhibition of Tie2 with the selective inhibitor, rebastinib, preclinically leads to decreased TMEM doorway function and dissemination in PDAC. Tie2 is a promising therapeutic target for decreasing dissemination and potential metastasis in PDAC that warrants further clinical development in the PDAC space. 1.Siegel, R.L., et al. CA: A Cancer Journal for Clinicians, 2022. 72(1): p. 7-33.2.Harney, A.S., et al. Cancer Discovery, 2015. 5(9): p. 932-943.3.Karagiannis, G.S., et al., Science Translational Medicine, 2017. 9(397): p. eaan0026.4.Harney, A.S., et al. Molecular Cancer Therapeutics, 2017. 16(11): p. 2486-2501. Citation Format: Jakeb Petersen, Robert Eddy, Xianjun Ye, Christian Adkisson, David Entenberg, Maja Oktay, John Condeelis, Nicole Panarelli, John Christopher McAuliffe. TMEM doorways are an actionable target in pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2512.

Trop-2 is a ubiquitous and promising target in pancreatic adenocarcinoma

BackgroundTrop-2 is overexpressed in tumor cells of various cancers, including pancreatic ductal adenocarcinoma (PDAC), and has emerged as a potent therapeutic target. We evaluated Trop-2 expression both at the transcriptomic and protein levels, and its correlation with tumor features and patients’ outcomes in a large cohort of PDAC. MethodsWe included patients undergoing pancreatic resection for PDAC in 5 academic hospitals in France and Belgium. Transcriptomic profiles were obtained from FFPE tissue samples, with paired primary -25and metastatic lesions when available. Protein expression was evaluated by immunohistochemistry (IHC) using tissue micro-arrays. Results495 patients (male 54%, median age 63 years) were included between 1996 and 2012. Trop-2 mRNA expression was significantly associated to tumor cellularity, but no association with survival nor with any clinical or pathological features was observed, with tumor cells showing an overall high expression among every subgroup. Trop-2 mRNA expression was maintained between primary and metastatic lesion in all 26 paired samples evaluated. In 50 tumors assessed by IHC, 30%, 68% and 2% harbored a high, medium, or low Trop-2 expression score, respectively. Trop-2 staining was significantly associated to mRNA expression, but not to survival or any pathological features. ConclusionsOur results suggest Trop-2 overexpression as a ubiquitous marker of PDAC tumor cells and thus a promising therapeutic target to evaluate in these patients.

Retraction Note: EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma.

Retraction Note: EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma.

High expression of RNF169 is associated with poor prognosis in pancreatic adenocarcinoma by regulating tumour immune infiltration.

Background: Pancreatic adenocarcinoma (PAAD) is a highly deadly and aggressive tumour with a poor prognosis. However, the prognostic value of RNF169 and its related mechanisms in PAAD have not been elucidated. In this study, we aimed to explore prognosis-related genes, especially RNF169 in PAAD and to identify novel potential prognostic predictors of PAAD. Methods: The GEPIA and UALCAN databases were used to investigate the expression and prognostic value of RNF169 in PAAD. The correlation between RNF169 expression and immune infiltration was determined by using TIMER and TISIDB. Correlation analysis with starBase was performed to identify a potential regulatory axis of lncRNA-miRNA-RNF169. Results: The data showed that the level of RNF169 mRNA expression in PAAD tissues was higher than that in normal tissues. High RNF169 expression was correlated with poor prognosis in PAAD. In addition, analysis with the TISIDB and TIMER databases revealed that RNF169 expression was positively correlated with tumour immune infiltration in PAAD. Correlation analysis suggested that the long non-coding RNA (lncRNA) AL049555.1 and the microRNA (miRNA) hsa-miR-324-5p were involved in the expression of RNF169, composing a potential regulatory axis to control the progression of PAAD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that RNF169 plays a role in PAAD through pathways such as TNF, Hippo, JAK-STAT and Toll-like receptor signaling. Conclusion: In summary, the upregulation of RNF169 expression mediated by ncRNAs might influence immune cell infiltration in the microenvironment; thus, it can be used as a prognostic biomarker and a potential therapeutic target in PAAD.

Identification of EMT-Related lncRNAs as Potential Prognostic Biomarkers and Therapeutic Targets for Pancreatic Adenocarcinoma.

