• clinical trials
• diabetes mellitus
• drug repurposing
• metformin
• pancreatic cancer
• pancreatic ductal adenocarcinoma
• risk
• survival outcomes

• Metformin/therapeutic use
• Humans
• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/pathology
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/pathology
• Hypoglycemic Agents/therapeutic use
• Randomized Controlled Trials as Topic

• cancer
• genetics
• immunology
• molecular biology
• diseases
• gastroenterology
• oncology

• Humans
• Adenocarcinoma/genetics
• CD8-Positive T-Lymphocytes
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms
• Prognosis
• RNA, Long Noncoding/genetics
• Tumor Microenvironment/genetics
• Apoptosis
• Copper

• Pancreatic Cancer
• drug repurposing
• genomics
• mutations
• precision medicine

• IL-1β
• Metformin
• Neutrophil extracellular traps
• Obesity
• TLR4

• oncology
• pancreatic cancer

• Humans
• Adaptor Proteins, Signal Transducing/metabolism
• Hedgehog Proteins/genetics
• YAP-Signaling Proteins
• Transcription Factors/genetics
• Trans-Activators/genetics
• Epithelial-Mesenchymal Transition
• Hyperglycemia
• Pancreatic Neoplasms/pathology
• Carcinoma, Pancreatic Ductal/pathology
• Phenotype
• Tumor Microenvironment
• Pancreatic Neoplasms

• JST SPRING, Grant Number JPMJSP2127
• Takeda Science Foundation
• Grant-in-Aid for Scientists (C); the Ministry of Education, Culture, Sports, Science, and Technology of Japan, No. 19K09177 Japanese Foundation for Multidisciplinary Treatment of Cancer, Japan

• Diabetes mellitus
• Meta-analysis
• Metformin
• Pancreatic cancer

• extracellular matrix
• immune cells
• metabolism
• mitochondria
• pancreatic ductal adenocarcinoma
• retrograde signaling
• therapy

The incidence of type 2 diabetes mellitus (T2DM) and its potential complications, such as cancers, are increasing worldwide at an astounding rate. There are many factors such as obesity, diabetes, alcohol consumption, and the adoption of sedentary lifestyles that are driving pancreatic cancer (PC) to become one of the leading causes of cancer mortality in the United States. PC is notorious for its generic symptoms and late-stage presentation with rapid metastasis. The connection between T2DM and the risk of PC development is multifaceted and complex. Some of the proposed theories reveal that chronic inflammation, insulin resistance, hyperinsulinemia, hyperglycemia, and abnormalities in the insulin and insulin-like growth factor axis (IGF) contribute to the disease association between these two conditions. This literature review aims to highlight relevant studies and explore the molecular mechanisms involved in the etiology of diabetes and its impact on PC development, as well as the role of anti-diabetic agents on PC. Despite extensive studies, the exact interaction between T2DM and PC remains obscure and will need further investigation. According to current knowledge, there is a substantial link between diabetes, obesity, and dietary patterns in the development and progression of PC. Consequently, focusing our efforts on preventive measures by reducing modifiable risk factors remains the most effective strategy to reduce the risk of PC at this time. Antidiabetic drugs can have various effects on the occurrence and prognosis of PC with metformin offering a clear benefit of inhibiting PC and insulin increasing the risk of PC. The development of future novel therapies will require a deeper knowledge of the triggering mechanisms and interplay between these two disease states.

Pancreatic cyst neoplasm (PCN) is a precursor of pancreatic cancer. Previous studies reported PCN was often concurrent with diabetes. We aim to examine the association between diabetes with PCN malignancy and to detect the potential role of diabetes in PCN management and treatment.

A total of 224 patients who were diagnosed with the three major types of PCN (IPMN, MCN, and SCN) and underwent surgical resection were selected. Patients were divided into three groups (normal group, new-onset diabetes group (NODM) (<4years), and long-standing diabetes group (LSDM) (>4years)) according to diabetic history and diagnostic time interval. Diabetes, fast blood glucose level, HbA1c, and insulin resistance level were measured. Malignant PCN (mPCN) radiological features (worrisome features and high-risk stigmata) were analyzed. Pathological features (PCN type, dysplasia grade, tumor stage, and tumor volume) and immunohistology of Ki67 and SMAD4 were performed. Diagnostic efficacy of each variable was determined by the ROC curve. mPCN diagnosis was the main outcome in diagnostic prediction and overall survival as the glucose controlling outcome variables.

Diabetes groups (NODM and LSDM) showed difference with the normal group in age, weight loss, malignancy, CA19-9 value, CEA value, Ki-67 value, tumor volume, pathological grade, and a lowered pancreatic fistula risk. NODM was related to insulin resistance, weight loss, and SMAD4 mutation. NODM (87.3%) and high insulin resistance rate (93.6%) significantly increased the sensitivity of radiological evidence-based mPCN diagnosis. Moreover, long-standing diabetes and elevated HbA1c led to reduced survival in mPCN patients than the normal PCN group. Anti-diabetic drugs showed limited influence on PCN malignancy and tumor volume.

