scholarly journals NF-κB and Pancreatic Cancer; Chapter and Verse

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4510
Author(s):  
John Silke ◽  
Lorraine Ann O’Reilly
Keyword(s):  
Pancreatic Cancer ◽  
Treatment Options ◽  
Pancreatic Injury ◽  
Ductal Adenocarcinoma ◽  
Cellular Activation ◽  
New Therapeutic Approaches ◽  
Cancer Cell Death ◽  
Anti Cancer ◽  
Smac Mimetics ◽  
Injury Progression

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the world’s most lethal cancers. An increase in occurrence, coupled with, presently limited treatment options, necessitates the pursuit of new therapeutic approaches. Many human cancers, including PDAC are initiated by unresolved inflammation. The transcription factor NF-κB coordinates many signals that drive cellular activation and proliferation during immunity but also those involved in inflammation and autophagy which may instigate tumorigenesis. It is not surprising therefore, that activation of canonical and non-canonical NF-κB pathways is increasingly recognized as an important driver of pancreatic injury, progression to tumorigenesis and drug resistance. Paradoxically, NF-κB dysregulation has also been shown to inhibit pancreatic inflammation and pancreatic cancer, depending on the context. A pro-oncogenic or pro-suppressive role for individual components of the NF-κB pathway appears to be cell type, microenvironment and even stage dependent. This review provides an outline of NF-κB signaling, focusing on the role of the various NF-κB family members in the evolving inflammatory PDAC microenvironment. Finally, we discuss pharmacological control of NF-κB to curb inflammation, focussing on novel anti-cancer agents which reinstate the process of cancer cell death, the Smac mimetics and their pre-clinical and early clinical trials.

scholarly journals Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer

2021 ◽  
Vol 118 (21) ◽  
pp. e2016904118
Author(s):  
Derek K. Cheng ◽  
Tobiloba E. Oni ◽  
Jennifer S. Thalappillil ◽  
Youngkyu Park ◽  
Hsiu-Chi Ting ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Success ◽  
Treatment Options ◽  
Mass Spectrometry Analysis ◽  
Ductal Adenocarcinoma ◽  
Ras Signaling ◽  
Wild Type ◽  
Feedback Mechanisms ◽  
Spectrometry Analysis ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC. Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways, and dose-limiting toxicities in normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil potential therapeutic targets. Here, we used proximity labeling to identify protein interactors of active KRAS in PDAC cells. We expressed fusions of wild-type (WT) (BirA-KRAS4B), mutant (BirA-KRAS4BG12D), and nontransforming cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 selectively interacts with membrane-bound KRASG12D, and we demonstrate that this interaction requires NF1 and SPRED2. We find that membrane RSK1 mediates negative feedback on WT RAS signaling and impedes the proliferation of pancreatic cancer cells upon the ablation of mutant KRAS. Our findings link NF1 to the membrane-localized functions of RSK1 and highlight a role for WT RAS signaling in promoting adaptive resistance to mutant KRAS-specific inhibitors in PDAC.

scholarly journals The Present Status of Immuno-Oncolytic Viruses in the Treatment of Pancreatic Cancer

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1318
Author(s):  
Scott D. Haller ◽  
Michael L. Monaco ◽  
Karim Essani
Keyword(s):  
United States ◽  
Pancreatic Cancer ◽  
Surgical Resection ◽  
Clinical Investigation ◽  
Treatment Options ◽  
Late Phase ◽  
The United States ◽  
Oncolytic Viruses ◽  
Ductal Adenocarcinoma ◽  
Treatment Regimens

Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death in Western countries. The incidence of PDAC has increased over the last 40 years and is projected to be the second leading cause of cancer death by 2030. Despite aggressive treatment regimens, prognosis for patients diagnosed with PDAC is very poor; PDAC has the lowest 5-year survival rate for any form of cancer in the United States (US). PDAC is very rarely detected in early stages when surgical resection can be performed. Only 20% of cases are suitable for surgical resection; this remains the only curative treatment when combined with adjuvant chemotherapy. Treatment regimens excluding surgical intervention such as chemotherapeutic treatments are associated with adverse effects and genetherapy strategies also struggle with lack of specificity and/or efficacy. The lack of effective treatments for this disease highlights the necessity for innovation in treatment options for patients diagnosed with early- to late-phase PDAC and immuno-oncolytic viruses (OVs) have been of particular interest since 2006 when the first oncolytic virus was approved as a therapy for nasopharyngeal cancers in China. Interest resurged in 2015 when T-Vec, an oncolytic herpes simplex virus, was approved in the United States for treatment of advanced melanoma. While many vectors have been explored, few show promise as treatment for pancreatic cancer, and fewer still have progressed to clinical trial evaluation. This review outlines recent strategies in the development of OVs targeting treatment of PDAC, current state of preclinical and clinical investigation and application.

