scholarly journals Precision Therapy of Pancreatic Cancer: From Bench to Bedside

2020 ◽  
Vol 36 (5) ◽  
pp. 373-380
Author(s):  
Katrin Jana Ciecielski ◽  
Alexandra Berninger ◽  
Hana Algül
Keyword(s):  
Pancreatic Cancer ◽  
Targeted Therapy ◽  
Molecular Mechanisms ◽  
Diagnostic Methods ◽  
Ductal Adenocarcinoma ◽  
Ongoing Research ◽  
Precision Therapy ◽  
Recent Developments ◽  
Palliative Setting ◽  
Insight Into

<b><i>Background:</i></b> Pancreatic ductal adenocarcinoma (PDAC), with a mortality rate of 94% and a 5-year-survival rate of only 8%, is one of the deadliest cancer entities worldwide, and early diagnostic methods as well as effective therapies are urgently needed. <b><i>Summary:</i></b> This review summarizes current clinical procedure and recent developments of oncological therapy in the palliative setting of metastatic PDAC. It further gives examples of successful, as well as failed, targeted therapy approaches and finally discusses promising ongoing research into the decade-old question of the “undruggability” of KRAS. <b><i>Key Messages:</i></b> Bench-driven concepts change the clinical landscape from “one size fits all” towards precision medicine. With growing insight into the molecular mechanisms of pancreatic cancer the era of targeted therapy in PDAC is gaining a new momentum.

scholarly journals Autophagy as a therapeutic target in pancreatic cancer

2020 ◽  
Author(s):  
Max Piffoux ◽  
Erwan Eriau ◽  
Philippe A. Cassier
Keyword(s):  
Targeted Therapy ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Adenocarcinoma ◽  
Extracellular Signal ◽  
Anti Cancer ◽  
Mitogen Activated Protein ◽  
Cellular Components

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterised by early metastasis and resistance to anti-cancer therapy, leading to an overall poor prognosis. Despite continued research efforts, no targeted therapy has yet shown meaningful efficacy in PDAC; mutations in the oncogene KRAS and the tumour suppressor TP53, which are the most common genomic alterations in PDAC, have so far shown poor clinical actionability. Autophagy, a conserved process allowing cells to recycle altered or unused organelles and cellular components, has been shown to be upregulated in PDAC and is implicated in resistance to both cytotoxic chemotherapy and targeted therapy. Autophagy is thus regarded as a potential therapeutic target in PDAC and other cancers. Although the molecular mechanisms of autophagy activation in PDAC are only beginning to emerge, several groups have reported interesting results when combining inhibitors of the extracellular-signal-regulated kinase/mitogen-activated protein kinase pathway and inhibitors of autophagy in models of PDAC and other KRAS-driven cancers. In this article, we review the existing preclinical data regarding the role of autophagy in PDAC, as well as results of relevant clinical trials with agents that modulate autophagy in this cancer.

Abstract CT156: Novel neoadjuvant targeted therapy trial yields insight into molecular mechanisms of response

2017 ◽  
Author(s):  
Scott E. Woodman ◽  
Peter Prieto ◽  
Miles C. Andrews ◽  
Rodabe N. Amaria ◽  
Michael Tetzlaff ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Molecular Mechanisms ◽  
Therapy Trial ◽  
Insight Into

Early Detection and Biomarkers in Pancreatic Cancer

2007 ◽  
Vol 5 (10) ◽  
pp. 1034-1041 ◽  
Author(s):  
David E. Misek ◽  
Tasneem H. Patwa ◽  
David M. Lubman ◽  
Diane M. Simeone
Keyword(s):  
Pancreatic Cancer ◽  
Early Detection ◽  
Cancer Control ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Protein Biomarkers ◽  
Recent Developments ◽  
New Biomarkers ◽  
Low Sensitivity ◽  
Sensitivity Specificity

