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Pesta M, Mrazova B, Kapalla M, Kulda V, Gkika E, Golubnitschaja O. Mitochondria-based holistic 3PM approach as the 'game-changer' for individualised rehabilitation-the proof-of-principle model by treated breast cancer survivors. EPMA J 2024; 15:559-571. [PMID: 39635015 PMCID: PMC11612048 DOI: 10.1007/s13167-024-00386-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 11/09/2024] [Indexed: 12/07/2024]
Abstract
Breast cancer belongs to the most commonly diagnosed malignancies worldwide, with its increasing incidence paralleled by advances in early diagnostics and effective treatments resulting in significantly improved survival rates. However, breast cancer survivors often experience significantly reduced quality of life linked to the long-term health burden as a consequence of aggressive oncological treatments applied. Their most frequently recorded complains include chronic fatigue, reduced physical activity, disordered sleep, chronification of pain, and severe mental health impairments-all per evidence are associated with compromised mitochondrial health and impaired homeostasis. Self-report of a breast cancer survivor is included in this article to illustrate currently uncovered patient needs. This article highlights mechanisms behind the suboptimal health of breast cancer survivors associated with mitochondrial damage, and introduces a novel, mitochondria-based holistic approach addressing rehabilitation concepts for breast cancer survivors following advanced principles of predictive, preventive and personalised medicine (3PM). By operating via mitochondrial function, the proposed holistic approach triggers systemic effects at molecular, sub/cellular and organismal levels positively affecting energy metabolism, repair mechanisms as well as physical and mental health creating, therefore, highly effective rehabilitation algorithms tailored to an individualised patient profile. The proposed methodology integrates mitochondrial health assessments utilising mitochondrial homeostasis biomarkers in tear fluid as a non-invasive diagnostic tool, tailored nutraceuticals and lifestyle adjustments. The introduced approach aligns with advanced principles of 3PM, offering a holistic and proactive framework for managing persistent post-treatment symptoms of suboptimal health in the cohort of cancer survivors. Furthermore, presented approach is also applicable to pre-habilitation programmes considering needs of other patient cohorts affected by chronic diseases such as CVD and orthopaedic disorders with planned major surgical incisions, who require individually adapted pre- and rehabilitation programmes. Implementing such innovative pre- and rehabilitation strategies may lead to a full recovery, sustainable health conditions and, therefore, facilitating patients' comeback to normal daily activities, family and professional life. Contextually, presented approach is considered a 'proof-of-principle' model for the 3PM-related paradigm shift from reactive medicine to a cost-effective holistic health management in both primary and secondary care benefiting a large spectrum of affected patient cohorts, individuals in suboptimal health conditions as well as society at large.
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Affiliation(s)
- Martin Pesta
- Department of Biology, Faculty of Medicine in Pilsen, Charles University, Plzen, Czech Republic
| | - Barbara Mrazova
- F. D, Roosevelt University Hospital, Banska Bystrica, Slovakia
| | - Marko Kapalla
- F. D, Roosevelt University Hospital, Banska Bystrica, Slovakia
| | - Vlastimil Kulda
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine in Pilsen, Charles University, Plzen, Czech Republic
| | - Eleni Gkika
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
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Spanjaard P, Petit JM, Schmitt A, Vergès B, Bouillet B. Screening and management of metabolic complications of mTOR inhibitors in real-life settings. ANNALES D'ENDOCRINOLOGIE 2024; 85:263-268. [PMID: 38043912 DOI: 10.1016/j.ando.2023.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/10/2023] [Accepted: 11/20/2023] [Indexed: 12/05/2023]
Abstract
INTRODUCTION Inhibitors of mTOR (mTORi) are frequently used as anticancer treatment. They were responsible for metabolic side-effects in phase 3 studies, which provided only an incomplete picture of these metabolic complications. The aim of our study was therefore to evaluate, in a real-life setting, outcomes for patients with dyslipidemia or diabetes under mTORi, and the incidence and management of metabolic abnormalities occurring under mTORi in the absence of known metabolic history. METHODS This single-center retrospective study included all 177 patients receiving everolimus in the Cancer Center of Dijon, France, between May 2015 and November 2018. RESULTS Diabetes was diagnosed in 15 patients (9%), with an estimated mean time to onset of 160±173 days. Antidiabetic treatment was introduced in 41% of these patients. After mTORi discontinuation, diabetes persisted in 60% of patients in whom it had been diagnosed. Dyslipidemia was diagnosed in 22 patients (14%): 55% with hypercholesterolemia and 45% with hypertriglyceridemia. 18% were placed on lipid-lowering therapy. While all patients were screened for hyperglycemia and monitored for known diabetes, only 42% of patients without dyslipidemia were screened for lipids, and only 8% of patients with known dyslipidemia were monitored for lipids. CONCLUSION Our study is one of the few to look at metabolic complications secondary to mTORi in a real-life situation. The incidence of diabetes was high, but the use of antidiabetic treatment was variable. Normalization of glucose homeostasis after mTORi discontinuation is possible, particularly in patients who have not been placed on antidiabetic therapy. Screening for dyslipidemia was clearly inadequate in our study, making the data on this point more difficult to interpret. It appears that adherence to guidelines needs to be improved to optimize the management of patients treated with mTORi.
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Affiliation(s)
- Pamela Spanjaard
- Department of Endocrinology, Diabetes and Metabolic Disorders, Dijon University Hospital, Dijon, France
| | - Jean Michel Petit
- Department of Endocrinology, Diabetes and Metabolic Disorders, Dijon University Hospital, Dijon, France; Inserm Unit, LNC-UMR 1231, University of Burgundy, Dijon, France
| | - Antonin Schmitt
- Inserm Unit, LNC-UMR 1231, University of Burgundy, Dijon, France; Department of Pharmacy, Centre Georges-François Leclerc, Dijon, France
| | - Bruno Vergès
- Department of Endocrinology, Diabetes and Metabolic Disorders, Dijon University Hospital, Dijon, France; Inserm Unit, LNC-UMR 1231, University of Burgundy, Dijon, France
| | - Benjamin Bouillet
- Department of Endocrinology, Diabetes and Metabolic Disorders, Dijon University Hospital, Dijon, France; Inserm Unit, LNC-UMR 1231, University of Burgundy, Dijon, France.
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Du Y, Cai X. Therapeutic potential of natural compounds from herbs and nutraceuticals in spinal cord injury: Regulation of the mTOR signaling pathway. Biomed Pharmacother 2023; 163:114905. [PMID: 37207430 DOI: 10.1016/j.biopha.2023.114905] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/13/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023] Open
Abstract
Spinal cord injury (SCI) is a disease in which the spinal cord is subjected to various external forces that cause it to burst, shift, or, in severe cases, injure the spinal tissue, resulting in nerve injury. SCI includes not only acute primary injury but also delayed and persistent spinal tissue injury (i.e., secondary injury). The pathological changes post-SCI are complex, and effective clinical treatment strategies are lacking. The mammalian target of rapamycin (mTOR) coordinates the growth and metabolism of eukaryotic cells in response to various nutrients and growth factors. The mTOR signaling pathway has multiple roles in the pathogenesis of SCI. There is evidence for the beneficial effects of natural compounds and nutraceuticals that regulate the mTOR signaling pathways in a variety of diseases. Therefore, the effects of natural compounds on the pathogenesis of SCI were evaluated by a comprehensive review using electronic databases, such as PubMed, Web of Science, Scopus, and Medline, combined with our expertise in neuropathology. In particular, we reviewed the pathogenesis of SCI, including the importance of secondary nerve injury after the primary mechanical injury, the roles of the mTOR signaling pathways, and the beneficial effects and mechanisms of natural compounds that regulate the mTOR signaling pathway on pathological changes post-SCI, including effects on inflammation, neuronal apoptosis, autophagy, nerve regeneration, and other pathways. This recent research highlights the value of natural compounds in regulating the mTOR pathway, providing a basis for developing novel therapeutic strategies for SCI.
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Affiliation(s)
- Yan Du
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Xue Cai
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, PR China.
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Lambros M, Moreno J, Fei Q, Parsa C, Orlando R, Van Haute L. Transcriptome Sequencing Reveals the Mechanism behind Chemically Induced Oral Mucositis in a 3D Cell Culture Model. Int J Mol Sci 2023; 24:5058. [PMID: 36902486 PMCID: PMC10003620 DOI: 10.3390/ijms24055058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/24/2023] [Accepted: 02/26/2023] [Indexed: 03/09/2023] Open
Abstract
Oral mucositis is a common side effect of cancer treatment, and in particular of treatment with the mTORC1 inhibitor everolimus. Current treatment methods are not efficient enough and a better understanding of the causes and mechanisms behind oral mucositis is necessary to find potential therapeutic targets. Here, we treated an organotypic 3D oral mucosal tissue model consisting of human keratinocytes grown on top of human fibroblasts with a high or low dose of everolimus for 40 or 60 h and investigated (1) the effect of everolimus on microscopic sections of the 3D cell culture for evidence of morphologic changes and (2) changes in the transcriptome by high throughput RNA-Seq analysis. We show that the most affected pathways are cornification, cytokine expression, glycolysis, and cell proliferation and we provide further details. This study provides a good resource towards a better understanding of the development of oral mucositis. It gives a detailed overview of the different molecular pathways that are involved in mucositis. This in turn provides information about potential therapeutic targets, which is an important step towards preventing or managing this common side effect of cancer treatment.
