Targeting Mutant KRAS in Pancreatic Cancer: Futile or Promising?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers with a dismal prognosis for the patient. This is due to limited diagnostic options for the early detection of the disease as well as its rather aggressive nature. Despite major advances in oncologic research in general, the treatment options in the clinic for PDAC have only undergone minor changes in the last decades. One major treatment advance would be the successful targeting of the oncogenic driver KRASmut. In the past, the indirect targeting of KRAS has been exploited, e. g., via upstream inhibition of receptor tyrosine kinases or via downstream MEK or PI3K inhibition. However, the experience gained from clinical trials and from the clinic itself in the treatment of KRASmut cancer entities has dampened the initial euphoria. Lately, with the development of KRASG12C-specific inhibitors, not only the direct but also the indirect targeting of KRASmut has gained momentum again. Though preclinical studies and preliminary early clinical studies of monotherapies have shown promising results, they have been overshadowed by the swift development of resistances resulting in inconsistent responses in patient cohorts. Currently, several different combination therapies for KRASmut cancer are being explored. If they hold the promise they have made in preclinical studies, they might also be suitable treatment options for patients suffering from PDAC.

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

Gastroenterology Research and Practice ◽

10.1155/2016/4508376 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 28

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.

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An Overview of Dementias

Perspectives on Swallowing and Swallowing Disorders (Dysphagia) ◽

10.1044/sasd21.3.75 ◽

2012 ◽

Vol 21 (3) ◽

pp. 75-84

Author(s):

Venkata Vijaya K. Dalai ◽

Jason E. Childress ◽

Paul E Schulz

Keyword(s):

Clinical Presentation ◽

Treatment Options ◽

Current Treatment ◽

Great Variability ◽

Health Concern ◽

Public Health Concern ◽

Life Threatening ◽

The Common ◽

Neurodegenerative Dementias ◽

Made In

Dementia is a major public health concern that afflicts an estimated 24.3 million people worldwide. Great strides are being made in order to better diagnose, prevent, and treat these disorders. Dementia is associated with multiple complications, some of which can be life-threatening, such as dysphagia. There is great variability between dementias in terms of when dysphagia and other swallowing disorders occur. In order to prepare the reader for the other articles in this publication discussing swallowing issues in depth, the authors of this article will provide a brief overview of the prevalence, risk factors, pathogenesis, clinical presentation, diagnosis, current treatment options, and implications for eating for the common forms of neurodegenerative dementias.

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Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

Cancers ◽

10.3390/cancers13020184 ◽

2021 ◽

Vol 13 (2) ◽

pp. 184

Author(s):

Kalpana K. Bhanumathy ◽

Amrutha Balagopal ◽

Frederick S. Vizeacoumar ◽

Franco J. Vizeacoumar ◽

Andrew Freywald ◽

...

Keyword(s):

Growth Factor ◽

Protein Kinase ◽

Tyrosine Kinase ◽

Protein Kinases ◽

Tyrosine Kinases ◽

Treatment Options ◽

Growth Factor Receptor ◽

Tyrosine Protein Kinase ◽

Mesenchymal Epithelial Transition Factor ◽

The Impact

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

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Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma

Cells ◽

10.3390/cells10071821 ◽

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.

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Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

Pharmaceuticals ◽

10.3390/ph14070626 ◽

2021 ◽

Vol 14 (7) ◽

pp. 626

Author(s):

Julie Bolcaen ◽

Shankari Nair ◽

Cathryn H. S. Driver ◽

Tebatso M. G. Boshomane ◽

Thomas Ebenhan ◽

...

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Tyrosine Kinases ◽

Radionuclide Therapy ◽

Kinase Inhibitors ◽

Nuclear Imaging ◽

Therapy Resistance ◽

Targeted Radionuclide Therapy ◽

Therapy Strategy ◽

Dismal Prognosis

Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.

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

BMJ Open ◽

10.1136/bmjopen-2020-037267 ◽

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

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Retargeting of NK-92 Cells against High-Risk Rhabdomyosarcomas by Means of an ERBB2 (HER2/Neu)-Specific Chimeric Antigen Receptor

Cancers ◽

10.3390/cancers13061443 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1443

Author(s):

Leonie D. H. Gossel ◽

Catrin Heim ◽

Lisa-Marie Pfeffermann ◽

Laura M. Moser ◽

Halvard B. Bönig ◽

...