Major advances in cancer control will be greatly aided by early detection for diagnosing and treating cancer in its preinvasive state before metastasis. Unfortunately, for pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer-related death in the United States, effective early detection and screening are currently not available and tumors are typically diagnosed at a late stage, frequently after metastasis. Partly because of low sensitivity/specificity, existing biomarkers such as CA19-9 are not adequate as early detection markers of pancreatic cancer. Thus, a great need exists for new biomarkers for pancreatic cancer. This article focuses on recent developments in the identification of new serum protein biomarkers that are useful in the early detection of PDAC.

scholarly journals SOX9 is a critical regulator of TSPAN8-mediated metastasis in pancreatic cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Junjian Li ◽  
Xiaoliang Chen ◽  
Liqun Zhu ◽  
Zhenghong Lao ◽  
Tianhao Zhou ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Tumor Stage ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Endogenous Expression ◽  
Egfr Tyrosine Kinase Inhibitors

AbstractPancreatic ductal adenocarcinoma (PDAC) is the deadliest cancer mainly owing to its proclivity to early metastasis and the lack of effective targeted therapeutic drugs. Hence, understanding the molecular mechanisms underlying early invasion and metastasis by PDAC is imperative for improving patient outcomes. The present study identified that upregulation of TSPAN8 expression in PDAC facilitates metastasis in vivo and in vitro. We found SOX9 as a key transcriptional regulator of TSPAN8 expression in response to EGF stimulation. SOX9 modulation was sufficient to positively regulate endogenous expression of TSPAN8, with concomitant in vitro phenotypic changes such as loss of cell–matrix adherence and increased invasion. Moreover, increased SOX9 and TSPAN8 levels were shown to correlate in human pancreatic cancer specimens and downregulated in vitro by EGFR tyrosine kinase inhibitors. High expression of SOX9 and TSPAN8 has been associated with tumor stage, poor prognosis and poor patient survival in PDAC. In conclusion, this study highlights the importance of the EGF-SOX9-TSPAN8 signaling cascade in the control of PDAC invasion and implies that TSPAN8 may be a promising novel therapeutic target for the treatment of PDAC.

scholarly journals Loss of p53 tumor suppression function drives invasion and genomic instability in models of murine pancreatic cancer

2022 ◽  
Author(s):  
Claudia Tonelli ◽  
Astrid Deschênes ◽  
Melissa A. Yao ◽  
Youngkyu Park ◽  
David A. Tuveson
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Treatment Options ◽  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
Wild Type

Pancreatic ductal adenocarcinoma (PDA) is a deadly disease with few treatment options. There is an urgent need to better understand the molecular mechanisms that drive disease progression, with the ultimate aim of identifying early detection markers and clinically actionable targets. To investigate the transcriptional and morphological changes associated with pancreatic cancer progression, we analyzed the KrasLSLG12D/+; Trp53LSLR172H/+; Pdx1-Cre (KPC) mouse model. We have identified an intermediate cellular event during pancreatic carcinogenesis in the KPC mouse model of PDA that is represented by a subpopulation of tumor cells that express KrasG12D, p53R172H and one allele of wild-type Trp53. In vivo, these cells represent a histological spectrum of pancreatic intraepithelial neoplasia (PanIN) and acinar-to-ductal metaplasia (ADM) and rarely proliferate. Following loss of wild-type p53, these precursor lesions undergo malignant de-differentiation and acquire invasive features. We have established matched organoid cultures of pre-invasive and invasive cells from murine PDA. Expression profiling of the organoids led to the identification of markers of the pre-invasive cancer cells in vivo and mechanisms of disease aggressiveness.

scholarly journals Identification of prognostic risk factors for pancreatic cancer using bioinformatics analysis

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9301
Author(s):  
Dandan Jin ◽  
Yujie Jiao ◽  
Jie Ji ◽  
Wei Jiang ◽  
Wenkai Ni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Gene Networks ◽  
Molecular Mechanisms ◽  
Functional Module ◽  
Disease Free Survival ◽  
Ductal Adenocarcinoma ◽  
Literature Mining ◽  
Ppi Network ◽  
Hub Genes