NODM in PCN patients was associated with malignancy, insulin resistance, weight loss, and SMAD4 mutation. Prediabetic status and NODM diagnosis enhanced the diagnostic accuracy of radiological standards (worrisome features and high-risk stigmata). Stable glucose surveillance is necessary for mPCN patients’ survival.

• funded by the National Natural Science Foundation of China

• Aged
• Humans
• Medicare
• Metformin/adverse effects
• Prospective Studies
• Retrospective Studies
• SEER Program
• Sarcoma/pathology
• Soft Tissue Neoplasms/pathology
• United States/epidemiology

• anti-diabetic drugs
• diabetes mellitus
• pancreatic cancer
• weight loss
• 减肥
• 糖尿病
• 胰腺癌
• 降糖药物

• Age of Onset
• Diabetes Mellitus
• Diabetes Mellitus, Type 2/complications
• Humans
• Hypoglycemic Agents
• Pancreatic Neoplasms/complications
• Retrospective Studies
• Risk Factors
• Weight Loss
• Pancreatic Neoplasms

• 2014CB542300 Major State Basic Research Development Program of China
• Major State Basic Research Development Program of China

• Insulin
• cancer metabolism
• diabetes mellitus
• hyperinsulinemia
• pancreatic ductal adenocarcinoma

• National Natural Science Foundation of China

Pancreatic cancer (PC) is often associated with a poor prognosis. Long-standing diabetes mellitus is considered as an important risk factor for its development. This risk can be modified by the use of certain antidiabetic medications. On the other hand, new-onset diabetes can signal towards an underlying PC in the elderly population. Recently, several attempts have been made to develop an effective clinical tool for PC screening using a combination of history of new-onset diabetes and several other clinical and biochemical markers. On the contrary, diabetes affects the survival after treatment for PC. We describe this intimate and complex two-way relationship of diabetes and PC in this review by exploring the underlying pathogenesis.

• Chronic pancreatitis
• Diabetes
• New onset diabetes
• Pancreatic adenocarcinoma
• Pancreatic cancer
• Type 3c diabetes

• Aged
• Diabetes Mellitus/diagnosis
• Diabetes Mellitus/epidemiology
• Early Detection of Cancer
• Humans
• Hypoglycemic Agents/therapeutic use
• Pancreatic Neoplasms/epidemiology
• Risk Factors

Pancreatic cancer is one of the common cancers globally, with a poor survival outcome. Metformin, a popular anti-diabetic drug, has gained popularity for its use in the chemoprevention of cancer. However, results regarding the survival benefit of metformin in pancreatic cancer have been unpredictable. In this review, we aim to analyze the use of metformin in pancreatic cancer patients with pre-existing diabetes mellitus for survival benefit. We systematically conducted a literature search in PubMed, Science Direct, and Scopus databases to collect the relevant articles and reviewed them. Eventually, 11 quality appraised articles were included accessing overall survival as the primary outcome. Our results concluded that metformin can efficaciously improve survival in pancreatic cancer patients with coexisting diabetes mellitus, but the results are still incongruent. Hence, further prospective studies and clinical trials are essential to provide a strong evidence-based recommendation that will help prolong the lifespan of patients.

• antidiabetic drugs
• diabetes mellitus
• metformin
• pancreatic cancer
• survival

Bisphosphonates are increasingly recognized for their anti-neoplastic properties, which are the result of their action on the mevalonate pathway. Our primary aim was to investigate the association between bisphosphonate use and survival in patients with pancreatic cancer. Since statins also act on the mevalonate pathway, we also investigated the effect of the combined use of bisphosphonates and statins on survival.

The Surveillance, Epidemiology, and End Results registry (SEER)-Medicare linked database was used to identify patients with pancreatic ductal adenocarcinoma (PDAC) between 2007 and 2015. Kaplan-Meier models were used to examine the association between survival with bisphosphonate use alone and in combination with statins within 1 year prior to the diagnosis of PDAC. Propensity score matching analysis and Cox-proportional hazard models were used to determine the association between overall survival with bisphosphonate use alone and combined with statins, after adjusting for relevant confounders, such as the Charlson comorbidity index score, stage, treatment, sociodemographic characteristics, and propensity score.

In total, 13,639 patients with PDAC were identified, and 1,203 (8.82%) used bisphosphonates. There was no difference in the mean survival duration between bisphosphonate users (7.27 months) and nonusers (7.25 months, p=0.61). After adjustment for confounders, bisphosphonate use was still not associated with improved survival (hazard ratio, 1.00; 95% confidence interval, 0.93 to 1.08; p=0.96). Combined bisphosphonate and statin use was also not associated with improved survival (hazard ratio, 0.97; 95% confidence interval, 0.87 to 1.07; p=0.48) after adjustment for confounders.