scholarly journals Metabolic plasticity imparts erlotinib-resistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Neha Sharma ◽  
Alok Bhushan ◽  
Jun He ◽  
Gagan Kaushal ◽  
Vikas Bhardwaj
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Treatment Options ◽  
Pentose Phosphate ◽  
Metabolic Phenotype ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Resistant Cells

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant forms of cancer. Lack of effective treatment options and drug resistance contributes to the low survival among PDAC patients. In this study, we investigated the metabolic alterations in pancreatic cancer cells that do not respond to the EGFR inhibitor erlotinib. We selected erlotinib-resistant pancreatic cancer cells from MiaPaCa2 and AsPC1 cell lines. Metabolic profiling of erlotinib-resistant cells revealed a significant downregulation of glycolytic activity and reduced level of glycolytic metabolites compared to the sensitive cells. The resistant cells displayed elevated expression of the pentose phosphate pathway (PPP) enzymes involved in ROS regulation and nucleotide biosynthesis. The enhanced PPP elevated cellular NADPH/NADP+ ratio and protected the cells from reactive oxygen species (ROS)-induced damage. Inhibition of PPP using 6-aminonicotinamide (6AN) elevated ROS levels, induced G1 cell cycle arrest, and sensitized resistant cells to erlotinib. Genetic studies identified elevated PPP enzyme glucose-6-phosphate dehydrogenase (G6PD) as an important contributor to erlotinib resistance. Mechanistically, our data showed that upregulation of inhibitor of differentiation (ID1) regulates G6PD expression in resistant cells thus contributing to altered metabolic phenotype and reduced response to erlotinib. Together, our results highlight an underlying role of tumor metabolism in PDAC drug response and identify G6PD as a target to overcome drug resistance.

scholarly journals Effects of Growth Hormone on Pancreatic Cancer Derived Exosomes

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1016-A1017
Author(s):  
Prateek Kulkarni ◽  
Reetobrata Basu ◽  
John J Kopchick
Keyword(s):  
Pancreatic Cancer ◽  
Growth Hormone ◽  
Drug Resistance ◽  
Efflux Pump ◽  
Treatment Options ◽  
The Body ◽  
Ductal Adenocarcinoma ◽  
Gh Treatment ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Abstract In 2020, the National Cancer Institute (NCI) estimates 57,600 new cases and 47,050 deaths in the US due to pancreatic ductal adenocarcinoma (PDAC). A dismal 10% five-year overall survival rate in PDAC is attributed to late diagnosis, limited treatment options, a remarkably high metastasis rate, and resistance of this cancer to available therapies. Therefore, a better understanding of the mechanisms of how PDAC tumors acquire drug resistance and spread to distal parts of the body are necessary for developing novel therapeutic approaches. Exosomes, microscopic vesicles released from most cells (both tumor and non-tumor) have been recently established to play a significant role in cell to cell communication. Exosomes modulate their target cell responses systematically depending on the nature of exosomal cargoes (nucleic acids, proteins, and lipids). PDAC derived exosomes have been implicated to promote metastasis via forming a pre-metastatic niche of cells as well as enhancing drug resistance. Growth hormone (GH) secreted primarily by the pituitary gland promotes metastasis and drug resistance as shown by plethora of studies. No study has directly assessed the effect of GH on exosomal cargoes in terms of promoting metastases and drug resistance. In this report, we show that GH modulates various pancreatic cancer cell exosomal cargoes which in turn potentially amplifies tumor invasion and metastases. Our data shows that GH treatment on human and mouse PDAC cells increases the exosomal protein levels of TGFβ - a critical inducer of epithelial-to-mesenchymal transition (EMT, a process leading to metastasis). In addition, GH treatment also increases extracellular matrix-degrading enzymes, MMP2 and 9, as well as multi-drug efflux pump ABCC1, ABCB1, and ABCG2 in PDAC cells. These results strongly implicate GH action in driving EMT and chemoresistance via exosomes in pancreatic cancer. Exosomes have a crucial impact especially in the areas of diagnostics and therapeutics. This report is the first to show that GH modulates the effects of exosomes secreted by pancreatic cancer cells. Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Student Enhancement Award and Edison Biotechnology Institute.