Background Pancreatic cancer is one of the most common malignant cancers worldwide. Currently, the pathogenesis of pancreatic cancer remains unclear; thus, it is necessary to explore its precise molecular mechanisms. Methods To identify candidate genes involved in the tumorigenesis and proliferation of pancreatic cancer, the microarray datasets GSE32676, GSE15471 and GSE71989 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between Pancreatic ductal adenocarcinoma (PDAC) and nonmalignant samples were screened by GEO2R. The Database for Annotation Visualization and Integrated Discovery (DAVID) online tool was used to obtain a synthetic set of functional annotation information for the DEGs. A PPI network of the DEGs was established using the Search Tool for the Retrieval of Interacting Genes (STRING) database, and a combination of more than 0.4 was considered statistically significant for the PPI. Subsequently, we visualized the PPI network using Cytoscape. Functional module analysis was then performed using Molecular Complex Detection (MCODE). Genes with a degree ≥10 were chosen as hub genes, and pathways of the hub genes were visualized using ClueGO and CluePedia. Additionally, GenCLiP 2.0 was used to explore interactions of hub genes. The Literature Mining Gene Networks module was applied to explore the cocitation of hub genes. The Cytoscape plugin iRegulon was employed to analyze transcription factors regulating the hub genes. Furthermore, the expression levels of the 13 hub genes in pancreatic cancer tissues and normal samples were validated using the Gene Expression Profiling Interactive Analysis (GEPIA) platform. Moreover, overall survival and disease-free survival analyses according to the expression of hub genes were performed using Kaplan-Meier curve analysis in the cBioPortal online platform. The relationship between expression level and tumor grade was analyzed using the online database Oncomine. Lastly, the eight snap-frozen tumorous and adjacent noncancerous adjacent tissues of pancreatic cancer patients used to detect the CDK1 and CEP55 protein levels by western blot. Conclusions Altogether, the DEGs and hub genes identified in this work can help uncover the molecular mechanisms underlying the tumorigenesis of pancreatic cancer and provide potential targets for the diagnosis and treatment of this disease.

scholarly journals Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy

Cancers ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 6 ◽  
Author(s):  
Neus Martinez-Bosch ◽  
Judith Vinaixa ◽  
Pilar Navarro
Keyword(s):  
Pancreatic Cancer ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
T Regulatory Cells ◽  
Immune Escape ◽  
Survival Rates ◽  
Ductal Adenocarcinoma ◽  
Cytokines And Chemokines ◽  
Tumor Recognition ◽  
Activated Fibroblasts

Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much of the mechanisms behind poor drug performance, as it is the main source of the cytokines and chemokines that orchestrate rapid and silent tumor progression to allow tumor cells to be isolated into an extensive fibrotic reaction, which results in inefficient drug delivery. However, since immunotherapy was proclaimed as the breakthrough of the year in 2013, the focus on the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play a part in the strong immune evasion that characterizes PDA. The PDA microenvironment is highly immunosuppressive and is basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressive cells (MDSCs), which block CD8+ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways that inhibit the immune attack as a key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy.

Copy number instability (CNI) combined with CA19-9 as a biomarker for postoperative prognostic prediction of pancreatic cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15730-e15730
Author(s):  
Qian Zhan ◽  
Dandan Ren ◽  
Beibei Mao ◽  
Xue Song ◽  
Yanna Ma ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Primary Tumor ◽  
Copy Number ◽  
Molecular Mechanisms ◽  
Tumor Tissue ◽  
Carbohydrate Antigen ◽  
Ductal Adenocarcinoma ◽  
Molecular Features ◽  
Prognostic Prediction