Our findings suggest that the use of bisphosphonates, whether alone or in combination with statins, does not confer a survival advantage in patients with PDAC. (Gut Liver 2021;15-790)

• Bisphosphonate
• Pancreas
• Statin
• Survival

Previous studies have suggested that β-adrenergic signaling may regulate the growth of various cancers. The aim of our study is to investigate the association between the incidental use of beta-blockers for various conditions on the overall survival of patients with pancreatic ductal adenocarcinoma (PDAC). Patients with histologically-confirmed PDAC between 2007 and 2011 were extracted from Surveillance, Epidemiology, and End Results registry (SEER)-Medicare linked database. Kaplan Meier and multivariable Cox Proportional-Hazard models were used to examine the association between beta-blocker usage before diagnosis and overall survival adjusting for appropriate confounders. As an additional analysis we also examined continuous beta-blocker use before and after diagnosis. From 2007 to 2011, 13,731 patients were diagnosed with PDAC. Of these, 7130 patients had Medicare Part D coverage in the 6-month period before diagnosis, with 2564 (36%) of these patients using beta-blockers in this period. Patients receiving beta-blockers had a mean survival time of 5.1 months compared to 6 months for non-users (p < 0.01). In multivariable analysis, beta-blockers usage was not associated with improved survival (Hazard Ratio (HR) 1.04, 95%, Confidence Interval (CI) 0.98–1.1, p = 0.2). When patients were stratified by conditions with indications for beta-blocker usage, such as hypertension, coronary artery disease and cardiac arrhythmia, differences in survival were insignificant compared to non-users in all groups (p > 0.05). After stratification by receptor selectivity, this lack of association with survival persisted (p > 0.05 for all). As a subgroup analysis, looking at patients with continuous Medicare Part D coverage who used beta-blockers in the 6-month period before and after cancer diagnosis, we identified 7085 patients, of which 1750 (24.7%) had continuous beta blocker use. In multivariable analysis, continuous beta-blockers usage was associated with improved survival (Hazard Ratio (HR) 0.86, 95%, Confidence Interval (CI) 0.8–0.9, p < 0.01). Beta-blocker usage before diagnosis does not confer a survival advantage in patients with PDAC, though continuous use before and after diagnosis did confer a survival advantage. Prospective studies into the mechanism for this advantage are needed.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant tumors due to the absence of biomarkers for early-stage detection and poor response to therapy. Since mounting evidence supports the role of microbiota composition in tumorigenesis and cancer treatment, the link between microbiome and PDAC has been described. In this review, we summarize the current knowledge regarding the impact of the gut and oral microbiome on the risk of PDAC development. Microenvironment-driven therapy and immune system interactions are also discussed. More importantly, we provide an overview of the clinical trials evaluating the microbiota role in the risk, prognosis, and treatment of patients suffering from PDAC and solid tumors. According to the research findings, immune tolerance might result from the microbiota-derived remodeling of pancreatic tumor microenvironment. Thus, microbiome profiling and targeting represent the potential trend to enhance antitumor immunity and improve the efficacy of PDAC treatment.

• cancer treatment
• immune suppression
• microbiota modulation
• pancreatic ductal adenocarcinoma (PDAC)
• pancreatic microbiome
• tumor microenvironment

Emerging evidence demonstrates that surveillance of individuals at high-risk (HRIs) of developing pancreatic adenocarcinoma allows for identification and treatment of resectable tumors with improved survival. Population-based data suggest that hyperglycemia may be present up to three years before the development of pancreatic cancer. We investigated whether elevated hemoglobin A1c (HbA1c) is associated with the development of pancreatic cysts in a pancreatic surveillance program.

We performed a retrospective study of HRIs who underwent pancreatic surveillance at a single institution between May 2013 and March 2019, according to published criteria. We collected demographic information, clinical data including HbA1c, and imaging results. We compared data using univariable and multivariable analyses. Our primary outcome was the presence of pancreatic cysts on initial surveillance in patients with elevated HbA1c.

Ninety-eight patients underwent surveillance imaging via EUS or MRCP and seventy-four patients met inclusion criteria. Thirty patients were found to have cysts on initial imaging. Older age (p < 0.01) and HbA1c in the prediabetic range or higher (p = 0.01) were associated with the presence of cysts or solid lesions on univariable analysis. After controlling for confounders, age (aOR 9.08, 95% CI 2.29–36.10), and HbA1c > 5.7% (aOR 5.82, 95% CI 1.50–22.54) remained associated with presence of cysts and solid lesions in HRIs. In patients with cysts or solid lesions there was a strong association between increased age and elevated HbA1c (p < 0.01).

HRIs with elevated HbA1c were more likely to have pancreatic cysts compared to individuals with lower HbA1c on initial imaging in a pancreatic surveillance program. These findings may help tailor the surveillance protocols for those at increased risk of developing pancreatic adenocarcinoma.

• Chemo therapy
• Combination therapy
• Phytochemicals
• Repurposed drug

Recently, there have been several randomized clinical trials (RCTs) conducted to evaluate the efficacy and safety of metformin plus standard treatment in inoperable cancer patients. Our meta-analysis aimed to assess the efficacy of metformin in combination with standard treatment in inoperable cancer patients.

PubMed and Embase databases were systematically searched for relevant RCTs investigating the efficacy of adding metformin to standard treatment for cancer patients. The pooled relative risk (RR) for tumor response and safety was calculated to assess the efficacy of combining metformin with standard treatment. Meta-analysis was subsequently performed to pool the hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS).