Keyword(s):

High Risk ◽

Tumor Cells ◽

Chimeric Antigen Receptor ◽

Treatment Options ◽

Antigen Receptor ◽

Proof Of Concept ◽

Cell Monolayers ◽

Novel Treatment ◽

Dismal Prognosis

The dismal prognosis of pediatric and young adult patients with high-risk rhabdomyosarcoma (RMS) underscores the need for novel treatment options for this patient group. In previous studies, the tumor-associated surface antigen ERBB2 (HER2/neu) was identified as targetable in high-risk RMS. As a proof of concept, in this study, a novel treatment approach against RMS tumors using a genetically modified natural killer (NK)-92 cell line (NK-92/5.28.z) as an off-the-shelf ERBB2-chimeric antigen receptor (CAR)-engineered cell product was preclinically explored. In cytotoxicity assays, NK-92/5.28.z cells specifically recognized and efficiently eliminated RMS cell suspensions, tumor cell monolayers, and 3D tumor spheroids via the ERBB2-CAR even at effector-to-target ratios as low as 1:1. In contrast to unmodified parental NK-92 cells, which failed to lyse RMS cells, NK-92/5.28.z cells proliferated and became further activated through contact with ERBB2-positive tumor cells. Furthermore, high amounts of effector molecules, such as proinflammatory and antitumoral cytokines, were found in cocultures of NK-92/5.28.z cells with tumor cells. Taken together, our data suggest the enormous potential of this approach for improving the immunotherapy of treatment-resistant tumors, revealing the dual role of NK-92/5.28.z cells as CAR-targeted killers and modulators of endogenous adaptive immunity even in the inhibitory tumor microenvironment of high-risk RMS.

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

Technology in Cancer Research & Treatment ◽

10.1177/1533033820920969 ◽

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.

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Identification and Characterization of Novel Rat Polyomavirus 2 in a Colony of X-SCID Rats by P-PIT assay

mSphere ◽

10.1128/msphere.00334-16 ◽

2016 ◽

Vol 1 (6) ◽

Cited By ~ 15

Author(s):

Lora H. Rigatti ◽

Tuna Toptan ◽

Joseph T. Newsome ◽

Patrick S. Moore ◽

Yuan Chang

Keyword(s):

T Cell ◽

Potential Model ◽

Treatment Options ◽

Pneumocystis Carinii ◽

Preclinical Studies ◽

Content Type ◽

Laboratory Rats ◽

Wide Range ◽

Disseminated Disease ◽

Human Polyomaviruses

ABSTRACT Although P-PIT was developed to detect diseases associated with known human polyomaviruses, the identification of a new polyomavirus in rats suggests that it may have utility as a broad-based screen for new, as well as known polyomaviruses. Our findings suggest that RatPyV2 may be a commensal infection of laboratory rats that can lead to disseminated disease in T cell immune-deficient rats. Infection of the X-SCID rats with RatPyV2 and Pneumocystis carinii is a potential model for coinfection pathogenesis and treatment options during transplant preclinical studies. Polyomaviruses (PyVs) are known to infect a wide range of vertebrates and invertebrates and are associated with a broad spectrum of diseases, including cancers, particularly in immune-suppressed hosts. A novel polyomavirus, designated rat polyomavirus 2 (RatPyV2), was identified from a breeding colony of rats having X-linked severe combined immunodeficiency. Using a human panpolyomavirus immunohistochemistry test (P-PIT), RatPyV2 was initially detected in the parotid salivary gland of a colony member. Rolling circle amplification using DNA from harderian and parotid glands identified a novel 5.1-kb polyomavirus genome closely related to human Washington University (WU) and Karolinska Institute (KI) and vole polyomaviruses but notably divergent from Rattus norvegicus PyV1 (RnorPyV1; also designated RatPyV1). Further screening showed RatPyV2 inclusion body infection in the lung epithelium and variably in other respiratory, reproductive, and glandular tissues of 12/12 (100%) rats. IMPORTANCE Although P-PIT was developed to detect diseases associated with known human polyomaviruses, the identification of a new polyomavirus in rats suggests that it may have utility as a broad-based screen for new, as well as known polyomaviruses. Our findings suggest that RatPyV2 may be a commensal infection of laboratory rats that can lead to disseminated disease in T cell immune-deficient rats. Infection of the X-SCID rats with RatPyV2 and Pneumocystis carinii is a potential model for coinfection pathogenesis and treatment options during transplant preclinical studies.

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

International Journal of Molecular Sciences ◽

10.3390/ijms19103219 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3219 ◽

Cited By ~ 11

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.

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