scholarly journals The Current Treatment Paradigm for Pancreatic Ductal Adenocarcinoma and Barriers to Therapeutic Efficacy

2021 ◽  
Vol 11 ◽  
Author(s):  
Daniel R. Principe ◽  
Patrick W. Underwood ◽  
Murray Korc ◽  
Jose G. Trevino ◽  
Hidayatullah G. Munshi ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Drug Efficacy ◽  
Current Treatment ◽  
Ductal Adenocarcinoma ◽  
Multi Drug Resistance ◽  
Dismal Prognosis ◽  
Treatment Paradigm ◽  
Cytotoxic Therapies ◽  
Poor Outcomes ◽  
Pancreatic Cancer Therapy

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a median survival time of 10-12 months. Clinically, these poor outcomes are attributed to several factors, including late stage at the time of diagnosis impeding resectability, as well as multi-drug resistance. Despite the high prevalence of drug-resistant phenotypes, nearly all patients are offered chemotherapy leading to modest improvements in postoperative survival. However, chemotherapy is all too often associated with toxicity, and many patients elect for palliative care. In cases of inoperable disease, cytotoxic therapies are less efficacious but still carry the same risk of serious adverse effects, and clinical outcomes remain particularly poor. Here we discuss the current state of pancreatic cancer therapy, both surgical and medical, and emerging factors limiting the efficacy of both. Combined, this review highlights an unmet clinical need to improve our understanding of the mechanisms underlying the poor therapeutic responses seen in patients with PDAC, in hopes of increasing drug efficacy, extending patient survival, and improving quality of life.

scholarly journals Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1821
Author(s):  
Ujjwal Mukund Mahajan ◽  
Ahmed Alnatsha ◽  
Qi Li ◽  
Bettina Oehrle ◽  
Frank-Ulrich Weiss ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Enrichment Analysis ◽  
Response Prediction ◽  
Ductal Adenocarcinoma ◽  
Pathway Enrichment Analysis ◽  
Metabolome Analysis ◽  
Dismal Prognosis ◽  
Chemotherapeutic Response ◽  
Plasma Metabolome ◽  
Metabolome Profiling

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Developing biomarkers for early detection and chemotherapeutic response prediction is crucial to improve the dismal prognosis of PDAC patients. However, molecular cancer signatures based on transcriptome analysis do not reflect intratumoral heterogeneity. To explore a more accurate stratification of PDAC phenotypes in an easily accessible matrix, plasma metabolome analysis using MxP® Global Profiling and MxP® Lipidomics was performed in 361 PDAC patients. We identified three metabolic PDAC subtypes associated with distinct complex lipid patterns. Subtype 1 was associated with reduced ceramide levels and a strong enrichment of triacylglycerols. Subtype 2 demonstrated increased abundance of ceramides, sphingomyelin and other complex sphingolipids, whereas subtype 3 showed decreased levels of sphingolipid metabolites in plasma. Pathway enrichment analysis revealed that sphingolipid-related pathways differ most among subtypes. Weighted correlation network analysis (WGCNA) implied PDAC subtypes differed in their metabolic programs. Interestingly, a reduced expression among related pathway genes in tumor tissue was associated with the lowest survival rate. However, our metabolic PDAC subtypes did not show any correlation to the described molecular PDAC subtypes. Our findings pave the way for further studies investigating sphingolipids metabolisms in PDAC.

scholarly journals New Onset of DiabetEs in aSsociation with pancreatic ductal adenocarcinoma (NODES Trial): protocol of a prospective, multicentre observational trial

BMJ Open ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. e037267
Author(s):  
Dóra Illés ◽  
Emese Ivány ◽  
Gábor Holzinger ◽  
Klára Kosár ◽  
M Gordian Adam ◽  
...  
Keyword(s):  
High Risk ◽  
Early Detection ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Clinical Symptoms ◽  
Risk Group ◽  
High Risk Group ◽  
Ductal Adenocarcinoma ◽  
Onset Diabetes ◽  
Dismal Prognosis ◽  
New Onset

IntroductionPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with an overall 5-year survival of approximately 8%. The success in reducing the mortality rate of PDAC is related to the discovery of new therapeutic agents, and to a significant extent to the development of early detection and prevention programmes. Patients with new-onset diabetes mellitus (DM) represent a high-risk group for PDAC as they have an eightfold higher risk of PDAC than the general population. The proposed screening programme may allow the detection of PDAC in the early, operable stage. Diagnosing more patients in the curable stage might decrease the morbidity and mortality rates of PDAC and additionally reduce the burden of the healthcare.Methods and analysisThis is a prospective, multicentre observational cohort study. Patients ≥60 years old diagnosed with new-onset (≤6 months) diabetes will be included. Exclusion criteria are (1) Continuous alcohol abuse; (2) Chronic pancreatitis; (3) Previous pancreas operation/pancreatectomy; (4) Pregnancy; (5) Present malignant disease and (6) Type 1 DM. Follow-up visits are scheduled every 6 months for up to 36 months. Data collection is based on questionnaires. Clinical symptoms, body weight and fasting blood will be collected at each, carbohydrate antigen 19–9 and blood to biobank at every second visit. The blood samples will be processed to plasma and analysed with mass spectrometry (MS)-based metabolomics. The metabolomic data will be used for biomarker validation for early detection of PDAC in the high-risk group patients with new-onset diabetes. Patients with worrisome features will undergo MRI or endoscopic ultrasound investigation, and surgical referral depending on the radiological findings. One of the secondary end points is the incidence of PDAC in patients with newly diagnosed DM.Ethics and disseminationThe study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (41085-6/2019). We plan to disseminate the results to several members of the healthcare system includining medical doctors, dietitians, nurses, patients and so on. We plan to publish the results in a peer-reviewed high-quality journal for professionals. In addition, we also plan to publish it for lay readers in order to maximalise the dissemination and benefits of this trial.Trial registration numberClinicalTrials.gov NCT04164602