Ten RCTs comprising 1033 patients were included in our current meta-analysis. In patients with breast cancer, results of meta-analysis showed that the addition of metformin to standard treatment was beneficial to objective response rate (ORR) with 30.3% (33/109) in the metformin plus standard treatment group and 16.1% (18/112) in the placebo group (RR 1.92, 95% CI: 1.19–3.10, P=0.008). OS and PFS were not significantly improved in patients who received metformin plus standard treatment compared with those who received placebo plus standard treatment (OS: HR 1.02, 95% CI: 0.71–1.46, P=0.916; PFS: HR 1.14, 95% CI: 0.86–1.50, P=0.366). For lung cancer patients, meta-analysis results showed adding metformin to standard treatment could benefit ORR (metformin 65.3% vs. placebo 54.6%, RR 1.22, 95% CI: 1.03–1.43, P=0.018) with no significant survival benefit in the metformin group. For patients with pancreatic cancer, the pooled ORR was 17.6% (16/91) in metformin plus standard treatment group and 20% (18/90) in the placebo group, indicating metformin did not benefit ORR (RR 0.85, 95% CI: 0.49–1.49, P=0.576). Besides, the addition of metformin to standard treatment did not increase the incidence rate of adverse effects.

Our results indicated that addition of metformin to standard treatment was beneficial to ORR in inoperable breast or lung cancer patients without increasing the incidence of adverse effects. However, adding metformin to standard treatment could not benefit OS and PFS.

• Metformin
• cancer
• meta-analysis
• overall survival (OS)
• progression-free survival (PFS)

• Autophagy
• Exosomes
• GBM
• Metformin
• U87 MG

• diabetes mellitus
• meta-analysis
• metformin
• pancreatic cancer
• survival

• Aged
• Clinical Trials as Topic
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/drug therapy
• Female
• Humans
• Hypoglycemic Agents/therapeutic use
• Male
• Metformin/therapeutic use
• Middle Aged
• Pancreatic Neoplasms/complications
• Pancreatic Neoplasms/mortality
• Proportional Hazards Models
• Survival Rate

Objective: To evaluate the survival benefit of metformin use for pancreatic cancer (PC) patients underwent pancreatectomy.

Methods: Databases including EMBASE, PubMed, the Cochrane Library were searched to identify studies relevant to the outcomes on the survival benefit of metformin use for the PC patients who underwent pancreatectomy until June 30, 2019. STATA 12.0 software was used to performed the meta-analysis.

Results: 12 studies involving 35,346 PC patients were included in this meta-analysis. With a random-model, there are significant differences in overall survival (HR = 0.85, 95% CI: 0.77–0.94, P = 0.002) between PC patients who were treated with metformin underwent pancreatectomy and those who underwent pancreatectomy without metformin use. Subgroup analyses showed Caucasians (HR = 0.903, 95% CI = 0.825–0.940, P = 0.008) and Asian (HR = 0.691, 95% CI = 0.588–0.813, P = 0.001) PC patients have a significantly reduced risk of death for metformin users. Subgroup analyses also showed a survival benefit for PC patients at stage I-II (HR = 0.762, 95% CI = 0.677–0.858, P = 0.0001).

Conclusions: Metformin use is related to a better survival benefit for PC patients who underwent pancreatectomy, which would be a potential drug for the treatment of PC.

• meta-analysis
• metformin
• overall survival
• pancreatectomy
• pancreatic cancer

Background: We assessed the association between the use of metformin and other antihyperglycemic medications on overall survival in diabetic patients with pancreatic cancer. Methods: Patients with pancreatic cancer and diabetes between 2000 and 2015 were identified from the Lithuanian Cancer Registry and the National Health Insurance Fund database. Cohort members were classified into six groups according to type 2 diabetes mellitus treatment: sulfonylurea monotherapy; metformin monotherapy; insulin monotherapy; metformin and sulfonylurea combination; metformin and other antihyperglycemic medications; all other combinations of oral antihyperglycemic medications. Survival was calculated from the date of cancer diagnosis to the date of death or the end of follow-up (31 December 2018). Results: Study group included 454 diabetic patients with pancreatic cancer. We found no statistically significant differences in overall survival between patients by glucose-lowering therapy. However, highest mortality risk was observed in patients on insulin monotherapy, and better survival was observed in the groups of patients using antihyperglycemic medication combinations, metformin alone, and metformin in combination with sulfonylurea. Analysis by cumulative dose of metformin showed significantly lower mortality risk in the highest cumulative dose category (HR 0.76, 95% CI 0.58–0.99). Conclusions: Our study showed that metformin might have a survival benefit for pancreatic cancer patients, suggesting a potentially available option for the treatment.