e15730 Background: Pancreatic cancer is one of the most aggressive human malignancies and has a poor prognosis. Large-scale studies have reported on its initiation, progression, diagnosis and prognosis. However, over the past several decades, the overall 5-year survival rate of pancreatic cancer has remained at less than 5%. Thus, the current major challenge in the postoperative management of pancreatic cancer is to identify high-risk recurrent patients. We retrospectively investigated the clinical, pathological and outcome data for 48 pancreatic cancer patients to clarify the associations of molecular mechanisms and prognosis. Methods: Eligible pancreatic cancer patients were included, and formalin-fixed paraffin-embedded (FFPE) tumor specimens and matched blood samples were collected at Ruijin Hospital, Shanghai Jiao tong University School of Medicine. Genome profiles were analyzed by using a designed 1408-gene panel based on next-generation sequencing (NGS). The copy number instability (CNI) score in primary tumor tissue was calculated to investigate the relationship between molecular features of the primary tumor and prognosis. Results: The CNI score in primary tumor tissue was positively correlated with lymph node metastasis, TP53 mutation, and early recurrence. Moreover, preoperative Carbohydrate antigen 19-9 (CA19-9) levels and CNI scores in primary tumor tissue were significant independent predictors associated with PFS in pancreatic ductal adenocarcinoma (PDAC). Finally, we performed an independent signature that includes CNI score and Carbohydrate antigen 19-9 (CA19-9) level to predict prognosis of pancreatic cancer. Conclusions: These results suggest that CNI score in primary tumor tissue is an independent predictive prognostic biomarker for PDAC. CNI combined with CA19-9 is a better predictor for postoperative prognostic prediction of pancreatic cancer.

Y RNAs: recent developments

2013 ◽  
Vol 4 (2) ◽  
pp. 103-110 ◽  
Author(s):  
Adam E. Hall ◽  
Carly Turnbull ◽  
Tamas Dalmay
Keyword(s):  
Molecular Mechanisms ◽  
Biological Function ◽  
Recent Literature ◽  
Chromosomal Dna ◽  
Cellular Processes ◽  
Recent Developments ◽  
Rna Fragments ◽  
High Conservation ◽  
Non Coding Rnas ◽  
Insight Into

AbstractNon-coding RNAs have emerged as key regulators in diverse cellular processes. Y RNAs are ∼100-nucleotide-long non-coding RNAs that show high conservation in metazoans. Human Y RNAs are known to bind to the Ro60 and La proteins to form the Ro ribonucleoprotein complex. Their main biological function appears to be in mediating the initiation of chromosomal DNA replication, regulating the autoimmune protein Ro60, and generating smaller RNA fragments following cellular stress, although the precise molecular mechanisms underlying these functions remain elusive. Here, we aim to review the most recent literature on Y RNAs and gain insight into the function of these intriguing molecules.

scholarly journals Advancement of NF-κB Signaling Pathway: A Novel Target in Pancreatic Cancer

2018 ◽  
Vol 19 (12) ◽  
pp. 3890 ◽  
Author(s):  
Kartick Pramanik ◽  
Monish Makena ◽  
Kuntal Bhowmick ◽  
Manoj Pandey
Keyword(s):  
Pancreatic Cancer ◽  
Human Cancer ◽  
Ductal Adenocarcinoma ◽  
Driver Mutations ◽  
Therapeutic Resistance ◽  
The Past ◽  
Novel Target ◽  
Novel Therapeutic Strategies ◽  
Light Chain Enhancer ◽  
Insight Into

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and is the third highest among cancer related deaths. Despite modest success with therapy such as gemcitabine, pancreatic cancer incidence remains virtually unchanged in the past 25 years. Among the several driver mutations for PDAC, Kras mutation contributes a central role for its development, progression and therapeutic resistance. In addition, inflammation is implicated in the development of most human cancer, including pancreatic cancer. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is recognized as a key mediator of inflammation and has been frequently observed to be upregulated in PDAC. Several lines of evidence suggest that NF-κB pathways play a crucial role in PDAC development, progression and resistance. In this review, we focused on emphasizing the recent advancements in the involvement of NF-κB in PADC’s progression and resistance. We also highlighted the interaction of NF-κB with other signaling pathways. Lastly, we also aim to discuss how NF-κB could be an excellent target for PDAC prevention or therapy. This review could provide insight into the development of novel therapeutic strategies by considering NF-κB as a target to prevent or treat PDAC.

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