scholarly journals The Roles of Frequently Mutated Genes of Pancreatic Cancer in Regulation of Tumor Microenvironment

2020 ◽  
Vol 19 ◽  
pp. 153303382092096
Author(s):  
Hongzhi Sun ◽  
Bo Zhang ◽  
Haijun Li
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Stromal Cells ◽  
Genomic Analysis ◽  
Ductal Adenocarcinoma ◽  
Genetic Mutations ◽  
Cellular Processes ◽  
Dismal Prognosis ◽  
Mutant Genes

Pancreatic ductal adenocarcinoma has extremely high malignancy and patients with pancreatic ductal adenocarcinoma have dismal prognosis. The failure of pancreatic ductal adenocarcinoma treatment is largely due to the tumor microenvironment, which is featured by ample stromal cells and complicated extracellular matrix. Recent genomic analysis revealed that pancreatic ductal adenocarcinoma harbors frequently mutated genes including KRAS, TP53, CDKN2A, and SMAD4, which can widely alter cellular processes and behaviors. As shown by accumulating studies, these mutant genes may also change tumor microenvironment, which in turn affects pancreatic ductal adenocarcinoma progression. In this review, we summarize the role of such genetic mutations in tumor microenvironment regulation and potential mechanisms.

scholarly journals The Emerging Role of Cyclin-Dependent Kinases (CDKs) in Pancreatic Ductal Adenocarcinoma

2018 ◽  
Vol 19 (10) ◽  
pp. 3219 ◽  
Author(s):  
Balbina García-Reyes ◽  
Anna-Laura Kretz ◽  
Jan-Philipp Ruff ◽  
Silvia von Karstedt ◽  
Andreas Hillenbrand ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Ductal Adenocarcinoma ◽  
Transcriptional Elongation ◽  
Cyclin Dependent Kinases ◽  
Dismal Prognosis ◽  
The Family ◽  
Cycle Regulation

The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC’s resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC.

scholarly journals Targeting PI3K Pathway in Pancreatic Ductal Adenocarcinoma: Rationale and Progress

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4434
Author(s):  
Siddharth Mehra ◽  
Nilesh Deshpande ◽  
Nagaraj Nagathihalli
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Pi3k Pathway ◽  
Tumor Burden ◽  
Ductal Adenocarcinoma ◽  
Cancer Type ◽  
Therapeutic Implications ◽  
Downstream Signaling ◽  
Genetic Mouse Model ◽  
Dismal Prognosis ◽  
Effector Pathways

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest solid tumors that remain treatment-refractory and show a dismal prognosis. More than 90% of PDAC tumors harbor mutations in the K-Ras that exert a strong pro-tumorigenic effect by activating several downstream effector pathways, including phosphatidylinositol-3-kinase (PI3K)-Akt. The role of frequently activated PI3K/Akt pathway in promoting PDAC aggressiveness is well established. Therapeutic approaches targeting PI3K and downstream signaling components in different cellular compartments, including tumor, stromal and immune cells, have directly impacted the tumor burden in this cancer type. Our previous work has demonstrated that targeting the PI3K/Akt/mTOR pathway reduced tumor growth and improved survival in the genetic mouse model of PDAC. Here, we discuss the significance of targeting PI3K signaling and the biological impact of PI3K inhibition in modulating the tumor–stromal immune crosstalk within the microenvironment of pancreatic cancer. Furthermore, this review updates on the current challenges involving the therapeutic implications of targeting this pathway in PDAC.

scholarly journals Survival and quality of life following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma

2021 ◽  
Vol 6 (2) ◽  
Keyword(s):  
Quality Of Life ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Short Review ◽  
Mortality Rates ◽  
Ductal Adenocarcinoma ◽  
Term Survival ◽  
Long Term Survival ◽  
Dismal Prognosis

Pancreatic ductal adenocarcinoma (PDAC) most commonly affects the head of the pancreas. This condition has a dismal prognosis. Patients with early disease may be candidates for pancreaticoduodenectomy (PD). This is a high-risk operation which is associated with considerable morbidity. Whilst perioperative mortality rates have fallen in recent times, the risk remains significant and long-term survival is poor, even in those who make an uncomplicated recovery. Furthermore, PD is known to affect quality of life (QoL) negatively. Most studies suggest it takes up to six months before a patient’s QoL returns to baseline. This is a considerable amount of time for a patient who is unlikely to achieve long-term survival. This short review discusses the recent literature surrounding mortality rates, long-term survival and QoL following PD for PDAC. A comprehensive understanding of these topics will allow clinicians and patients to consider the risks and benefits before surgical resection is considered.