• antihyperglycemic medications
• metformin
• pancreatic cancer
• population-based study

• Aged
• Aged, 80 and over
• Cohort Studies
• Diabetes Mellitus, Type 2/complications
• Female
• Humans
• Hypoglycemic Agents/therapeutic use
• Male
• Middle Aged
• Pancreatic Neoplasms/complications
• Pancreatic Neoplasms/mortality
• Patients
• Retrospective Studies

Cancer cells reprogram their metabolism to meet bioenergetics and biosynthetic demands. The first observation of metabolic reprogramming in cancer cells was made a century ago (“Warburg effect” or aerobic glycolysis), leading to the classical view that cancer metabolism relies on a glycolytic phenotype. There is now accumulating evidence that most cancers also rely on mitochondria to satisfy their metabolic needs. Indeed, the current view of cancer metabolism places mitochondria as key actors in all facets of cancer progression. Importantly, mitochondrial metabolism has become a very promising target in cancer therapy, including for refractory cancers such as Pancreatic Ductal AdenoCarcinoma (PDAC). In particular, mitochondrial oxidative phosphorylation (OXPHOS) is an important target in cancer therapy. Other therapeutic strategies include the targeting of glutamine and fatty acids metabolism, as well as the inhibition of the TriCarboxylic Acid (TCA) cycle intermediates. A better knowledge of how pancreatic cancer cells regulate mitochondrial metabolism will allow the identification of metabolic vulnerabilities and thus novel and more efficient therapeutic options for the benefit of each patient.

• OXPHOS
• biguanides
• cancer metabolism
• energetic metabolism
• metabolic heterogeneity
• mitochondria
• mitochondrial complex I
• mitochondrial metabolism
• pancreatic ductal adenocarcinoma
• therapeutic strategy

Retrospective studies on the association between metformin and clinical outcomes have mainly been performed on patients with non-resectable pancreatic ductal adenocarcinoma and may have been affected by time-related bias. To avoid this bias, recent studies have used time-varying analysis; however, they have only considered the start date of metformin use and not the stop date. We studied 283 patients with type 2 diabetes and pancreatic ductal adenocarcinoma following pancreaticoduodenectomy, and performed analysis using a Cox model with time-varying covariates, while considering both start and stop dates of metformin use. When start and stop dates were not considered, the metformin group showed significantly better survival. Compared with previous studies, adjusted analysis based on Cox models with time-varying covariates only considering the start date of postoperative metformin use showed no significant differences in survival. However, although adjusted analysis considering both start and stop dates showed no significant difference in recurrence-free survival, the overall survival was significantly better in the metformin group (Hazard ratio (HR), 0.747; 95% confidence interval (CI), 0.562–0.993; p = 0.045). Time-varying analysis incorporating both start and stop dates thus revealed that metformin use is associated with a higher overall survival following pancreaticoduodenectomy in patients with type 2 diabetes and pancreatic ductal adenocarcinoma.

• metformin
• pancreatic cancer
• pancreaticoduodenectomy
• type 2 diabetes

• Carcinoembryonic antigen
• Diabetes mellitus
• Metformin
• Pancreatic ductal adenocarcinoma

• Diabetes mellitus
• Meta-analysis
• Overall survival
• Pancreatic cancer

• Case-Control Studies
• Chemotherapy, Adjuvant
• Diabetes Complications/diagnosis
• Diabetes Complications/drug therapy
• Diabetes Complications/epidemiology
• Diabetes Mellitus/diagnosis
• Diabetes Mellitus/drug therapy
• Diabetes Mellitus/epidemiology
• Diabetes Mellitus/pathology
• Humans
• Neoplasm Staging
• Pancreatic Neoplasms/complications
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/epidemiology
• Prognosis
• Treatment Outcome

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, with a five-year survival rate of around 5% to 8%. To date, very few available drugs have been successfully used to treat PDAC due to the poor understanding of the tumor-specific features. One of the hallmarks of pancreatic cancer cells is the deregulated cellular energetics characterized by the “Warburg effect”. It has been known for decades that cancer cells have a dramatically increased glycolytic flux even in the presence of oxygen and normal mitochondrial function. Glycolytic flux is the central carbon metabolism process in all cells, which not only produces adenosine triphosphate (ATP) but also provides biomass for anabolic processes that support cell proliferation. Expression levels of glucose transporters and rate-limiting enzymes regulate the rate of glycolytic flux. Intermediates that branch out from glycolysis are responsible for redox homeostasis, glycosylation, and biosynthesis. Beyond enhanced glycolytic flux, pancreatic cancer cells activate nutrient salvage pathways, which includes autophagy and micropinocytosis, from which the generated sugars, amino acids, and fatty acids are used to buffer the stresses induced by nutrient deprivation. Further, PDAC is characterized by extensive metabolic crosstalk between tumor cells and cells in the tumor microenvironment (TME). In this review, we will give an overview on recent progresses made in understanding glucose metabolism-related deregulations in PDAC.

• glucose metabolism
• pancreatic cancer

• R01 CA214793 NCI NIH HHS
• R01CA214793 NCI NIH HHS
• 17-20-25-YING Pancreatic Cancer Action Network
• 16-70-25-YAO Pancreatic Cancer Action Network

• bidirectional relationship
• pancreatic cancer
• type 2 diabetes

• Obstructive Jaundice
• Outcome
• Pancreatic Adenocarcinoma
• Stent

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC. Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network. Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.