scholarly journals Primary Thromboprophylaxis in Pancreatic Cancer Patients: Why Clinical Practice Guidelines Should Be Implemented

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 618 ◽  
Author(s):  
Dominique Farge ◽  
Barbara Bournet ◽  
Thierry Conroy ◽  
Eric Vicaut ◽  
Janusz Rak ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Practice ◽  
Cancer Patients ◽  
Clinical Practice Guidelines ◽  
Practice Guidelines ◽  
Randomized Trials ◽  
Treatment Options ◽  
Locally Advanced ◽  
Ductal Adenocarcinoma ◽  
Recent Advances

Exocrine pancreatic ductal adenocarcinoma, simply referred to as pancreatic cancer (PC) has the worst prognosis of any malignancy. Despite recent advances in the use of adjuvant chemotherapy in PC, the prognosis remains poor, with fewer than 8% of patients being alive at 5 years after diagnosis. The prevalence of PC has steadily increased over the past decades, and it is projected to become the second-leading cause of cancer-related death by 2030. In this context, optimizing and integrating supportive care is important to improve quality of life and survival. Venous thromboembolism (VTE) is a common but preventable complication in PC patients. VTE occurs in one out of five PC patients and is associated with significantly reduced progression-free survival and overall survival. The appropriate use of primary thromboprophylaxis can drastically and safely reduce the rates of VTE in PC patients as shown from subgroup analysis of non-PC targeted placebo-controlled randomized trials of cancer patients and from two dedicated controlled randomized trials in locally advanced PC patients receiving chemotherapy. Therefore, primary thromboprophylaxis with a Grade 1B evidence level is recommended in locally advanced PC patients receiving chemotherapy by the International Initiative on Cancer and Thrombosis clinical practice guidelines since 2013. However, its use and potential significant clinical benefit continues to be underrecognized worldwide. This narrative review aims to summarize the main recent advances in the field including on the use of individualized risk assessment models to stratify the risk of VTE in each patient with individual available treatment options.

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 Local Ablative Strategies for Ductal Pancreatic Cancer (Radiofrequency Ablation, Irreversible Electroporation): A Review

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Salvatore Paiella ◽  
Roberto Salvia ◽  
Marco Ramera ◽  
Roberto Girelli ◽  
Isabella Frigerio ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Radiofrequency Ablation ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Locally Advanced ◽  
Irreversible Electroporation ◽  
Advanced Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Dismal Prognosis ◽  
Ablative Techniques

Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis. Locally advanced pancreatic cancer (LAPC) accounts for the 40% of the new diagnoses. Current treatment options are based on chemo- and radiotherapy regimens. Local ablative techniques seem to be the future therapeutic option for stage-III patients with PDAC. Radiofrequency Ablation (RFA) and Irreversible Electroporation (IRE) are actually the most emerging local ablative techniques used on LAPC. Initial clinical studies on the use of these techniques have already demonstrated encouraging results in terms of safety and feasibility. Unfortunately, few studies on their efficacy are currently available. Even though some reports on the overall survival are encouraging, randomized studies are still required to corroborate these findings. This study provides an up-to-date overview and a thematic summary of the current available evidence on the application of RFA and IRE on PDAC, together with a comparison of the two procedures.

scholarly journals Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ligia I. Bastea ◽  
Laeticia M. A. Hollant ◽  
Heike R. Döppler ◽  
Elizabeth M. Reid ◽  
Peter Storz
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Treatment Options ◽  
Histone H3 ◽  
Current Treatment ◽  
Cancer Cell Death ◽  
H3 Phosphorylation ◽  
Histone H3 Phosphorylation