Comparison of Pancreatic Ductal Adenocarcinoma Imaging Modalities

2020 ◽  
Vol 6 (4) ◽  
pp. 1-5
Author(s):  
Mohamed Nashnoush
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Sensitivity And Specificity ◽  
Gold Standard ◽  
Epigastric Pain ◽  
Imaging Modality ◽  
Whipple Procedure ◽  
Patient Comfort ◽  
Ductal Adenocarcinoma ◽  
Dismal Prognosis ◽  
Highly Sensitive

Pancreatic ductal adenocarcinoma (PDAC) is a fatal type of cancer with an increasing incidence rate in North America. The only curative procedure of this disease is the Whipple procedure, which is restricted only to those that received an early diagnosis. The remainder of the patients are informed of a dismal prognosis and undergo palliative care through systemic chemotherapy. Multiple modalities are involved in the staging and diagnosis of this disease. However, there seems to be a controversy regarding a gold standard or whether a gold standard exists. Additionally, there are various emerging techniques that warrant heightened sensitivity and specificity in their designated modalities. Transabdominal ultrasound that is most commonly used as the first line of imaging for patients with epigastric pain is found to be virtually insensitive to neoplasms that have a size of 2 cm or less, limiting its application. However, sonographers could resort to contrasts and elastography to increase the conspicuity of the neoplasms. Moreover, endoscopic ultrasound has shown to be a promising imaging modality with an unprecedented degree of sensitivity to tumors with a diameter less than 1.5 cm. The sensitivity and specificity values of MDCT, MRI, and PET were found to be comparable. The main conclusions consist of the fact that EUS is a highly sensitive test that should be accompanied by MRI, MDCT, PET, or TUS to increase its specificity. Lastly, empathetic communication is vital not only for patient comfort but also to improve the quality of the imaging assessment.

scholarly journals The Tumor Microenvironment of Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3076
Author(s):  
Eva Karamitopoulou
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Incidence Rates ◽  
Ductal Adenocarcinoma ◽  
Dismal Prognosis ◽  
The Future ◽  
Rising Incidence

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis along with rising incidence rates and will be responsible for many cancer deaths in the future [...]

Analysis of associations of CXCR3 ligands with immune microenvironment and aggressiveness in murine and human pancreatic ductal adenocarcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 762-762
Author(s):  
Andrew Cannon ◽  
Christopher M Thompson ◽  
Pranita Atri ◽  
Rakesh Bhatia ◽  
Sushil Kumar ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Bioinformatics Analyses ◽  
Dismal Prognosis ◽  
M1 Macrophage

762 Background: The complex milieu of cytokines within pancreatic ductal adenocarcinoma (PDAC) promotes tumor progression and immune suppression thereby contributing to the dismal prognosis of patients with PDAC. However, the roles of many cytokines, including CXCR3 ligands, in PDAC have not been thoroughly investigated. Methods: Bioinformatics analyses of PDAC microarray and TCGA datasets were used to identify cytokines overexpressed in PDAC, their association with patient survival as well as the expression of cognate cytokine receptors. Comparative analysis of cytokine expression in KrasLSL-G12D-P53LSL-R172H-Pdx1-Cre (KPC) and KrasLSL-G12D-Pdx1-Cre (KC) murine PDAC models were used to validate these findings. Pathway and CIBERSORT analyses were employed to determine mechanistic basis of altered survival associated with cytokines of interest. Results: Of the 149 cytokines analyzed, CXCR3 ligands CXCL9 and CXCL10 were highly and consistently overexpressed in PDAC datasets. Concurrently, CXCL9, CXCL10 and PF4 were overexpressed in the aggressive KPC murine model compared to the indolent KC model. CXCR3 showed robust expression in PDAC in microarray, TCGA and IHC analyses. Interestingly, high expression of CXCR3 ligands was associated with shorter overall survival (p = 0.04 for CXCL9, 10 and 11 and p = 0.02 for PF4) while high expression of CXCR3 was associated with increased overall survival (p = 0.03). Pathway analysis of genes correlated with CXCR3 and/or its ligands showed that CXCR3 ligands may promote T-cell exhaustion (p < 0.001). Finally, CIBERSORT analysis of TCGA data demonstrated that high CXCR3 expression was associated with increased CD8 T-cell and naïve B-cell signatures and loss of plasma cells signatures. High CXCR3 ligand expression was associated with increased CD8 T-cell, and M1 macrophage, and loss of NK-cell signatures(p < 0.05). Conclusions: CXCR3 ligands are overexpressed in PDAC and are associated with poor survival, likely related to alterations in tumor immune infiltrate/activity and may represent targets to augment anti-tumor immunity.

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