• Pancreatic cancer
• Yes-associated protein and WW-domain-containing transcriptional co-activator with PDZ-binding motif
• Oncogenic Kras
• Obesity
• Signaling network and loops

• Adaptor Proteins, Signal Transducing/antagonists & inhibitors
• Adaptor Proteins, Signal Transducing/metabolism
• Animals
• Carcinogenesis/drug effects
• Carcinogenesis/genetics
• Carcinogenesis/pathology
• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/genetics
• Carcinoma, Pancreatic Ductal/mortality
• Carcinoma, Pancreatic Ductal/pathology
• Drug Repositioning
• Gene Expression Regulation, Neoplastic
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Intracellular Signaling Peptides and Proteins/antagonists & inhibitors
• Intracellular Signaling Peptides and Proteins/metabolism
• Metformin/pharmacology
• Metformin/therapeutic use
• Molecular Targeted Therapy/methods
• Mutation
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/pathology
• Phosphoproteins/antagonists & inhibitors
• Phosphoproteins/metabolism
• Prognosis
• Proto-Oncogene Proteins p21(ras)/genetics
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Trans-Activators
• Transcription Factors
• Transcription, Genetic/drug effects
• Transcription, Genetic/genetics
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• YAP-Signaling Proteins

Endoscopic retrograde cholangiopancreatography (ERCP) is the recommended technique for biliary decompression in pancreatic cancer. Previous studies have suggested racial, socioeconomic and geographic differences in diagnosis, treatment and outcomes of pancreatic cancer patients.

To examine geographic, racial, socioeconomic and clinical factors associated with utilization of ERCP.

Surveillance, Epidemiology and End Results and linked Medicare claims data were used to identify pancreatic cancer patients between 2000-2011. Claims data were used to identify patients who had ERCP and other treatments. The primary outcome was receipt of ERCP. Chi-squared analyses were used to compare demographic information. Trends in use of ERCP over time were assessed using Cochran Armitage test. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for receipt ERCP were calculated using logistic regression, controlling for other characteristics.

Among 32510 pancreatic cancer patients, 14704 (45.2%) underwent ERCP. Patients who had cancer located in the head of the pancreas (aOR 3.27, 95%CI: 2.99-3.57), had jaundice (aOR 7.59, 95%CI: 7.06-8.17), cholangitis (aOR 4.22, 95%CI: 3.71-4.81) or pruritus (aOR 1.42, 95%CI: 1.22-1.66) and lived in lower education zip codes (aOR 1.14, 95%CI: 1.04-1.24) were more likely to receive ERCP. In contrast, patients who were older (aOR 0.88, 95%CI: 0.83, 0.94), not married (aOR 0.92, 95%CI: 0.86, 0.98), and lived in a non-metropolitan area (aOR 0.89, 95%CI: 0.82, 0.98) were less likely to receive ERCP. Compared to white patients, non-white/non-black patients (aOR 0.83, 95%CI: 0.70-0.97) were less likely to receive ERCP. Patients diagnosed later in the study period were less likely to receive ERCP (aOR 2004-2007 0.85, 95%CI: 0.78-0.92; aOR 2008-2011 0.76, 95%CI: 0.70-0.83). After stratifying by indications for ERCP including jaundice, racial differences persisted (aOR black patients 0.80, 95%CI: 0.67-0.95, nonwhite/nonblack patients 0.73, 95%CI: 0.58-0.91). Among patients with jaundice, those who underwent surgery were less likely to undergo ERCP (aOR 0.60, 95%CI: 0.52, 0.69).

ERCP utilization in pancreatic cancer varies based on patient age, marital status, and factors related to where the patient lives. Further studies are needed to guide appropriate biliary intervention for these patients.

• Pancreatic cancer
• Endoscopic retrograde cholangiopancreatography
• Socioeconomic disparities
• Racial disparities
• Jaundice
• Outcomes research

• Carcinoma, Pancreatic Ductal/diagnosis
• Carcinoma, Pancreatic Ductal/genetics
• Carcinoma, Pancreatic Ductal/metabolism
• Carcinoma, Pancreatic Ductal/mortality
• Early Detection of Cancer
• Genetic Diseases, Inborn/diagnosis
• Genetic Diseases, Inborn/genetics
• Genetic Diseases, Inborn/metabolism
• Genetic Diseases, Inborn/mortality
• Genetic Predisposition to Disease
• Genetic Testing
• Humans
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/mortality
• Risk Factors

• EP-C-16-015 EPA

Metformin is the most commonly used first-line medicine for type II diabetes mellitus. Acting via AMP-activated protein kinase, it has been used for more than 60 years and has an outstanding safety record. Metformin also offers protection against cancer, but its precise mechanisms remain unclear.

We first examined the cytotoxic effects of metformin in the HeLa human cervical carcinoma and ZR-75-1 breast cancer cell lines using assays of cell viability, cleaved poly-ADP-ribose polymerase, and Annexin V-fluorescein isothiocyanate apoptosis, as well as flow cytometric analyses of the cell cycle profile and reactive oxygen species (ROS). We later clarified the effect of metformin on p53 protein stability using transient transfection and cycloheximide chase analyses.