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Affiliation(s)
- Maria Lambros
- Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Jonathan Moreno
- Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Qinqin Fei
- Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Cyrus Parsa
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Robert Orlando
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
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Hernandez-Rienda L, del Olmo-García MI, Merino-Torres JF. Impact of Diabetes Mellitus in Patients with Pancreatic Neuro-Endocrine Tumors: Causes, Consequences, and Future Perspectives. Metabolites 2022; 12:1103. [PMID: 36422243 PMCID: PMC9698930 DOI: 10.3390/metabo12111103] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/03/2022] [Accepted: 11/07/2022] [Indexed: 09/05/2023] Open
Abstract
Diabetes mellitus (DM) and pancreatic neuroendocrine tumors (pNETs) are two entities closely linked together. DM has been described as a risk factor for the development of pNETs and for the aggressiveness of the disease. On the other hand, DM due to pNETs is frequently undiagnosed or misclassified as type 2 DM when it is due to type 3 DM. In addition, metformin, a commonly prescribed drug for type 2 DM, has an antiproliferative property and is gaining increasing attention as an antitumor agent. This review article presents the findings published in the last few years on pNETs and DMs. Emphasis will be placed on DM as a risk factor, pNET as a risk factor for the development of type 3 DM, the management of type 3 DM on pNET, and DM as a prognostic factor in patients with pNET, as well as the future clinical implications of DM in these patients. The coexistence of DM and pNET is extensively presented. It is important to perform future clinical trials, which are necessary to establish the role of metformin on pNET disease. Increasing awareness among professionals managing pNET on the importance of a correct DM diagnosis and management of the disease must be a priority due to the implications on mortality and comorbidities it may have in these patients.
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Affiliation(s)
- Lorena Hernandez-Rienda
- Endocrinology and Nutrition Department, University and Politecnic Hospital La Fe, 46026 Valencia, Spain
- Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute Hospital La Fe-University of Valencia, 46026 Valencia, Spain
| | - Maria Isabel del Olmo-García
- Endocrinology and Nutrition Department, University and Politecnic Hospital La Fe, 46026 Valencia, Spain
- Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute Hospital La Fe-University of Valencia, 46026 Valencia, Spain
| | - Juan Francisco Merino-Torres
- Endocrinology and Nutrition Department, University and Politecnic Hospital La Fe, 46026 Valencia, Spain
- Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute Hospital La Fe-University of Valencia, 46026 Valencia, Spain
- Department of Medicine, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain
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Parrella A, Iannuzzi A, Annunziata M, Covetti G, Cavallaro R, Aliberti E, Tortori E, Iannuzzo G. Haematological Drugs Affecting Lipid Metabolism and Vascular Health. Biomedicines 2022; 10:biomedicines10081935. [PMID: 36009482 PMCID: PMC9405726 DOI: 10.3390/biomedicines10081935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/05/2022] [Accepted: 08/08/2022] [Indexed: 01/19/2023] Open
Abstract
Many drugs affect lipid metabolism and have side effects which promote atherosclerosis. The prevalence of cancer-therapy-related cardiovascular (CV) disease is increasing due to development of new drugs and improved survival of patients: cardio-oncology is a new field of interest and research. Moreover, drugs used in transplanted patients frequently have metabolic implications. Increasingly, internists, lipidologists, and angiologists are being consulted by haematologists for side effects on metabolism (especially lipid metabolism) and arterial circulation caused by drugs used in haematology. The purpose of this article is to review the main drugs used in haematology with side effects on lipid metabolism and atherosclerosis, detailing their mechanisms of action and suggesting the most effective therapies.
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Affiliation(s)
- Antonio Parrella
- Department of Medicine and Medical Specialties, A. Cardarelli Hospital, 80131 Naples, Italy
| | - Arcangelo Iannuzzi
- Department of Medicine and Medical Specialties, A. Cardarelli Hospital, 80131 Naples, Italy
| | | | - Giuseppe Covetti
- Department of Medicine and Medical Specialties, A. Cardarelli Hospital, 80131 Naples, Italy
| | - Raimondo Cavallaro
- Department of Medicine and Medical Specialties, A. Cardarelli Hospital, 80131 Naples, Italy
| | - Emilio Aliberti
- North Tees University Hospital, Stockton-on-Tees TS19 8PE, UK
| | - Elena Tortori
- Pharmacy Unit, Ospedale del Mare, 80147 Naples, Italy
| | - Gabriella Iannuzzo
- Department of Clinical Medicine and Surgery, Federico II University, 80131 Naples, Italy
- Correspondence:
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Joharatnam-Hogan N, Morganstein DL. Diabetes and Cancer - optimising glycaemic control. J Hum Nutr Diet 2022; 36:504-513. [PMID: 35748508 DOI: 10.1111/jhn.13051] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/31/2022] [Indexed: 01/08/2023]
Abstract
Diabetes and cancer are both common and increasingly prevalent conditions, but emerging epidemiological evidence confirms that the risk of developing a number of common cancers is increased in those with type 2 diabetes. The risk of cancer in type 1 diabetes is less clearly defined, and therefore this review will focus on type 2 diabetes. Emerging evidence also supports an influence of diabetes on outcomes of cancer treatment. However, this relationship is bi-directional, with cancer and its treatment impacting on glucose control, whilst there is also emerging evidence that diabetes care can deteriorate after a cancer diagnosis (summarised in Figure 1). Despite these clear links there is a lack of evidence to guide clinicians in how to manage patients with diabetes during their cancer treatment. Although recent UK guidelines have started to address this, with the development of guidance for the management of hyperglycaemia in cancer, there is a clear need for wider guidance on the management of multi-morbidity during cancer, including diabetes and obesity, to incorporate nutritional management We have therefore undertaken a narrative review of the evidence of links between type 2 diabetes and cancer incidence and outcomes, and discuss the challenges to diabetes care during cancer treatment. This article is protected by copyright. All rights reserved.
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Affiliation(s)
| | - Daniel L Morganstein
- Royal Marsden Hospital, Fulham Roal, London, SW3 6JJ, UK.,Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK
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8
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Leitner BP, Siebel S, Akingbesote ND, Zhang X, Perry RJ. Insulin and cancer: a tangled web. Biochem J 2022; 479:583-607. [PMID: 35244142 PMCID: PMC9022985 DOI: 10.1042/bcj20210134] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/13/2022] [Accepted: 02/15/2022] [Indexed: 12/13/2022]
Abstract
For a century, since the pioneering work of Otto Warburg, the interwoven relationship between metabolism and cancer has been appreciated. More recently, with obesity rates rising in the U.S. and worldwide, epidemiologic evidence has supported a link between obesity and cancer. A substantial body of work seeks to mechanistically unpack the association between obesity, altered metabolism, and cancer. Without question, these relationships are multifactorial and cannot be distilled to a single obesity- and metabolism-altering hormone, substrate, or factor. However, it is important to understand the hormone-specific associations between metabolism and cancer. Here, we review the links between obesity, metabolic dysregulation, insulin, and cancer, with an emphasis on current investigational metabolic adjuncts to standard-of-care cancer treatment.
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Affiliation(s)
- Brooks P. Leitner
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
| | - Stephan Siebel
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Pediatrics, Yale School of Medicine, New Haven, CT, U.S.A
| | - Ngozi D. Akingbesote
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
| | - Xinyi Zhang
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
| | - Rachel J. Perry
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
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Yang L, Zhang Z, Wang D, Jiang Y, Liu Y. Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications. Curr Drug Targets 2022; 23:692-710. [PMID: 35021971 DOI: 10.2174/1389450123666220111115528] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/21/2021] [Accepted: 12/01/2021] [Indexed: 11/22/2022]
Abstract
The mechanistic target of rapamycin (mTOR) is a pivotal regulator of cell metabolism and growth. In the form of two different multi-protein complexes, mTORC1 and mTORC2, mTOR integrates cellular energy, nutrient and hormonal signals to regulate cellular metabolic homeostasis. In type 2 diabetes mellitus (T2DM) aberrant mTOR signaling underlies its pathological conditions and end-organ complications. Substantial evidence suggests that two mTOR-mediated signaling schemes, mTORC1-p70S6 kinase 1 (S6K1) and mTORC2-protein kinase B (AKT), play a critical role in insulin sensitivity and that their dysfunction contributes to development of T2DM. This review summaries our current understanding of the role of mTOR signaling in T2DM and its associated complications, as well as the potential use of mTOR inhibitors in treatment of T2DM.
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Affiliation(s)
- Lin Yang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Zhixin Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Doudou Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yu Jiang
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Ying Liu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China
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Hertzberg C, Franz DN. Anti-convulsant Agents: Everolimus. NEUROPSYCHOPHARMACOTHERAPY 2022:3721-3751. [DOI: 10.1007/978-3-030-62059-2_306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Natalicchio A, Faggiano A, Zatelli MC, Argentiero A, D'Oronzo S, Marrano N, Beretta GD, Acquati S, Adinolfi V, Di Bartolo P, Danesi R, Ferrari P, Gori S, Morviducci L, Russo A, Tuveri E, Montagnani M, Gallo M, Silvestris N, Giorgino F. Metabolic disorders and gastroenteropancreatic-neuroendocrine tumors (GEP-NETs): How do they influence each other? An Italian Association of Medical Oncology (AIOM)/ Italian Association of Medical Diabetologists (AMD)/ Italian Society of Endocrinology (SIE)/ Italian Society of Pharmacology (SIF) multidisciplinary consensus position paper. Crit Rev Oncol Hematol 2021; 169:103572. [PMID: 34954047 DOI: 10.1016/j.critrevonc.2021.103572] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 12/13/2022] Open
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of malignancies derived from neuroendocrine cells that can occur anywhere along the gastrointestinal tract. GEP-NETs incidence has been steadily increasing over the past decades, in parallel with the increasing incidence of the metabolic syndrome (MetS). It is not yet fully known whether the MetS components (such as obesity, dyslipidemia and type 2 diabetes) could be involved in the etiology of GEP-NETs or could influence their outcomes. In this review, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) provides a critical view of the experimental and clinical evidence about the association of GEP-NETs risk, outcomes, and therapies with the metabolic disorders typical of MetS. The potential therapeutic strategies for an optimal management of patients with both GEP-NETs and MetS are also discussed.