Abstract Current treatment options for patients with pancreatic cancer are suboptimal, resulting in a five year survival rate of about 9%. Difficulties with treatment are due to an immunosuppressive, fibrotic tumor microenvironment that prevents drugs from reaching tumor cells, but also to the limited efficacy of existing FDA-approved chemotherapeutic compounds. We here show that the nucleoside analog Sangivamycin and its closely-related compound Toyocamycin target PDA cell lines, and are significantly more efficient than Gemcitabine. Using KINOMEscan screening, we identified the kinase Haspin, which is overexpressed in PDA cell lines and human PDA samples, as a main target for both compounds. Inhibition of Haspin leads to a decrease in Histone H3 phosphorylation and prevents Histone H3 binding to survivin, thus providing mechanistic insight of how Sangivamycin targets cell proliferation, mitosis and induces apoptotic cell death. In orthotopically implanted tumors in mice, Sangivamycin was efficient in decreasing the growth of established tumors. In summary, we show that Sangivamycin and derivatives can be an efficient new option for treatment of PDA.

scholarly journals Novel 3D µtissues Mimicking the Fibrotic Stroma in Pancreatic Cancer to Study Cellular Interactions and Stroma-Modulating Therapeutics

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5006
Author(s):  
Kunal P. Pednekar ◽  
Marcel A. Heinrich ◽  
Joop van Baarlen ◽  
Jai Prakash
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Collagen Gel ◽  
Current Treatment ◽  
Ductal Adenocarcinoma ◽  
Tumor Type ◽  
Cellular Interactions

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type with low patient survival due to the low efficacy of current treatment options. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) create a dense fibrotic environment around the tumor cells, preventing therapies from reaching their target. Novel 3D in vitro models are needed that mimic this fibrotic barrier for the development of therapies in a biologically relevant environment. Here, novel PDAC microtissues (µtissues) consisting of pancreatic cancer cell core surrounded by a CAF-laden collagen gel are presented, that is based on the cells own contractility to form a hard-to-penetrate barrier. The contraction of CAFs is demonstrated facilitating the embedding of tumor cells in the center of the µtissue as observed in patients. The µtissues displayed a PDAC-relevant gene expression by comparing their gene profile with transcriptomic patient data. Furthermore, the CAF-dependent proliferation of cancer cells is presented, as well as the suitability of the µtissues to serve as a platform for the screening of CAF-modulating therapies in combination with other (nano)therapies. It is envisioned that these PDAC µtissues can serve as a high-throughput platform for studying cellular interactions in PDAC and for evaluating different treatment strategies in the future.

scholarly journals Anti-cancer effect of orally absorbable heparin on orthotopically induced exocrine and endocrine pancreatic cancer

2021 ◽  
Author(s):  
Hae Hyun Hwang ◽  
Hee Jeong Jeong ◽  
Sangwoo Yoon ◽  
Youngro Byun ◽  
Teruo Okano ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Endothelial Cells ◽  
Cancer Cells ◽  
Pancreatic Neuroendocrine Tumor ◽  
Tube Formation ◽  
Ductal Adenocarcinoma ◽  
Orthotopic Model ◽  
Pancreatic Cancers ◽  
Anti Cancer

Abstract Pancreatic cancers are classified based on where they occur into those derived from exocrine glands and endocrine glands, thereby showing different anti-cancer effect with medication. Therefore, it is necessary to develop anti-cancer drugs that can inhibit both of these types. To this end, we developed a heparin-taurocholate conjugate, i.e., LHT, to suppress tumor growth via its anti-angiogenic activity. Here we conducted a study to determine the anti-cancer efficacy of LHT on various types of pancreatic cancer, i.e., human pancreatic ductal adenocarcinoma (PDAC) and human pancreatic neuroendocrine tumor (PNET), at orthotopic animal model. LHT reduced not only proliferation of all three cancer cells, but also attenuated the production of VEGF through ERK dephosphorylation. Especially, these effects of LHT were much stronger to PNET (RINm cells). Also, LHT effectively reduced the migration, invasion and tube formation of endothelial cells via dephosphorylation of VEGFR, ERK1/2, and FAK protein. Eventually LHT reduced strongly ~ 50% tumor weights and tumor volumes of all three cancer cells at orthotopic model via anti-proliferation of cancer cells and anti-angiogenesis of endothelial cells. Interestingly, LHT was highly effective to PNET tumor tissue in vivo. Collectively, these findings demonstrated that LHT could be a potential anti-pancreatic cancer medication, regardless of pancreatic cancer types.

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