We observed that metformin represses cell cycle progression, thereby inducing subG1 populations, and had induced apoptosis through downregulation of p53 protein and a target gene, differentiated embryo chondrocyte 1 (DEC1). In addition, metformin increased intracellular ROS levels, but N-acetyl cysteine, a ROS scavenger, failed to suppress metformin-induced apoptosis. Further results showed that metformin disrupted the electron transport chain and collapsed the mitochondrial membrane potential, which may be the cause of the elevated ROS levels. Examination of the mechanisms underlying metformin-induced HeLa cell death revealed that reduced stability of p53 in metformin-treated cells leads to decreases in DEC1 and induction of apoptosis.

The involvement of DEC1 provides new insight into the positive or negative functional roles of p53 in the metformin-induced cytotoxicity in tumor cells.

• Apoptosis
• DEC1
• Metformin
• Reactive oxygen species
• p53

• Metformin
• Pancreatic cancer
• Proof of concept
• Survival

• 2DG, 2-deoxy-D-glucose
• ADP, adenosine diphosphate
• ATP, adenosine triphosphate
• CT, computed tomography
• Caix, carbonic anhydrase IX
• Col6a1, collagen
• ECM, extracellular matrix
• Egr2, early growth response 2
• FBS, fetal bovine serum
• Glucose Metabolism
• IHC, immunohistochemistry
• Metastasis
• PBS, phosphate-buffered saline
• PCR, polymerase chain reaction
• PDAC, pancreatic ductal adenocarcinoma
• PET, positron emission tomography
• Pancreatic Cancer
• RA, retinoic acid
• Rarb, retinoic acid receptor beta
• Retinoic Acid
• Runx3, runt related transcription factor 3
• qRT-PCR, quantitative real-time polymerase chain reaction
• type VI, alpha 1

• Animals
• Carcinoma, Pancreatic Ductal/blood supply
• Carcinoma, Pancreatic Ductal/pathology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Collagen Type VI/metabolism
• Core Binding Factor Alpha 3 Subunit/metabolism
• DNA Methylation/drug effects
• DNA Methylation/genetics
• Diabetes Mellitus/pathology
• Epigenesis, Genetic/drug effects
• Gene Ontology
• Histones/metabolism
• Humans
• Hyperglycemia/pathology
• Hypoglycemia/pathology
• Metformin/pharmacology
• Mice
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neovascularization, Pathologic/pathology
• Pancreatic Neoplasms/blood supply
• Pancreatic Neoplasms/pathology
• Promoter Regions, Genetic/genetics
• Receptors, Retinoic Acid/metabolism
• Pancreatic Neoplasms

The prognosis of people with pancreatic cancer is extremely unfavorable. However, the prognostic factors remain largely undefined. We aimed to perform comprehensive analyses of clinicopathologic characteristics, laboratory parameters, and treatment protocols for exploring their role as prognostic factors of pancreatic cancer.

Patients diagnosed with pancreatic cancer and hospitalized at the China National Cancer Center between April 2006 and May 2016 were enrolled in this retrospective cohort study. Clinicopathologic characteristics, laboratory parameters, and treatment protocols were compared among patients at different stages of the disease. The association between these factors and overall survival (OS) was analyzed using the Kaplan–Meier method and Cox proportional hazards model.

The present study included 1,433 consecutive patients with pancreatic cancer. Median OS was 10.6 months (95% confidence interval [CI] 9.8–11.3 months), with 1-, 3-, and 5-year survival rates of 43.7%, 14.8%, and 8.8%, respectively. Cox multivariate analysis findings identified the following factors as independent predictors of OS: gender (female vs male, hazard ratio 0.72, 95% CI [0.54–0.95]); elevated total bilirubin (TBil; 1.82, 1.34–2.47); elevated carbohydrate antigen 19-9 (CA19-9; 1.72, 1.17–2.54); tumor being located in pancreatic body and tail (1.52, 1.10–2.10); advanced T stage (T3-4 vs T1-2, 1.62, 1.15–2.27); lymph node metastasis (1.57, 1.20–2.07); distant metastasis (1.59, 1.12–2.27); the presence of surgical resection (0.53, 0.34–0.81); and the presence of systemic chemotherapy (0.62, 0.45–0.82).

Being male, elevated TBil and carcinoembryonic antigen, tumor being located in pancreatic body and tail, advanced T stage, lymph node and distant metastasis, the absence of surgical resection, and the absence of systematic chemotherapy were associated with worse OS in patients with pancreatic cancer.