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Affiliation(s)
- Annalisa Natalicchio
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical & Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.
| | - Maria Chiara Zatelli
- Section of Endocrinology & Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
| | | | - Stella D'Oronzo
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy.
| | - Nicola Marrano
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | | | - Silvia Acquati
- Endocrinology Unit, Ospedale Pierantoni-Morgagni, Forlì, Italy.
| | - Valerio Adinolfi
- Endocrinology and Diabetology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
| | - Paolo Di Bartolo
- Diabetology Clinic, Rete Clinica di Diabetologia Aziendale - Dipartimento, Internistico di Ravenna - AUSL Romagna, Ravenna, Italy.
| | - Romano Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
| | - Pietro Ferrari
- Palliative Care Unit, Istituti Clinici Scientifici Maugeri SPA SB, IRCCS (PV), Italy.
| | - Stefania Gori
- Oncologia Medica, IRCCS Ospedale Sacro Cuore Don Calabria di Negrar, Verona, Italy.
| | - Lelio Morviducci
- Diabetology and Nutrition Unit, Department of Medical Specialities, ASL Roma 1 - S. Spirito Hospital, Rome, Italy.
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Italy.
| | - Enzo Tuveri
- Diabetology, Endocrinology and Metabolic Diseases Service, ATS Sardegna - ASSL Carbonia-Iglesias, Italy.
| | - Monica Montagnani
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy.
| | - Marco Gallo
- Endocrinology and Metabolic Diseases Unit, AO SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.
| | - Nicola Silvestris
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy; Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy.
| | - Francesco Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
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12
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Yim C, Mansell K, Hussein N, Arnason T. Current cancer therapies and their influence on glucose control. World J Diabetes 2021; 12:1010-1025. [PMID: 34326951 PMCID: PMC8311484 DOI: 10.4239/wjd.v12.i7.1010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/11/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes. These groups of medications were selected due to their significant association with new onset hyperglycemia, or of potentially severe clinical consequences when present. These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments, and the antimetabolite class of 5-fluorouracil-related drugs. Both of these classes have been in use in cancer therapy since the 1950s. Also considered are the phosphatidyl inositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-inhibitors that provide cancer response advantages by disrupting cell growth, proliferation and survival signaling pathways, and have been in clinical use as early as 2007. The final class to be reviewed are the monoclonal antibodies selected to function as immune checkpoint inhibitors (ICIs). These were first used in 2011 for advanced melanoma and are rapidly becoming widely utilized in many solid tumors. For each drug class, the literature has been reviewed to answer relevant questions about these medications related specifically to the characteristics of the hyperglycemia that develops with use. The incidence of new glucose elevations in euglycemic individuals, as well as glycemic changes in those with established diabetes has been considered, as has the expected onset of hyperglycemia from their first use. This comparison emphasizes that some classes exhibit very immediate impacts on glucose levels, whereas other classes can have lengthy delays of up to 1 year. A comparison of the spectrum of severity of hyperglycemic consequences stresses that the appearance of diabetic ketoacidosis is rare for all classes except for the ICIs. There are distinct differences in the reversibility of glucose elevations after treatment is stopped, as the mTOR inhibitors and ICI classes have persistent hyperglycemia long term. These four highlighted drug categories differ in their underlying mechanisms driving hyperglycemia, with clinical presentations ranging from potent yet transient insulin resistant states [type 2 diabetes mellitus (T2DM) -like] to rare permanent insulin-deficient causes of hyperglycemia. Knowledge of the relative incidence of new onset hyperglycemia and the underlying causes are critical to appreciate how and when to best screen and treat patients taking any of these cancer drug therapies.
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Affiliation(s)
- Carly Yim
- Department of Medicine, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Kerry Mansell
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
| | - Nassrein Hussein
- Department of Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Terra Arnason
- Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
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13
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Agricola K, Stires G, Krueger DA, Capal JK, Franz DN, Ritter DM. Diabetes in Individuals With Tuberous Sclerosis Complex Treated With mTOR Inhibitors. Pediatr Neurol 2021; 120:7-10. [PMID: 33962348 DOI: 10.1016/j.pediatrneurol.2021.03.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 03/18/2021] [Accepted: 03/19/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Tuberous sclerosis complex (TSC) is a genetic disorder that is manifested in multiple body systems. A mammalian target of rapamycin (mTOR) inhibitor (mTORi), either everolimus or sirolimus, is now routinely prescribed for multiple clinical manifestations of TSC, including subependymal giant cell astrocytoma and epilepsy. These medications are generally well tolerated. Side effects previously identified in well-designed clinical trials tend to be mild and readily manageable. Regulatory approvals for the treatment of TSC have expanded the use of everolimus and sirolimus clinically, enlarging clinician experience and enabling identification of potential treatment-related effects that are rarer than could be identified or recognized in previous clinical trials. METHODS The medical records of clinical patients from our TSC center who were treated with an mTORi and later developed diabetes mellitus (DM) were analyzed and compared with those who were not treated with an mTORi. Eight individuals received detailed analysis, including laboratory results, concomitant medications, and body mass indices. RESULTS Among the 1576 individuals with TSC, 4% taking an mTORi developed diabetes compared with 0.6% of those not on mTORi, showing a significant interaction between DM and mTORi (chi-square = 18.1, P < 0.001). Details of eight patients who developed DM were presented. CONCLUSIONS The long-term use of mTORi agents in TSC may contribute to a risk of diabetes. Early detection can be critical in management. Additional studies are need to further investigate a causal relationship, but clinicians should be aware of this possible association when initiating and monitoring ongoing treatment.
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Affiliation(s)
- Karen Agricola
- Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
| | - Gabrielle Stires
- Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Darcy A Krueger
- Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Jamie K Capal
- Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - David N Franz
- Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - David M Ritter
- Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio
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14
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Miner M, Elbaum M, Jawiarczyk-Przybyłowska A, Kubicka E. Endocrine complications of new anticancer therapies. POSTEP HIG MED DOSW 2021. [DOI: 10.5604/01.3001.0014.8121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Studying and analyzing of complex molecular mechanisms and immunological processes of
cancer enables oncology to introduce new cancer therapies. In the treatment of cancer, we
successively increase the use of targeted therapies with tyrosine kinase inhibitors and mTOR
inhibitors and immunotherapy using checkpoint inhibitors CTLA-4 (cytotoxic T-cell antigen-4)
and PD-1/PD-L1 (programmed death receptor 1/programmed death ligand 1). New anticancer
drugs gradually replace conventional chemotherapy and have already found application in the
treatment of many cancers, including thyroid cancer, hepatocellular carcinoma, non-small
cell lung cancer, kidney cancer, bladder cancer, melanoma, breast cancer, acute and chronic
myelogenous leukemia. The use of these drugs is less toxic than classical chemotherapy, but
it can cause gastrointestinal, cardiovascular, respiratory, skin and endocrine complications.
Most of the side effects of new cancer therapies are mild and moderate disorders, however
some might be severe and life-threatening. Endocrinopathies are one of the more common
side effects of these treatments. They can affect many endocrine glands (pituitary, thyroid,
parathyroid, adrenal, pancreas) and cause both transient and permanent disorders.
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Affiliation(s)
- Michał Miner
- Katedra i Klinika Endokrynologii, Diabetologii i Leczenia Izotopami, Uniwersytet Medyczny im. Piastów Śląskich we Wrocławiu
| | - Michał Elbaum
- Katedra i Klinika Endokrynologii, Diabetologii i Leczenia Izotopami, Uniwersytet Medyczny im. Piastów Śląskich we Wrocławiu
| | | | - Eliza Kubicka
- Katedra i Klinika Endokrynologii, Diabetologii i Leczenia Izotopami, Uniwersytet Medyczny im. Piastów Śląskich we Wrocławiu
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15
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Silvestris N, Argentiero A, Beretta GD, Di Bartolo P, Montagnani M, Danesi R, Ferrari P, D'Oronzo S, Gori S, Russo A, Acquati S, Gallo M. Management of metabolic adverse events of targeted therapies and immune checkpoint inhibitors in cancer patients: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper. Crit Rev Oncol Hematol 2020; 154:103066. [PMID: 32853883 DOI: 10.1016/j.critrevonc.2020.103066] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/22/2020] [Accepted: 07/23/2020] [Indexed: 12/16/2022] Open
Abstract
The growing insights in the next-generation immunotherapy and the state-of-the-art advancement in targeted-agents significantly improved clinical outcome of cancer patients by pointing towards a unexplored Achilles' heel. Novel toxicity profiles have been uncovered, representing unmet medical needs. Thus, a panel of expert provide comprehensive pharmacological and clinical evidence, to provide a patient-tailored approach to metabolic adverse events associated with novel anti-cancer treatments. Prompted by the need of a multidisciplinary cooperation, a working group of Associazione Italiana Oncologia Medica (AIOM), Associazione Medici Diabetologi (AMD) and Società Italiana Farmacologia (SIF) examined the available literature data. The identification of patient risk profile and the characterization of metabolic effects of novel anti-tumour drugs is clearly a clinical challenge that can be addressed by a multidisciplinary clinical approach. Therefore, this review pinpoints the relevance of the challenging profiling of the patient suffering from dysmetabolic conditions induced by the novel therapeutics in medical oncology.