Epithelial-mesenchymal transition (EMT) can promote carcinoma progression by multiple mechanisms; many studies demonstrated the invasiveness of pancreatic adenocarcinoma (PAAD) associated with the EMT, but how it acts through an lncRNA-dependent manner is unknown. Here, we investigated 146 samples from The Cancer Genome Atlas (TCGA) and 92 samples from the International Cancer Genome Consortium (ICGC). By gene set variation analysis (GSVA) and weighted correlation network analysis (WGCNA), we explored the EMT-related long noncoding RNAs (EMTlnc). Then, we performed univariate Cox regression analysis to screen their prognostic value for PAAD. The least absolute contraction and selection operator (LASSO) Cox regression was used to establish EMT-related lncRNA prognostic signal (EMT-LPS). In addition, we established a competitive endogenous ceRNA network. Then, we identified 33 prognostic EMTlnc as prognostic lncRNAs and established an EMT-LPS which showed strong prognostic ability in stratification analysis. By corresponding risk scores, patients were divided into low-risk and high-risk subgroups. Principal component analysis (PCA) showed that these subgroups had individual EMT status. Enrichment analysis showed that in the high-risk subgroup, biological processes, pathways, and hallmarks related to malignant tumors are more common. What is more, we constructed a nomogram that had powerful ability to predict the overall survival rate (OS) of PAAD patients in two datasets. So, EMT-LPS are a principal element in PAAD's carcinoma progression and may help us in choosing the way of prognosis assessment and provide some clues to design the new drugs for PAAD.

Abstract PO-091: Histamine receptor 1 (HRH1): A potentially novel G protein-coupled receptor (GPCR) therapeutic target in pancreatic adenocarcinoma (PDAC) cells and tumors

Abstract A recent study reported that patients taking HRH1 antihistamines have decreased progression of various tumors, including PDAC; the authors inferred that this was an immune effect (Fritz et al., PMID: 33550204). We have initiated studies to test an alternative hypothesis: HRH1 expressed by PDAC cells may contribute to the malignant phenotype and if so, FDA-approved HRH1 antihistamines might be therapeutics to treat or perhaps prevent PDAC. We have undertaken bioinformatic and experimental approaches to test this hypothesis. Our bioinformatic analysis revealed that PDAC tumors in The Cancer Genome Atlas (TCGA) have &amp;gt;30-fold higher HRH1 expression than in normal pancreas (GTEx database) and is highly expressed in PDAC cell lines in the Cancer Cell Line Encyclopedia (CCLE). HRH1 expression was selectively associated with markers of PDAC cells and not with markers of other cell types in the tumor microenvironment. Higher expression of HRH1 in TCGA-PDAC tumors negatively impacts on patient survival. Our experimental studies indicate that human and mouse PDAC cells express HRH1 mRNA, protein and signaling and that HRH1 is present on the surface of PDAC cells. We found that histamine prominently increases calcium [Ca2+] in multiple human PDAC cell lines with EC50 values comparable to that in other cell types. The histamine-stimulated increase in [Ca2+] occurs via a Gq/11 (heterotrimeric GTP binding protein)-dependent mechanism and is blocked by multiple FDA-approved HRH1 antihistamines (with pKi values similar to those of HRH1 inhibition of other cell types). HRH1 activation by histamine increases PDAC cell migration. Histamine also increases the production of numerous cytokines (including VEGF) from PDAC cells, and in preliminary studies, stimulates growth of multiple PDAC cell lines at low concentrations (1-10 nM). Together with published data indicating that mast cells (which synthesize and release histamine) in PDAC tumors are associated with PDAC cell growth/invasion, angiogenesis and worse prognosis, our findings suggest that independent of immune cells, a "mast cell-histamine-PDAC cell HRH1 axis" may contribute to the malignant phenotype of PDAC tumors. Importantly, HRH1 on PDAC cells could be targeted by repurposing approved HRH1 antihistamines as a novel therapeutic approach for PDAC tumors. Supported by grants from the University of California Cancer Research Coordinating Committee and Tobacco-Related Disease Research Program. Citation Format: Cristina Salmeron, Krishna Sriram, Mehrak Javadi-Paydar, Paul A. Insel. Histamine receptor 1 (HRH1): A potentially novel G protein-coupled receptor (GPCR) therapeutic target in pancreatic adenocarcinoma (PDAC) cells and tumors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-091.

Overexpression of Interferon-Inducible Protein 16 Promotes Progression of Human Pancreatic Adenocarcinoma Through Interleukin-1β-Induced Tumor-Associated Macrophage Infiltration in the Tumor Microenvironment.

Activation of inflammasomes has been reported in human pancreatic adenocarcinoma (PAAD); however, the expression pattern and functional role of inflammasome-related proteins in PAAD have yet to be identified. In this study, we systemically examined the expression and role of different inflammasome proteins by retrieving human expression data. Several genes were found to be differentially expressed; however, only interferon-inducible protein 16 (IFI16) expression was found to be adversely correlated with the overall survival of PAAD patients. Overexpression of IFI16 significantly promoted tumor growth, increased tumor size and weight in the experimental PAAD model of mice, and specifically increased the population of tumor-associated macrophages (TAMs) in the tumor microenvironment. Depletion of TAMs by injection of liposome clodronate attenuated the IFI16 overexpression-induced tumor growth in PAAD. In vitro treatment of conditioned medium from IFI16-overexpressing PAAD cells induced maturation, proliferation, and migration of bone marrow-derived monocytes, suggesting that IFI16 overexpression resulted in cytokine secretion that favored the TAM population. Further analysis suggested that IFI16 overexpression activated inflammasomes, thereby increasing the release of IL-1β. Neutralization of IL-1β attenuated TAM maturation, proliferation, and migration induced by the conditioned medium from IFI16-overexpressing PAAD cells. Additionally, knockdown of IFI16 could significantly potentiate gemcitabine treatment in PAAD, which may be associated with the reduced infiltration of TAMs in the tumor microenvironment. The findings of our study shed light on the role of IFI16 as a potential therapeutic target for PAAD.

Expression and prognostic impact of FZDs in pancreatic adenocarcinoma

BackgroundDespite the high number of researches on pancreatic adenocarcinoma (PAAD) over past decades, little progress had been made due to lack of effective treatment regimens. We aimed to investigate the expression level, mutation, and clinical significance of the Frizzled (FZD) family in PAAD so as to establish a sufficient scientific evidence for clinical decisions and risk management.MethodsPAAD samples were extracted from The Cancer Genome Atlas (TCGA). Oncomine, Gene expression profiling interactive analysis (GEPIA), human protein atlas (HPA), Kaplan–Meier Plotter, cBioPortal, LinkedOmics, DAVID database, and R software (× 64 3.6.2) were used to comprehensively analyze the roles of FZDs. p value below to 0.05 was considered as significant difference.ResultsIn total, 179 PAAD tissues and 171 paracancerous tissues were included. The expression levels of FZD1, 2, 6, 7, and 8 were higher in PAAD tissues than those in normal pancreatic tissue. The higher the expression levels of FZD2 and FZD7, the higher the clinical stage. The overall survival (OS) time was significantly different between low FZD3, 4, 5, 6, and 9 expression group and high expression group. Multivariable analysis showed that FZD3 and FZD6 were independent prognostic factors. The recurrence free survival (RFS) time was significantly different between low FZD4 and FZD8 expression group and high expression group. The RFS difference between low FZD6 expression group and high expression group had not reached statistical significance (p = 0.067), which might be due to the small sample size. However, multivariable analysis showed that FZD6 was the only independent factor for RFS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that FZDs played a critical role in the Wnt signaling pathway, which was further confirmation that FZDs were transmembrane receptors of Wnt signaling pathway.ConclusionsOur results strongly indicated a crucial role of the FZD family in PAAD. FZD3 and FZD6 could be potential prognostic and predictive markers, and FZD6 might also function as a potential therapeutic target in PAAD by blocking Wnt/β-catenin pathway.

High TXLNA Expression Predicts Favourable Outcome for Pancreatic Adenocarcinoma Patients.

TXLNA (taxilin alpha), a binding partner of the syntaxin family, was identified as a key factor in the coordination of intracellular vesicle trafficking and highly expressed in various tumor cells. However, the accurate relation between TXLNA and tumorigenesis and progression of pancreatic adenocarcinoma (PAAD) is still unclear. The present study was designed to examine the expression profile of TXLNA and explore its prognostic significance in PAAD patients and the possible molecular regulatory mechanism by analyzing a series of data from databases, including GEPIA, LOGpc, STRING, and GeneMANIA. The results indicate that TXLNA mRNA and protein were remarkably increased in PAAD tissues compared with normal pancreatic tissues. The high TXLNA expression was significantly correlated with superior overall survival (OS), disease-free interval (DFI), disease specific survival (DSS), and progression-free interval (PFI) for PAAD patients. In summary, high TXLNA expression could predict favourable OS, DFI, DSS, and PFI for PAAD patients, and it might be as potential prognostic biomarkers and targets for PAAD.

P38α Mitogen-Activated Protein Kinase Is a Druggable Target in Pancreatic Adenocarcinoma.

p38 mitogen-activated protein kinases are signaling molecules with major involvement in cancer. A detailed mechanistic understanding of how p38 MAPK family members function is urgently warranted for cancer targeted therapy. The conformational dynamics of the most common member of p38 MAPK family, p38α, are crucial for its function but poorly understood. Here we found that, unlike in other cancer types, p38α is significantly activated in pancreatic adenocarcinoma samples, suggesting its potential for anti-pancreatic cancer therapy. Using a state of the art supercomputer, Anton, long-timescale (39 μs) unbiased molecular dynamics simulations of p38α show that apo p38α has high structural flexibility in six regions, and reveal potential catalysis mechanism involving a “butterfly” motion. Moreover, in vitro studies show the low-selectivity of the current p38α inhibitors in both human and mouse pancreatic cancer cell lines, while computational solvent mapping identified 17 novel pockets for drug design. Taken together, our study reveals the conformational dynamics and potentially druggable pockets of p38α, which may potentiate p38α-targeting drug development and benefit pancreatic cancer patients.

Exosomes harbor B cell targets in pancreatic adenocarcinoma and exert decoy function against complement-mediated cytotoxicity

Although B cell response is frequently found in cancer, there is little evidence that it alters tumor development or progression. The process through which tumor-associated antigens trigger humoral response is not well delineated. We investigate the repertoire of antigens associated with humoral immune response in pancreatic ductal adenocarcinoma (PDAC) using in-depth proteomic profiling of immunoglobulin-bound proteins from PDAC patient plasmas and identify tumor antigens that induce antibody response together with exosome hallmark proteins. Additional profiling of PDAC cell-derived exosomes reveals significant overlap in their protein content with immunoglobulin-bound proteins in PDAC plasmas, and significant autoantibody reactivity is observed between PDAC cell-derived exosomes and patient plasmas compared to healthy controls. Importantly, PDAC-derived exosomes induce a dose-dependent inhibition of PDAC serum-mediated complement-dependent cytotoxicity towards cancer cells. In summary, we provide evidence that exosomes display a large repertoire of tumor antigens that induce autoantibodies and exert a decoy function against complement-mediated cytotoxicity.

Novel therapeutic targets for pancreatic adenocarcinoma revealed by a multi-omics analysis of patient-derived xenografts

Novel therapeutic targets for pancreatic adenocarcinoma revealed by a multi-omics analysis of patient-derived xenografts

Selecting Tumor-Specific Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery.

PurposeThe purpose of this study was to identify suitable molecular targets for tumor-specific imaging of pancreatic adenocarcinoma.ProceduresThe expression of eight potential imaging targets was assessed by the target selection criteria (TASC)—score and immunohistochemical analysis in normal pancreatic tissue (n = 9), pancreatic (n = 137), and periampullary (n = 28) adenocarcinoma.ResultsIntegrin αvβ6, carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), and urokinase plasminogen activator receptor (uPAR) showed a significantly higher (all p < 0.001) expression in pancreatic adenocarcinoma compared to normal pancreatic tissue and were confirmed by the TASC score as promising imaging targets. Furthermore, these biomarkers were expressed in respectively 88 %, 71 %, 69 %, and 67 % of the pancreatic adenocarcinoma patients.ConclusionsThe results of this study show that integrin αvβ6, CEA, EGFR, and uPAR are suitable targets for tumor-specific imaging of pancreatic adenocarcinoma.

Cdc7 is a potent anti-cancer target in pancreatic cancer due to abrogation of the DNA origin activation checkpoint.

PurposeCdc7 is a serine/threonine kinase which is responsible for the ‘firing’ of replication origins leading to initiation of DNA replication. Inhibition or depletion of Cdc7 in normal cells triggers a DNA origin activation checkpoint causing a reversible G1 arrest. Here we investigate Cdc7 as a novel therapeutic target in pancreatic cancer.Experimental designCdc7 target validation was performed by immunoexpression profiling in a cohort of 73 patients with pancreatic adenocarcinoma including 24 controls. Secondly Cdc7 kinase was targeted in Capan-1 and PANC-1 pancreatic cancer cell line models using either an siRNA against Cdc7 or alternatively a small molecule inhibitor (SMI) of Cdc7 (PHA-767491).ResultsCdc7 was significantly overexpressed in pancreatic adenocarcinoma compared to benign pancreatic tissue (median LI 34.3% vs. 1.3%; P<0.0001). Cdc7 knockdown using siRNA in Capan-1 and PANC-1 cells resulted in marked apoptotic cell death when compared with control cells. A prominent sub-G1 peak was seen on flow cytometry (sub-G1 51% vs. 3% and 45% vs. 0.7% in Capan-1 and PANC-1 cells, respectively). Annexin V labelling confirmed apoptosis in 64% vs. 11% and 75% vs. 8%, respectively. Western blotting showed cleavage of PARP-1 and caspase-3 and presence of γH2A.X. TUNEL assay showed strong staining in treated cells. These results were mirrored following Cdc7 kinase inhibition with PHA-767491.ConclusionsOur findings show that Cdc7 is a potent anti-cancer target in pancreatic adenocarcinoma and that Cdc7 immunoexpression levels might be used as a companion diagnostic to predict response to therapeutic siRNAs or SMIs directed against this kinase.