• Clinicopathologic characteristic
• Pancreatic cancer
• Prognosis
• Survival
• Treatment

• AMPK
• Metformin
• Rapamycin
• Signal transduction inhibitors
• mTORC1

• Animals
• Carcinoma, Pancreatic Ductal/drug therapy
• Diabetes Mellitus, Type 2
• Drug Interactions
• Humans
• Metformin/therapeutic use
• Pancreatic Neoplasms/drug therapy
• Signal Transduction/drug effects
• Sirolimus/therapeutic use
• Pancreatic Neoplasms

Pancreatic ductal adenocarcinoma (PDAC) is generally a fatal disease with no efficacious treatment modalities. Elucidation of signaling mechanisms that will lead to the identification of novel targets for therapy and chemoprevention is urgently needed. Here, we review the role of Yes-associated protein (YAP) and WW-domain-containing Transcriptional co-Activator with a PDZ-binding motif (TAZ) in the development of PDAC. These oncogenic proteins are at the center of a signaling network that involves multiple upstream signals and downstream YAP-regulated genes. We also discuss the clinical significance of the YAP signaling network in PDAC using a recently published interactive open-access database (www.proteinatlas.org/pathology) that allows genome-wide exploration of the impact of individual proteins on survival outcomes. Multiple YAP/TEAD-regulated genes, including AJUBA, ANLN, AREG, ARHGAP29, AURKA, BUB1, CCND1, CDK6, CXCL5, EDN2, DKK1, FOSL1,FOXM1, HBEGF, IGFBP2, JAG1, NOTCH2, RHAMM, RRM2, SERP1, and ZWILCH, are associated with unfavorable survival of PDAC patients. Similarly, components of AP-1 that synergize with YAP (FOSL1), growth factors (TGFα, EPEG, and HBEGF), a specific integrin (ITGA2), heptahelical receptors (P2Y₂R, GPR87) and an inhibitor of the Hippo pathway (MUC1), all of which stimulate YAP activity, are associated with unfavorable survival of PDAC patients. By contrast, YAP inhibitory pathways (STRAD/LKB-1/AMPK, PKA/LATS, and TSC/mTORC1) indicate a favorable prognosis. These associations emphasize that the YAP signaling network correlates with poor survival of pancreatic cancer patients. We conclude that the YAP pathway is a major determinant of clinical aggressiveness in PDAC patients and a target for therapeutic and preventive strategies in this disease.

Yes-associated protein (YAP) signaling contributes to pancreatic cancer progression and is associated with poor patient survival. Previous studies have shown that YAP activates genes involved in cell proliferation to incite tumor growth and metastasis. Enrique Rozengurt and colleagues at University of California Los Angeles review the latest knowledge on YAP signaling and used the open access database The Human Protein Atlas to analyze the gene expression profile and prognosis of 176 patients with pancreatic ductal adenocarcinoma. Activation of upstream or downstream elements of the YAP signaling pathway correlated with shorter survival in patients. Conversely, the activation of signaling pathways that oppose YAP signaling were associated with a more favorable prognosis. These findings highlight YAP signaling pathway components as both prognostic markers and potential targets for developing much needed therapeutic and preventative strategies.

Pancreatic ductal adenocarcinoma (PDAC) is a particularly deadly disease. Chronic conditions, including obesity and type-2 diabetes are risk factors, thus making PDAC amenable to preventive strategies. We aimed to characterize the chemo-preventive effects of metformin, a widely used anti-diabetic drug, on PDAC development using the Kras^G12D mouse model subjected to a diet high in fats and calories (HFCD). LSL-Kras^G12D/+;p48-Cre (KC) mice were given control diet (CD), HFCD, or HFCD with 5 mg/ml metformin in drinking water for 3 or 9 months. After 3 months, metformin prevented HFCD-induced weight gain, hepatic steatosis, depletion of intact acini, formation of advanced PanIN lesions, and stimulation of ERK and mTORC1 in pancreas. In addition to reversing hepatic and pancreatic histopathology, metformin normalized HFCD-induced hyperinsulinemia and hyperleptinemia among the 9-month cohort. Importantly, the HFCD-increased PDAC incidence was completely abrogated by metformin (p < 0.01). The obesogenic diet also induced a marked increase in the expression of TAZ in pancreas, an effect abrogated by metformin. In conclusion, administration of metformin improved the metabolic profile and eliminated the promoting effects of diet-induced obesity on PDAC formation in KC mice. Given the established safety profile of metformin, our findings have a strong translational potential for novel chemo-preventive strategies for PDAC.

• Obesity
• Pancreatic cancer
• Prevention
• Review
• Type 2 diabetes mellitus

• Carcinoma, Pancreatic Ductal/epidemiology
• Carcinoma, Pancreatic Ductal/etiology
• Diabetes Mellitus, Type 2/complications
• Humans
• Incidence
• Obesity/complications
• Pancreatic Neoplasms/epidemiology
• Pancreatic Neoplasms/etiology
• Risk Factors
• United States/epidemiology

• U01 DK108323 NIDDK NIH HHS
• P01 DK098108 NIDDK NIH HHS
• U01 DK108326 NIDDK NIH HHS
• P01 CA163200 NCI NIH HHS
• U01 DK108300 NIDDK NIH HHS
• R01 CA075059 NCI NIH HHS
• R01 AA019954 NIAAA NIH HHS
• U01 DK108314 NIDDK NIH HHS
• U01 DK108327 NIDDK NIH HHS

• Diabetes mellitus
• Glucose intolerance
• Mortality
• Pancreatectomy
• Pancreatic cancer