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Affiliation(s)
- Nicola Silvestris
- IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, Italy; Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy.
| | | | | | - Paolo Di Bartolo
- Diabetology Unit, Rete Clinica di Diabetologia Aziendale - Dipartimento, Internistico di Ravenna - AUSL Romagna, Ravenna, Italy
| | - Monica Montagnani
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Romano Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Pietro Ferrari
- Palliative Care Unit, Istituti Clinici Scientifici Maugeri SPA SB, IRCCS (PV), Italy
| | - Stella D'Oronzo
- IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, Italy; Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Stefania Gori
- Oncologia Medica, IRCCS Ospedale Don Calabria-Sacro Cuore di Negrar, Verona, Italy
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Italy
| | - Silvia Acquati
- Endocrinology Unit, Ospedale Pierantoni-Morgagni, Forlì, Italy
| | - Marco Gallo
- Oncological Endocrinology Unit, Department of Medical Sciences, University of Torino, AOU Città della Salute e della Scienza di Torino, Torino, Italy
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16
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Milluzzo A, Vigneri P, Martorana F, Vigneri R, Sciacca L. Type 2 diabetes and cancer: problems and suggestions for best patient management. EXPLORATION OF MEDICINE 2020. [DOI: 10.37349/emed.2020.00013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Diabetes and cancer are widespread worldwide and the number of subjects presenting both diseases increased over the years. The management of cancer patients having diabetes represents a challenge not only because of the complexity and heterogeneity of these pathologies but also for the lack of standardised clinical guidelines. The diagnosis of cancer is traumatizing and monopolizes the attention of both patients and caregivers. Thus, pre-existent or new-onset diabetes can be overshadowed thus increasing the risk for short- and long-term adverse events. Moreover, drugs used for each disease can interfere with the clinical course of the concomitant disease, making challenging the management of these patients. Over the years, this issue has become more relevant because of the increased patients’ life expectancy due to the improved efficacy of diabetes and cancer therapies.
The purpose of this review is to highlight what is known and what should be taken into consideration to optimise the clinical management of patients with diabetes and cancer. Due to the complexity of these diseases, a multidisciplinary, shared approach, including all the protagonists involved, is necessary to improve patients’ quality of life and lifespan.
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Affiliation(s)
- Agostino Milluzzo
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, 95122 Catania, Italy
| | - Paolo Vigneri
- Center of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, University of Catania, A.O.U. Policlinico-Vittorio Emanuele, 95124 Catania, Italy
| | - Federica Martorana
- Center of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, University of Catania, A.O.U. Policlinico-Vittorio Emanuele, 95124 Catania, Italy
| | - Riccardo Vigneri
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, 95122 Catania, Italy; Institute of Crystallography, Catania Section, National Research Council, CNR, 95126 Catania, Italy
| | - Laura Sciacca
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, 95122 Catania, Italy
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17
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Mühlenberg T, Ketzer J, Heinrich MC, Grunewald S, Marino-Enriquez A, Trautmann M, Hartmann W, Wardelmann E, Treckmann J, Worm K, Bertram S, Herold T, Schildhaus HU, Glimm H, Stenzinger A, Brors B, Horak P, Hohenberger P, Fröhling S, Fletcher JA, Bauer S. KIT-Dependent and KIT-Independent Genomic Heterogeneity of Resistance in Gastrointestinal Stromal Tumors - TORC1/2 Inhibition as Salvage Strategy. Mol Cancer Ther 2019; 18:1985-1996. [PMID: 31308077 DOI: 10.1158/1535-7163.mct-18-1224] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 01/21/2019] [Accepted: 07/08/2019] [Indexed: 11/16/2022]
Abstract
Sporadic gastrointestinal stromal tumors (GIST), characterized by activating mutations of KIT or PDGFRA, favorably respond to KIT inhibitory treatment but eventually become resistant. The development of effective salvage treatments is complicated by the heterogeneity of KIT secondary resistance mutations. Recently, additional mutations that independently activate KIT-downstream signaling have been found in pretreated patients-adding further complexity to the scope of resistance. We collected genotyping data for KIT from tumor samples of pretreated GIST, providing a representative overview on the distribution and incidence of secondary KIT mutations (n = 80). Analyzing next-generation sequencing data of 109 GIST, we found that 18% carried mutations in KIT-downstream signaling intermediates (NF1/2, PTEN, RAS, PIK3CA, TSC1/2, AKT, BRAF) potentially mediating resistance to KIT inhibitors. Notably, we found no apparent other driver mutations in refractory cases that were analyzed by whole exome/genome sequencing (13/109). Using CRISPR/Cas9 methods, we generated a panel of GIST cell lines harboring mutations in KIT, PTEN, KRAS, NF1, and TSC2 We utilized this panel to evaluate sapanisertib, a novel mTOR kinase inhibitor, as a salvage strategy. Sapanisertib had potent antiproliferative effects in all cell lines, including those with KIT-downstream mutations. Combinations with KIT or MEK inhibitors completely abrogated GIST-survival signaling and displayed synergistic effects. Our isogenic cell line panel closely approximates the genetic heterogeneity of resistance observed in heavily pretreated patients with GIST. With the clinical development of novel, broad spectrum KIT inhibitors, emergence of non-KIT-related resistance may require combination treatments with inhibitors of KIT-downstream signaling such as mTOR or MEK.
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Affiliation(s)
- Thomas Mühlenberg
- Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Julia Ketzer
- Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Michael C Heinrich
- Portland VA Health Care System, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
| | - Susanne Grunewald
- Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Adrian Marino-Enriquez
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Marcel Trautmann
- Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Wolfgang Hartmann
- Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Eva Wardelmann
- Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Jürgen Treckmann
- Department of Visceral and Transplant Surgery, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany
| | - Karl Worm
- Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Germany
| | - Stefanie Bertram
- Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Germany
| | - Thomas Herold
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Germany
| | | | - Hanno Glimm
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden University Hospital, Dresden, Germany
| | - Albrecht Stenzinger
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Benedikt Brors
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Department of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg University, Heidelberg, Germany
| | - Peter Horak
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg University Hospital, Heidelberg, Germany
| | | | - Stefan Fröhling
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg University Hospital, Heidelberg, Germany
| | - Jonathan A Fletcher
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Sebastian Bauer
- Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.
- German Cancer Consortium (DKTK), Heidelberg, Germany
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18
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Phenformin as an Anticancer Agent: Challenges and Prospects. Int J Mol Sci 2019; 20:ijms20133316. [PMID: 31284513 PMCID: PMC6651400 DOI: 10.3390/ijms20133316] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 06/28/2019] [Accepted: 07/03/2019] [Indexed: 12/13/2022] Open
Abstract
Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as fat-induced chronic inflammation, hyperglycemia, hyperinsulinemia, and angiogenesis. Chemotherapeutic agents are used in the treatment of cancer, but in most cases, patients develop resistance. Phenformin, an oral biguanide drug used to treat type 2 diabetes mellitus, was removed from the market due to a high risk of fatal lactic acidosis. However, it has been shown that phenformin is, with other biguanides, an authentic tumor disruptor, not only by the production of hypoglycemia due to caloric restriction through AMP-activated protein kinase with energy detection (AMPK) but also as a blocker of the mTOR regulatory complex. Moreover, the addition of phenformin eliminates resistance to antiangiogenic tyrosine kinase inhibitors (TKI), which prevent the uncontrolled metabolism of glucose in tumor cells. In this review, we evidence the great potential of phenformin as an anticancer agent. We thoroughly review its mechanism of action and clinical trial assays, specially focusing on current challenges and future perspectives of this promising drug.
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19
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Kokuho N, Terasaki Y, Kunugi S, Saito Y, Urushiyama H, Terasaki M, Hayashi H, Gemma A, Shimizu A. Analyses of alveolar epithelial injury via lipid-related stress in mammalian target of rapamycin inhibitor-induced lung disease. J Transl Med 2019; 99:853-865. [PMID: 30728465 DOI: 10.1038/s41374-018-0158-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Revised: 09/22/2018] [Accepted: 10/18/2018] [Indexed: 11/09/2022] Open
Abstract
Although mammalian target of rapamycin inhibitors (mTORi) are used to treat various malignancies, they frequently induce active alveolitis and dyslipidemia. Abnormal lipid metabolism affects alveolar surfactant function and results in pulmonary disorders; however, the pathophysiology of lung injury and its relationship with lipid metabolism remain unknown. We investigated the relationship between lipid metabolism and alveolar epithelial injury, focusing on peroxisome proliferator-activated receptor-γ (PPAR-γ) as a lipid stress-related factor in mTORi-induced lung injury. We clinicopathologically examined three patients with mTORi-induced lung injury. We constructed an mTORi injury mouse model using temsirolimus in mice (30 mg/kg/day), with the vehicle control and bleomycin injury groups. We also constructed a cultured alveolar epithelial cell injury model using temsirolimus (0-40 μM) in the mouse lung epithelial cell line MLE-12 and performed analysis with or without pioglitazone (PPAR-γ agonist) treatment. All three patients had dyslipidemia and lung lesions of hyperplastic pneumocytes with foamy and enlarged changes. In the mouse model, temsirolimus induced significantly higher levels of total cholesterol and free fatty acids in serum and higher levels of surfactant protein D in serum and BAL fluid with an increase in inflammatory cytokines in the lung compared to control. Temsirolimus also induced hyperplastic foamy pneumocytes with increased lipid-associated spots and larger round electron-lucent bodies compared to the control or bleomycin groups in microscopic analyses. Multiple lipid-associated spots within the cytoplasm were also induced by temsirolimus administration in MLE-12 cells. Temsirolimus downregulated PPAR-γ expression in mouse lung and MLE-12 cells but upregulated cleaved caspase-3 in MLE-12 cells. Pioglitazone blocked the upregulated cleaved caspase-3 expression in MLE-12 cells. The pathogenesis of mTORi-induced lung disease may be involved in alveolar epithelial injury, via lipid metabolic stress associated with downregulated PPAR-γ expression. Focusing on the relationship between lipid metabolic stress and alveolar epithelial injury represents a potentially novel approach to the study of pulmonary damage.
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Affiliation(s)
- Nariaki Kokuho
- Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.,Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Yasuhiro Terasaki
- Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
| | - Shinobu Kunugi
- Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Yoshinobu Saito
- Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Hirokazu Urushiyama
- Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Mika Terasaki
- Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Hiroki Hayashi
- Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Akihiko Gemma
- Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Akira Shimizu
- Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
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20
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Huang KY, Wang JN, Zhou YY, Wu SZ, Tao LY, Peng YP, Que JQ, Xue YJ, Ji KT. Antithrombin III Alleviates Myocardial Ischemia/Reperfusion Injury by Inhibiting Excessive Autophagy in a Phosphoinositide 3-Kinase/Akt-Dependent Manner. Front Pharmacol 2019; 10:516. [PMID: 31133861 PMCID: PMC6522837 DOI: 10.3389/fphar.2019.00516] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 04/24/2019] [Indexed: 01/05/2023] Open
Abstract
Autophagy is fundamental to myocardial ischemia/reperfusion (I/R) injury. Antithrombin III (AT) has been shown to protect cardiomyocytes against I/R injury; however, it is unknown whether it modulates autophagy. The objective of this study was to investigate whether AT regulates autophagy during I/R injury and, if so, to identify the potential mechanism involved. Our study showed that AT attenuated I/R injury in vivo and hypoxia/reoxygenation (H/R) injury in vitro. Autophagy was increased both in H9C2 cardiomyocytes during H/R injury and in mouse hearts following I/R injury. The stimulation of autophagy by rapamycin attenuated the protective effect of AT against H9C2 cell injury, indicating that autophagy is involved in the protective role of AT. Furthermore, the cardioprotective effects of AT were abolished by A6730, a specific Akt inhibitor. This study shows that AT exhibits cardioprotective effects by modulating autophagy during I/R injury in a phosphoinositide 3-kinase/Akt-dependent manner.
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Affiliation(s)
- Kai-Yu Huang
- Department of Cardiology, The Second Affiliated and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jiao-Ni Wang
- Department of Cardiology, The Second Affiliated and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ying-Ying Zhou
- Department of Endocrinology, The Second Affiliated and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shao-Ze Wu
- Department of Cardiology, The Second Affiliated and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Cardiology, Zhejiang Hospital, Hangzhou, China
| | - Lu-Yuan Tao
- Department of Cardiology, The Second Affiliated and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Cardiology, Taizhou First People's Hospital, Taizhou, China
| | - Yang-Pei Peng
- Department of Cardiology, The Second Affiliated and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jia-Qun Que
- Department of Cardiology, The Second Affiliated and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yang-Jing Xue
- Department of Cardiology, The Second Affiliated and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kang-Ting Ji
- Department of Cardiology, The Second Affiliated and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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21
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Chow EJ, Leger KJ, Bhatt NS, Mulrooney DA, Ross CJ, Aggarwal S, Bansal N, Ehrhardt MJ, Armenian SH, Scott JM, Hong B. Paediatric cardio-oncology: epidemiology, screening, prevention, and treatment. Cardiovasc Res 2019; 115:922-934. [PMID: 30768157 PMCID: PMC6452306 DOI: 10.1093/cvr/cvz031] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 01/18/2019] [Accepted: 02/13/2019] [Indexed: 12/11/2022] Open
Abstract
With 5-year survival of children with cancer exceeding 80% in developed countries, premature cardiovascular disease is now a major cause of early morbidity and mortality. In addition to the acute and chronic cardiotoxic effects of anthracyclines, related chemotherapeutics, and radiation, a growing number of new molecular targeted agents may also have detrimental effects on the cardiovascular system. Survivors of childhood cancer also may have earlier development of conventional cardiovascular risk factors such as hypertension, dyslipidaemia, and diabetes, which further increase their risk of serious cardiovascular disease. This review will examine the epidemiology of acute and chronic cardiotoxicity relevant to paediatric cancer patients, including genetic risk factors. We will also provide an overview of current screening recommendations, including the evidence regarding both imaging (e.g. echocardiography and magnetic resonance imaging) and blood-based biomarkers. Various primary and secondary prevention strategies will also be discussed, primarily in relation to anthracycline-related cardiomyopathy. Finally, we review the available evidence related to the management of systolic and diastolic dysfunction in paediatric cancer patients and childhood cancer survivors.
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Affiliation(s)
- Eric J Chow
- Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA, USA
- Clinical Research and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., PO Box 19024, Mailstop M4-C308, Seattle, WA 98109, USA
| | - Kasey J Leger
- Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA, USA
| | - Neel S Bhatt
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Daniel A Mulrooney
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Colin J Ross
- Faculty of Pharmaceutical Sciences, University of British Columbia, BC Children’s Hospital, Vancouver, BC, Canada
| | - Sanjeev Aggarwal
- Division of Pediatric Cardiology, Children’s Hospital of Michigan, Wayne State University, Detroit, MI, USA
| | - Neha Bansal
- Division of Pediatric Cardiology, Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Matthew J Ehrhardt
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Saro H Armenian
- Department of Population Sciences, City of Hope Medical Center, Duarte, CA, USA
| | - Jessica M Scott
- Exercise Oncology Research Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Borah Hong
- Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA, USA
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22
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Milluzzo A, Tumminia A, Vella V, Gianì F, Manzella L, Frittitta L, Belfiore A, Vigneri R, Sciacca L. Short-term adverse effects of anticancer drugs in patients with type 2 diabetes. J Chemother 2019; 31:150-159. [DOI: 10.1080/1120009x.2019.1572297] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Agostino Milluzzo
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
| | - Andrea Tumminia
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
| | - Veronica Vella
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
- School of Human and Social Science, University “Kore” of Enna, Enna, Italy
| | - Fiorenza Gianì
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
| | - Livia Manzella
- Department of Clinical and Experimental Medicine, University of Catania Medical School, Center of Experimental Oncology and Hematology, Catania, Italy
| | - Lucia Frittitta
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
| | - Antonino Belfiore
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
| | - Riccardo Vigneri
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
- Institute of Bioimages and Biostructures, CNR, Catania, Italy
| | - Laura Sciacca
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
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23
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Shariff AI, Syed S, Shelby RA, Force J, Clarke JM, D'Alessio D, Corsino L. Novel cancer therapies and their association with diabetes. J Mol Endocrinol 2019; 62:R187-R199. [PMID: 30532995 DOI: 10.1530/jme-18-0002] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 10/25/2018] [Indexed: 12/29/2022]
Abstract
Over the last decade, there has been a shift in the focus of cancer therapy from conventional cytotoxic drugs to therapies more specifically directed to cancer cells. These novel therapies include immunotherapy, targeted therapy and precision medicine, each developed in great part with a goal of limiting collateral destruction of normal tissues, while enhancing tumor destruction. Although this approach is sound in theory, even new, specific therapies have some undesirable, 'off target effects', in great part due to molecular pathways shared by neoplastic and normal cells. One such undesirable effect is hyperglycemia, which results from either the loss of immune tolerance and autoimmune destruction of pancreatic β-cells or dysregulation of the insulin signaling pathway resulting in insulin resistance. These distinct pathogenic mechanisms lead to clinical presentations similar to type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. Both types of diabetes have been reported in patients across clinical trials, and data on the mechanism(s) for developing hyperglycemia, prevalence, prognosis and effect on cancer mortality is still emerging. With the rapidly expanding list of clinical indications for new cancer therapies, it is essential to understand the impact of their adverse effects. In this review, we focus on hyperglycemia and diabetes related to cancer therapies, describe what is known about mechanism(s) leading to dysregulated glucose metabolism and provide a guide to management of complex oncology patients with a new diagnosis of diabetes.
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Affiliation(s)
- Afreen Idris Shariff
- Division of Endocrinology, Metabolism and Nutrition, Duke University School of Medicine, Durham, North Carolina, USA
| | - Sohail Syed
- Virginia Commonwealth University, Richmond, Virginia, USA
| | - Rebecca A Shelby
- Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jeremy Force
- Division of Medical Oncology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jeffrey Melson Clarke
- Division of Medical Oncology, Duke University School of Medicine, Durham, North Carolina, USA
| | - David D'Alessio
- Division of Endocrinology, Metabolism and Nutrition, Duke University School of Medicine, Durham, North Carolina, USA
| | - Leonor Corsino
- Division of Endocrinology, Metabolism and Nutrition, Duke University School of Medicine, Durham, North Carolina, USA
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24
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Therapeutic Use of mTOR Inhibitors in Renal Diseases: Advances, Drawbacks, and Challenges. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:3693625. [PMID: 30510618 PMCID: PMC6231362 DOI: 10.1155/2018/3693625] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 09/07/2018] [Accepted: 09/25/2018] [Indexed: 02/06/2023]
Abstract
The mammalian (or mechanistic) target of rapamycin (mTOR) pathway has a key role in the regulation of a variety of biological processes pivotal for cellular life, aging, and death. Impaired activity of mTOR complexes (mTORC1/mTORC2), particularly mTORC1 overactivation, has been implicated in a plethora of age-related disorders, including human renal diseases. Since the discovery of rapamycin (or sirolimus), more than four decades ago, advances in our understanding of how mTOR participates in renal physiological and pathological mechanisms have grown exponentially, due to both preclinical studies in animal models with genetic modification of some mTOR components as well as due to evidence coming from the clinical experience. The main clinical indication of rapamycin is as immunosuppressive therapy for the prevention of allograft rejection, namely, in renal transplantation. However, considering the central participation of mTOR in the pathogenesis of other renal disorders, the use of rapamycin and its analogs meanwhile developed (rapalogues) everolimus and temsirolimus has been viewed as a promising pharmacological strategy. This article critically reviews the use of mTOR inhibitors in renal diseases. Firstly, we briefly overview the mTOR components and signaling as well as the pharmacological armamentarium targeting the mTOR pathway currently available or in the research and development stages. Thereafter, we revisit the mTOR pathway in renal physiology to conclude with the advances, drawbacks, and challenges regarding the use of mTOR inhibitors, in a translational perspective, in four classes of renal diseases: kidney transplantation, polycystic kidney diseases, renal carcinomas, and diabetic nephropathy.
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25
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Bouillet B, Buffier P, Smati S, Archambeaud F, Cariou B, Vergès B. Expert opinion on the metabolic complications of mTOR inhibitors. ANNALES D'ENDOCRINOLOGIE 2018; 79:583-590. [PMID: 30144939 DOI: 10.1016/j.ando.2018.07.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Using mTOR inhibitors (mTORi) as anticancer drugs led to hyperglycemia (12-50%) and hyperlipidemia (7-73%) in phase-III trials. These high rates require adapted treatment in cancer patients. Before initiating mTORi treatment, lipid profile screening should be systematic, with fasting glucose assay in non-diabetic patients and HbA1C in diabetic patients. After initiation, lipid profile monitoring should be systematic, with fasting glucose assay in non-diabetic patients, every 2 weeks for the first month and then monthly. The HbA1C target is≤8%, before and after treatment initiation in known diabetic patients and in case of onset of diabetes under mTORi. LDL-cholesterol targets should be adapted to general health status and cardiovascular and oncologic prognosis. If treatment is indicated, pravastatin should be prescribed in first line; atorvastatin and simvastatin are contraindicated. Fenofibrate should be prescribed for hypertriglyceridemia>5g/l resisting dietary measures adapted to oncologic status. In non-controllable hypertriglyceridemia exceeding 10g/l, mTORi treatment should be interrupted and specialist opinion should be sought.
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Affiliation(s)
- Benjamin Bouillet
- Service d'endocrinologie, diabétologie, maladies métaboliques, CHU de Dijon, 2, boulevard du Maréchal-de-Lattre, BP 77908, 21000 Dijon, France; Unité Inserm, LNC-UMR 1231, université de Bourgogne, Dijon, France.
| | - Perrine Buffier
- Service d'endocrinologie, diabétologie, maladies métaboliques, CHU de Dijon, 2, boulevard du Maréchal-de-Lattre, BP 77908, 21000 Dijon, France
| | - Sarra Smati
- Clinique d'endocrinologie, Institut du Thorax, CHU de Nantes, Nantes, France
| | | | - Bertrand Cariou
- Clinique d'endocrinologie, Institut du Thorax, CHU de Nantes, Nantes, France
| | - Bruno Vergès
- Service d'endocrinologie, diabétologie, maladies métaboliques, CHU de Dijon, 2, boulevard du Maréchal-de-Lattre, BP 77908, 21000 Dijon, France; Unité Inserm, LNC-UMR 1231, université de Bourgogne, Dijon, France
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26
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Chow EJ, Antal Z, Constine LS, Gardner R, Wallace WH, Weil BR, Yeh JM, Fox E. New Agents, Emerging Late Effects, and the Development of Precision Survivorship. J Clin Oncol 2018; 36:2231-2240. [PMID: 29874142 PMCID: PMC6053298 DOI: 10.1200/jco.2017.76.4647] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Incremental improvements in the treatment of children and adolescents with cancer have led to 5-year survival rates reaching nearly 85%. In the past decade, impressive progress has been made in understanding the biology of many pediatric cancers. With that understanding, multiple new agents have become available that offer the promise of more-effective and less-toxic treatment. These include agents that target various cell surface antigens and engage the adaptive immune system, as well as those that interfere with key signaling pathways involved in tumor development and growth. For local control, surgery and radiation techniques also have evolved, becoming less invasive or featuring new techniques and particles that more precisely target the tumor and limit the dose to normal tissue. Nevertheless, targeted agents, like conventional chemotherapy, radiotherapy, and surgery, may have off-target effects and deserve long-term follow-up of their safety and efficacy. These include injury to the endocrine, cardiovascular, and immunologic systems. New radiation and surgical techniques that theoretically reduce morbidity and improve long-term quality of life must also be validated with actual patient outcomes. Finally, with advances in genomics, information on host susceptibility to late effects is beginning to emerge. Such knowledge, coupled with improved metrics that better describe the spectrum of potential late effects across the entire lifespan, can lead to the development of decision models that project the potential long-term health outcomes associated with various treatment and follow-up strategies. These developments will help extend the current focus on precision medicine to precision survivorship, where clinicians, patients, and families will have a better grasp of the potential risks, benefits, and tradeoffs associated with the growing number of cancer treatment options.
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Affiliation(s)
- Eric J Chow
- Eric J. Chow and Rebecca Gardner, Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, and University of Washington, Seattle, WA; Zoltan Antal, Weill Cornell Medical College, New York Presbyterian Hospital, and Memorial Sloan Kettering Cancer Center, New York; Louis S. Constine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY; W. Hamish Wallace, Royal Hospital for Sick Children, University of Edinburgh, Edinburgh, United Kingdom; Brent R. Weil and Jennifer M. Yeh, Boston Children's Hospital, Harvard Medical School, Boston, MA; and Elizabeth Fox, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
| | - Zoltan Antal
- Eric J. Chow and Rebecca Gardner, Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, and University of Washington, Seattle, WA; Zoltan Antal, Weill Cornell Medical College, New York Presbyterian Hospital, and Memorial Sloan Kettering Cancer Center, New York; Louis S. Constine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY; W. Hamish Wallace, Royal Hospital for Sick Children, University of Edinburgh, Edinburgh, United Kingdom; Brent R. Weil and Jennifer M. Yeh, Boston Children's Hospital, Harvard Medical School, Boston, MA; and Elizabeth Fox, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
| | - Louis S Constine
- Eric J. Chow and Rebecca Gardner, Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, and University of Washington, Seattle, WA; Zoltan Antal, Weill Cornell Medical College, New York Presbyterian Hospital, and Memorial Sloan Kettering Cancer Center, New York; Louis S. Constine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY; W. Hamish Wallace, Royal Hospital for Sick Children, University of Edinburgh, Edinburgh, United Kingdom; Brent R. Weil and Jennifer M. Yeh, Boston Children's Hospital, Harvard Medical School, Boston, MA; and Elizabeth Fox, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
| | - Rebecca Gardner
- Eric J. Chow and Rebecca Gardner, Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, and University of Washington, Seattle, WA; Zoltan Antal, Weill Cornell Medical College, New York Presbyterian Hospital, and Memorial Sloan Kettering Cancer Center, New York; Louis S. Constine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY; W. Hamish Wallace, Royal Hospital for Sick Children, University of Edinburgh, Edinburgh, United Kingdom; Brent R. Weil and Jennifer M. Yeh, Boston Children's Hospital, Harvard Medical School, Boston, MA; and Elizabeth Fox, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
| | - W Hamish Wallace
- Eric J. Chow and Rebecca Gardner, Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, and University of Washington, Seattle, WA; Zoltan Antal, Weill Cornell Medical College, New York Presbyterian Hospital, and Memorial Sloan Kettering Cancer Center, New York; Louis S. Constine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY; W. Hamish Wallace, Royal Hospital for Sick Children, University of Edinburgh, Edinburgh, United Kingdom; Brent R. Weil and Jennifer M. Yeh, Boston Children's Hospital, Harvard Medical School, Boston, MA; and Elizabeth Fox, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
| | - Brent R Weil
- Eric J. Chow and Rebecca Gardner, Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, and University of Washington, Seattle, WA; Zoltan Antal, Weill Cornell Medical College, New York Presbyterian Hospital, and Memorial Sloan Kettering Cancer Center, New York; Louis S. Constine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY; W. Hamish Wallace, Royal Hospital for Sick Children, University of Edinburgh, Edinburgh, United Kingdom; Brent R. Weil and Jennifer M. Yeh, Boston Children's Hospital, Harvard Medical School, Boston, MA; and Elizabeth Fox, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
| | - Jennifer M Yeh
- Eric J. Chow and Rebecca Gardner, Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, and University of Washington, Seattle, WA; Zoltan Antal, Weill Cornell Medical College, New York Presbyterian Hospital, and Memorial Sloan Kettering Cancer Center, New York; Louis S. Constine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY; W. Hamish Wallace, Royal Hospital for Sick Children, University of Edinburgh, Edinburgh, United Kingdom; Brent R. Weil and Jennifer M. Yeh, Boston Children's Hospital, Harvard Medical School, Boston, MA; and Elizabeth Fox, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
| | - Elizabeth Fox
- Eric J. Chow and Rebecca Gardner, Fred Hutchinson Cancer Research Center, Seattle Children's Hospital, and University of Washington, Seattle, WA; Zoltan Antal, Weill Cornell Medical College, New York Presbyterian Hospital, and Memorial Sloan Kettering Cancer Center, New York; Louis S. Constine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY; W. Hamish Wallace, Royal Hospital for Sick Children, University of Edinburgh, Edinburgh, United Kingdom; Brent R. Weil and Jennifer M. Yeh, Boston Children's Hospital, Harvard Medical School, Boston, MA; and Elizabeth Fox, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
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27
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Veiga SR, Ge X, Mercer CA, Hernández-Álvarez MI, Thomas HE, Hernandez-Losa J, Ramón Y Cajal S, Zorzano A, Thomas G, Kozma SC. Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR. Clin Cancer Res 2018; 24:3767-3780. [PMID: 29691292 DOI: 10.1158/1078-0432.ccr-18-0177] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 04/05/2018] [Accepted: 04/19/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mTOR for the treatment of HCC. However, such inhibitors induce hyperglycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor phenformin could reverse both side effects, impose an energetic stress on cancer cells, and suppress the growth of HCC.Experimental Design: Human HCC cell lines were used in vitro to access the signaling and energetic impact of mTOR inhibitors and phenformin, either alone or in combination. Next, the therapeutic utility of these drugs alone or in combination was investigated preclinically in human orthotopic tumors implanted in mice, by analyzing their impact on the tumor burden and overall survival.Results: We found phenformin caused mitochondrial dysfunction and fragmentation, inducing a compensatory shift to glycolysis. In contrast, dual inhibition of mTOR impaired cell growth and glycolysis, while increasing mitochondrial fusion and efficiency. In a mouse model of human HCC, dual inhibition of mTOR, together with phenformin, was highly efficacious in controlling tumor burden. However, more strikingly, pretreatment with phenformin sensitized tumors to dual inhibition of mTOR, leading to a dramatic improvement in survival.Conclusions: Treatment of HCC cells in vitro with the biguanide phenformin causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation, and dramatically sensitizes orthotopic liver tumors to dual inhibition of mTOR. We therefore propose this therapeutic approach should be tested clinically in HCC. Clin Cancer Res; 24(15); 3767-80. ©2018 AACR.
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Affiliation(s)
- Sónia R Veiga
- Laboratory of Cancer Metabolism, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Xuemei Ge
- Laboratory of Cancer Metabolism, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Carol A Mercer
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio
| | - María I Hernández-Álvarez
- Complex Metabolic Diseases and Mitochondria Group, Institute for Research in Biomedicine (IRB), Barcelona, Spain
| | - Hala Elnakat Thomas
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Javier Hernandez-Losa
- Department of Anatomy/Pathology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Santiago Ramón Y Cajal
- Department of Anatomy/Pathology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Antonio Zorzano
- Complex Metabolic Diseases and Mitochondria Group, Institute for Research in Biomedicine (IRB), Barcelona, Spain.,Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - George Thomas
- Laboratory of Cancer Metabolism, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.,Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio.,Physiological Sciences Department, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
| | - Sara C Kozma
- Laboratory of Cancer Metabolism, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. .,Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio
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28
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Peláez-Jaramillo MJ, Cárdenas-Mojica AA, Gaete PV, Mendivil CO. Post-Liver Transplantation Diabetes Mellitus: A Review of Relevance and Approach to Treatment. Diabetes Ther 2018; 9:521-543. [PMID: 29411291 PMCID: PMC6104273 DOI: 10.1007/s13300-018-0374-8] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Indexed: 02/08/2023] Open
Abstract
Post-liver transplantation diabetes mellitus (PLTDM) develops in up to 30% of liver transplant recipients and is associated with increased risk of mortality and multiple morbid outcomes. PLTDM is a multicausal disorder, but the main risk factor is the use of immunosuppressive agents of the calcineurin inhibitor (CNI) family (tacrolimus and cyclosporine). Additional factors, such as pre-transplant overweight, nonalcoholic steatohepatitis and hepatitis C virus infection, may further increase risk of developing PLTDM. A diagnosis of PLTDM should be established only after doses of CNI and steroids are stable and the post-operative stress has been overcome. The predominant defect induced by CNI is insulin secretory dysfunction. Plasma glucose control must start immediately after the transplant procedure in order to improve long-term results for both patient and transplant. Among the better known antidiabetics, metformin and DPP-4 inhibitors have a particularly benign profile in the PLTDM context and are the preferred oral agents for long-term management. Insulin therapy is also an effective approach that addresses the prevailing pathophysiological defect of the disorder. There is still insufficient evidence about the impact of newer families of antidiabetics (GLP-1 agonists, SGLT-2 inhibitors) on PLTDM. In this review, we summarize current knowledge on the epidemiology, pathogenesis, course of disease and medical management of PLTDM.
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Affiliation(s)
| | | | - Paula V Gaete
- Universidad de los Andes School of Medicine, Bogotá, Colombia
| | - Carlos O Mendivil
- Universidad de los Andes School of Medicine, Bogotá, Colombia.
- Endocrinology Section, Department of Internal Medicine, Fundación Santa Fe de Bogotá, Bogotá, Colombia.
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29
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Abstract
Mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. mTORC1 and mTORC2 play key physiological roles as they control anabolic and catabolic processes in response to external cues in a variety of tissues and organs. However, mTORC1 and mTORC2 activities are deregulated in widespread human diseases, including cancer. Cancer cells take advantage of mTOR oncogenic signaling to drive their proliferation, survival, metabolic transformation, and metastatic potential. Therefore, mTOR lends itself very well as a therapeutic target for innovative cancer treatment. mTOR was initially identified as the target of the antibiotic rapamycin that displayed remarkable antitumor activity in vitro Promising preclinical studies using rapamycin and its derivatives (rapalogs) demonstrated efficacy in many human cancer types, hence supporting the launch of numerous clinical trials aimed to evaluate the real effectiveness of mTOR-targeted therapies. However, rapamycin and rapalogs have shown very limited activity in most clinical contexts, also when combined with other drugs. Thus, novel classes of mTOR inhibitors with a stronger antineoplastic potency have been developed. Nevertheless, emerging clinical data suggest that also these novel mTOR-targeting drugs may have a weak antitumor activity. Here, we summarize the current status of available mTOR inhibitors and highlight the most relevant results from both preclinical and clinical studies that have provided valuable insights into both their efficacy and failure.
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30
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De Gennaro Colonna V, Pavanello C, Rusconi F, Sartore-Bianchi A, Siena S, Castelnuovo S, Sirtori CR, Mombelli G. Lipid-lowering therapy of everolimus-related severe hypertriglyceridaemia in a pancreatic neuroendocrine tumour (pNET). J Clin Pharm Ther 2018; 43:114-116. [DOI: 10.1111/jcpt.12588] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 06/06/2017] [Indexed: 01/18/2023]
Affiliation(s)
- V. De Gennaro Colonna
- Department of Clinical Sciences and Community Health; University of Milano; Milano Italy
- Dyslipidemia Center; ASST Grande Ospedale Metropolitano Niguarda; Milano Italy
| | - C. Pavanello
- Department of Pharmacological and Biomolecular Sciences and; University of Milano; Milano Italy
| | - F. Rusconi
- Department of Hematology and Oncology; Niguarda Cancer Center; ASST Grande Ospedale Metropolitano Niguarda; Milano Italy
| | - A. Sartore-Bianchi
- Department of Hematology and Oncology; Niguarda Cancer Center; ASST Grande Ospedale Metropolitano Niguarda; Milano Italy
| | - S. Siena
- Department of Hematology and Oncology; Niguarda Cancer Center; ASST Grande Ospedale Metropolitano Niguarda; Milano Italy
- Department of Oncology and Hematology; University of Milano; Milano Italy
| | - S. Castelnuovo
- Dyslipidemia Center; ASST Grande Ospedale Metropolitano Niguarda; Milano Italy
| | - C. R. Sirtori
- Dyslipidemia Center; ASST Grande Ospedale Metropolitano Niguarda; Milano Italy
| | - G. Mombelli
- Dyslipidemia Center; ASST Grande Ospedale Metropolitano Niguarda; Milano Italy
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31
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Guo H, Zhong Y, Jackson AL, Clark LH, Kilgore J, Zhang L, Han J, Sheng X, Gilliam TP, Gehrig PA, Zhou C, Bae-Jump VL. Everolimus exhibits anti-tumorigenic activity in obesity-induced ovarian cancer. Oncotarget 2018; 7:20338-56. [PMID: 26959121 PMCID: PMC4991459 DOI: 10.18632/oncotarget.7934] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 01/24/2016] [Indexed: 01/21/2023] Open
Abstract
Everolimus inhibits mTOR kinase activity and its downstream targets by acting on mTORC1 and has anti-tumorigenic activity in ovarian cancer. Clinical and epidemiologic data find that obesity is associated with worse outcomes in ovarian cancer. In addition, obesity leads to hyperactivation of the mTOR pathway in epithelial tissues, suggesting that mTOR inhibitors may be a logical choice for treatment in obesity-driven cancers. However, it remains unclear if obesity impacts the effect of everolimus on tumor growth in ovarian cancer. The present study was aimed at evaluating the effects of everolimus on cytotoxicity, cell metabolism, apoptosis, cell cycle, cell stress and invasion in human ovarian cancer cells. A genetically engineered mouse model of serous ovarian cancer fed a high fat diet or low fat diet allowed further investigation into the inter-relationship between everolimus and obesity in vivo. Everolimus significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, reduced invasion and caused cellular stress via inhibition of mTOR pathways in vitro. Hypoglycemic conditions enhanced the sensitivity of cells to everolimus through the disruption of glycolysis. Moreover, everolimus was found to inhibit ovarian tumor growth in both obese and lean mice. This reduction coincided with a decrease in expression of Ki-67 and phosphorylated-S6, as well as an increase in cleaved caspase 3 and phosphorylated-AKT. Metabolite profiling revealed that everolimus was able to alter tumor metabolism through different metabolic pathways in the obese and lean mice. Our findings support that everolimus may be a promising therapeutic agent for obesity-driven ovarian cancers.
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Affiliation(s)
- Hui Guo
- Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan University, Jinan, P.R. China.,Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.,School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Shandong, P.R. China
| | - Yan Zhong
- Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.,Department of Gynecologic Oncology, Linyi Cancer Hospital, Linyi, P.R. China
| | - Amanda L Jackson
- Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA
| | - Leslie H Clark
- Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA
| | - Josh Kilgore
- Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA
| | - Lu Zhang
- Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan University, Jinan, P.R. China.,Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.,School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Shandong, P.R. China
| | - Jianjun Han
- Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.,Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Jinan, P.R. China
| | - Xiugui Sheng
- Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan University, Jinan, P.R. China
| | - Timothy P Gilliam
- Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA
| | - Paola A Gehrig
- Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Chunxiao Zhou
- Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Victoria L Bae-Jump
- Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
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Jahrling JB, Lin AL, DeRosa N, Hussong SA, Van Skike CE, Girotti M, Javors M, Zhao Q, Maslin LA, Asmis R, Galvan V. mTOR drives cerebral blood flow and memory deficits in LDLR -/- mice modeling atherosclerosis and vascular cognitive impairment. J Cereb Blood Flow Metab 2018; 38:58-74. [PMID: 28511572 PMCID: PMC5757441 DOI: 10.1177/0271678x17705973] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 02/01/2017] [Accepted: 02/27/2017] [Indexed: 12/14/2022]
Abstract
We recently showed that mTOR attenuation blocks progression and abrogates established cognitive deficits in Alzheimer's disease (AD) mouse models. These outcomes were associated with the restoration of cerebral blood flow (CBF) and brain vascular density (BVD) resulting from relief of mTOR inhibition of NO release. Recent reports suggested a role of mTOR in atherosclerosis. Because mTOR drives aging and vascular dysfunction is a universal feature of aging, we hypothesized that mTOR may contribute to brain vascular and cognitive dysfunction associated with atherosclerosis. We measured CBF, BVD, cognitive function, markers of inflammation, and parameters of cardiovascular disease in LDLR-/- mice fed maintenance or high-fat diet ± rapamycin. Cardiovascular pathologies were proportional to severity of brain vascular dysfunction. Aortic atheromas were reduced, CBF and BVD were restored, and cognitive dysfunction was attenuated potentially through reduction in systemic and brain inflammation following chronic mTOR attenuation. Our studies suggest that mTOR regulates vascular integrity and function and that mTOR attenuation may restore neurovascular function and cardiovascular health. Together with our previous studies in AD models, our data suggest mTOR-driven vascular damage may be a mechanism shared by age-associated neurological diseases. Therefore, mTOR attenuation may have promise for treatment of cognitive impairment in atherosclerosis.
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Affiliation(s)
- Jordan B Jahrling
- Department of Cellular and Integrative
Physiology and The Barshop Institute for Longevity and Aging Studies, University of
Texas Health Science Center at San Antonio, TX, USA
| | - Ai-Ling Lin
- Sanders-Brown Center on Aging,
Department of Pharmacology and Nutritional Sciences and Department of Biomedical
Engineering, University of Kentucky, KY, USA
| | - Nicholas DeRosa
- Department of Cellular and Integrative
Physiology and The Barshop Institute for Longevity and Aging Studies, University of
Texas Health Science Center at San Antonio, TX, USA
| | - Stacy A Hussong
- Department of Cellular and Integrative
Physiology and The Barshop Institute for Longevity and Aging Studies, University of
Texas Health Science Center at San Antonio, TX, USA
| | - Candice E Van Skike
- Department of Cellular and Integrative
Physiology and The Barshop Institute for Longevity and Aging Studies, University of
Texas Health Science Center at San Antonio, TX, USA
| | - Milena Girotti
- Department of Pharmacology, University
of Texas Health Science Center at San Antonio, TX, USA
| | - Martin Javors
- Department of Psychiatry, University of
Texas Health Science Center at San Antonio, TX, USA
| | - Qingwei Zhao
- Department of Medicine, University of
Texas Health Science Center at San Antonio, TX, USA
| | - Leigh Ann Maslin
- Department of Clinical Laboratory
Sciences, University of Texas Health Science Center at San Antonio, TX, USA
| | - Reto Asmis
- Department of Clinical Laboratory
Sciences, University of Texas Health Science Center at San Antonio, TX, USA
- Department of Biochemistry, University
of Texas Health Science Center at San Antonio, TX, USA
| | - Veronica Galvan
- Department of Cellular and Integrative
Physiology and The Barshop Institute for Longevity and Aging Studies, University of
Texas Health Science Center at San Antonio, TX, USA
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Jobard E, Trédan O, Bachelot T, Vigneron AM, Aït-Oukhatar CM, Arnedos M, Rios M, Bonneterre J, Diéras V, Jimenez M, Merlin JL, Campone M, Elena-Herrmann B. Longitudinal serum metabolomics evaluation of trastuzumab and everolimus combination as pre-operative treatment for HER-2 positive breast cancer patients. Oncotarget 2017; 8:83570-83584. [PMID: 29137365 PMCID: PMC5663537 DOI: 10.18632/oncotarget.18784] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 05/23/2017] [Indexed: 12/11/2022] Open
Abstract
The mammalian target of rapamycin complex 1 (mTORC1) is an attractive target for HER-2 positive breast cancer therapy because of its key role in protein translation regulation, cell growth and metabolism. We present here a metabolomic investigation exploring the impact of mTOR inhibition on serum metabolic profiles from patients with non-metastatic breast cancer overexpressing HER-2. Baseline, treatment-related and post-treatment serum samples were analyzed for 79 patients participating in the French clinical trial RADHER, in which randomized patients with HER-2 positive breast cancer received either trastuzumab alone (arm T) or a trastuzumab and everolimus combination (arm T+E). Longitudinal series of NMR serum metabolic profiles were exploited to investigate treatment effects on the patients metabolism over time, in both group. Trastuzumab and everolimus combination induces faster changes in patients metabolism than trastuzumab alone, visible after only one week of treatment as well as a residual effect detectable up to three weeks after ending the treatment. These metabolic fingerprints highlight the involvement of several metabolic pathways reflecting a systemic effect, particularly on the liver and visceral fat. Comparison of serum metabolic profiles between the two arms shows that everolimus, an mTORC1 inhibitor, is responsible for host metabolism modifications observed in arm T+E. In HER-2 positive breast cancer, our metabolomic approach confirms a fast and persistent host metabolism modification caused by mTOR inhibition.
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Affiliation(s)
- Elodie Jobard
- Université de Lyon, Institut des Sciences Analytiques, UMR 5280, CNRS, Université Lyon 1, ENS de Lyon, Villeurbanne, France.,Université de Lyon, Centre Léon Bérard, Département d'oncologie médicale, Lyon, France
| | - Olivier Trédan
- Université de Lyon, Centre Léon Bérard, Département d'oncologie médicale, Lyon, France
| | - Thomas Bachelot
- Université de Lyon, Centre Léon Bérard, Département d'oncologie médicale, Lyon, France
| | - Arnaud M Vigneron
- Université de Lyon, Centre de Cancérologie de Lyon, UMR Inserm 1052 CNRS 5286, Centre Léon Bérard, Lyon, France
| | | | - Monica Arnedos
- Department of Medicine, Gustave Roussy, Villejuif, France
| | - Maria Rios
- Department of Medical Oncology, Centre Alexis Vautrin, Vandoeuvre-les-Nancy, France
| | | | | | | | - Jean-Louis Merlin
- CNRS UMR7039 CRAN, Université de Lorraine, Vandoeuvre-les-Nancy, France.,Department of Biopathology Unit, Institut de Cancérologie de Lorraine, Vandoeuvre-Les-Nancy, France
| | - Mario Campone
- Institut de Cancérologie de l'Ouest, Centre René Gauducheau, Saint-Herblain, France
| | - Bénédicte Elena-Herrmann
- Université de Lyon, Institut des Sciences Analytiques, UMR 5280, CNRS, Université Lyon 1, ENS de Lyon, Villeurbanne, France
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Li Q, Xia X, Ji J, Ma J, Tao L, Mo L, Chen W. MiR-199a-3p enhances cisplatin sensitivity of cholangiocarcinoma cells by inhibiting mTOR signaling pathway and expression of MDR1. Oncotarget 2017; 8:33621-33630. [PMID: 28422725 PMCID: PMC5464895 DOI: 10.18632/oncotarget.16834] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 03/26/2017] [Indexed: 12/17/2022] Open
Abstract
Several studies have reported reduced miRNA-199a-3p (miR-199a-3p) in different human malignancies, however, little is known about miR-199a-3p in cholangiocarcinoma cells. In this study, we demonstrate the essential role and mechanism of miR-199a-3p in regulating cisplatin sensitivity in cholangiocarcinoma cell lines. