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Belum V.R.,Sloan Kettering Cancer Center | Serna-Tamayo C.,Sloan Kettering Cancer Center | Wu S.,State University of New York at Stony Brook | Wu S.,Northport Medical Center | Lacouture M.E.,Sloan Kettering Cancer Center
Clinical and Experimental Dermatology

Background Cabozantinib is approved in the treatment of progressive, metastatic medullary thyroid cancer (MTC). It is a small molecule inhibitor, which targets multiple receptors, including vascular endothelial growth factor receptor, tyrosine kinase with Ig and epidermal growth factor homology domains-2 and the proto-oncogenes MET (mesenchymal-epithelial transition factor) and RET (rearranged during transfection). The drug is currently in phase I/II/III clinical trials for a number of other solid tumours and haematological malignancies. The adverse event (AE) profile is similar to that of other newer angiogenesis inhibitors. Hand-foot skin reaction (HFSR) is an important dose-limiting dermatological adverse event of this class of drugs. Aim To ascertain the incidence and risk of HFSR in patients with cancer during treatment with cabozantinib. Methods Electronic databases (PubMed, Web of Science) and the American Society of Clinical Oncology Meeting Library were queried from inception to July 2014. Only phase II/III studies investigating cabozantinib for the treatment of cancer were shortlisted. The incidence, relative risk (RR) and 95% CI were calculated using random- or fixed-effects models, depending on the heterogeneity of the included studies. Results We included 831 patients treated with cabozantinib for various solid malignancies in the analysis. The overall incidence was 35.3% (95% CI 27.9-43.6%) for all-grade and 9.5% (95% CI 7.6-11.7%) for high-grade HFSR. The RR of all-grade and high-grade HFSR with cabozantinib, compared with controls, was increased for both all-grade (27.3; 95% CI 6.9-108.3; P < 0.001) and high-grade (28.1; 95% CI 1.7-457; P < 0.02) HFSR, respectively. Conclusions The incidence and risk of developing HFSR with cabozantinib are high. Timely recognition of this dose-limiting AE is critical to direct supportive care efforts including patient counselling, and to institute preventative and/or treatment interventions. © 2015 British Association of Dermatologists. Source

Lu Z.,State University of New York at Stony Brook | Jiang Y.-P.,State University of New York at Stony Brook | Wu C.-Y.C.,State University of New York at Stony Brook | Ballou L.M.,State University of New York at Stony Brook | And 7 more authors.

Diabetes is an independent risk factor for sudden cardiac death and ventricular arrhythmia complications of acute coronary syndrome. Prolongation of the QT interval on the electrocardiogram is also a risk factor for arrhythmias and sudden death, and the increased prevalence of QT prolongation is an independent risk factor for cardiovascular death in diabetic patients. The pathophysiological mechanisms responsible for this lethal complication are poorly understood. Diabetes is associated with a reduction in phosphoinositide 3-kinase (PI3K) signaling, which regulates the action potential duration (APD) of individual myocytes and thus the QT interval by altering multiple ion currents, including the persistent sodium current INaP. Here, we report a mechanism for diabetes-induced QT prolongation that involves an increase in INaP caused by defective PI3K signaling. Cardiac myocytes of mice with type 1 or type 2 diabetes exhibited an increase in APD that was reversed by expression of constitutively active PI3K or intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate (PIP3), the second messenger produced by PI3K. The diabetic myocytes also showed an increase in INaP that was reversed by activated PI3K or PIP3. The increases in APD and INaP in myocytes translated into QT interval prolongation for both types of diabetic mice. The long QT interval of type 1 diabetic hearts was shortened by insulin treatment ex vivo, and this effect was blocked by a PI3K inhibitor. Treatment of both types of diabetic mouse hearts with an INaP blocker also shortened the QT interval. These results indicate that downregulation of cardiac PI3K signaling in diabetes prolongs the QT interval at least in part by causing an increase in INaP. This mechanism may explain why the diabetic population has an increased risk of life-threatening arrhythmias. © 2013 by the American Diabetes Association. Source

Adada M.,Health Science University | Canals D.,Health Science University | Hannun Y.A.,Health Science University | Obeid L.M.,Health Science University | Obeid L.M.,Northport Medical Center
FEBS Journal

Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid involved in cell proliferation, angiogenesis, inflammation and malignant transformation among other functions. S1P acts either directly on intracellular targets or activates G protein-coupled receptors, specifically five S1P receptors (S1PRs). The identified S1PRs differ in cellular and tissue distribution, and each is coupled to specific G proteins, which mediate unique functions. Here, we describe functional characteristics of all five receptors, emphasizing S1PR2, which is critical in the immune, nervous, metabolic, cardiovascular, musculoskeletal, and renal systems. This review also describes the role of this receptor in tumor growth and metastasis and suggests potential therapeutic avenues that exploit S1PR2. Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid involved in cell proliferation, angiogenesis, inflammation, and malignant transformation among other functions. S1P acts either directly on intracellular targets or activates G-protein coupled receptors, specifically five S1P receptors (S1PRs). Here, we describe functional characteristics of all five receptors, emphasizing S1PR2 and its role in tumor growth and metastasis. © 2013 FEBS. Source

Wu C.-Y.C.,State University of New York at Stony Brook | Carpenter E.S.,State University of New York at Stony Brook | Takeuchi K.K.,Mayo Clinic Florida | Halbrook C.J.,State University of New York at Stony Brook | And 10 more authors.

BACKGROUND & AIMS: New drug targets are urgently needed for the treatment of patients with pancreatic ductal adenocarcinoma (PDA). Nearly all PDAs contain oncogenic mutations in the KRAS gene. Pharmacological inhibition of KRAS has been unsuccessful, leading to a focus on downstream effectors that are more easily targeted with small molecule inhibitors. We investigated the contributions of phosphoinositide 3-kinase (PI3K) to KRAS-initiated tumorigenesis.METHODS: Tumorigenesis was measured in the KrasG12D/+;Ptf1aCre/+ mouse model of PDA; these mice were crossed with mice with pancreas-specific disruption of genes encoding PI3K p110α (Pik3ca), p110β (Pik3cb), or RAC1 (Rac1). Pancreatitis was induced with 5 daily intraperitoneal injections of cerulein. Pancreata and primary acinar cells were isolated; acinar cells were incubated with an inhibitor of p110α (PIK75) followed by a broad-spectrum PI3K inhibitor (GDC0941). PDA cell lines (NB490 and MiaPaCa2) were incubated with PIK75 followed by GDC0941. Tissues and cells were analyzed by histology, immunohistochemistry, quantitative reverse-transcription polymerase chain reaction, and immunofluorescence analyses for factors involved in the PI3K signaling pathway. We also examined human pancreas tissue microarrays for levels of p110α and other PI3K pathway components.RESULTS: Pancreas-specific disruption of Pik3ca or Rac1, but not Pik3cb, prevented the development of pancreatic tumors in KrasG12D/+;Ptf1aCre/+ mice. Loss of transformation was independent of AKT regulation. Preneoplastic ductal metaplasia developed in mice lacking pancreatic p110α but regressed. Levels of activated and total RAC1 were higher in pancreatic tissues from KrasG12D/+;Ptf1aCre/+ mice compared with controls. Loss of p110α reduced RAC1 activity and expression in these tissues. p110α was required for the up-regulation and activity of RAC guanine exchange factors during tumorigenesis. Levels of p110α and RAC1 were increased in human pancreatic intraepithelial neoplasias and PDAs compared with healthy pancreata.CONCLUSIONS: KRAS signaling, via p110α to activate RAC1, is required for transformation in KrasG12D/+;Ptf1aCre/+ mice. © 2014 AGA Institute. Source

Ballou L.M.,State University of New York at Stony Brook | Lin R.Z.,State University of New York at Stony Brook | Lin R.Z.,Northport Medical Center | Cohen I.S.,State University of New York at Stony Brook
Circulation Research

Upregulation of phosphoinositide 3-kinase (PI3K) signaling is a common alteration in human cancer, and numerous drugs that target this pathway have been developed for cancer treatment. However, recent studies have implicated inhibition of the PI3K signaling pathway as the cause of a drug-induced long-QT syndrome in which alterations in several ion currents contribute to arrhythmogenic drug activity. Surprisingly, some drugs that were thought to induce long-QT syndrome by direct block of the rapid delayed rectifier (IKr) also seem to inhibit PI3K signaling, an effect that may contribute to their arrhythmogenicity. The importance of PI3K in regulating cardiac repolarization is underscored by evidence that QT interval prolongation in diabetes mellitus also may result from changes in multiple currents because of decreased insulin activation of PI3K in the heart. How PI3K signaling regulates ion channels to control the cardiac action potential is poorly understood. Hence, this review summarizes what is known about the effect of PI3K and its downstream effectors, including Akt, on sodium, potassium, and calcium currents in cardiac myocytes. We also refer to some studies in noncardiac cells that provide insight into potential mechanisms of ion channel regulation by this signaling pathway in the heart. Drug development and safety could be improved with a better understanding of the mechanisms by which PI3K regulates cardiac ion channels and the extent to which PI3K inhibition contributes to arrhythmogenic susceptibility. © 2014 American Heart Association, Inc. Source

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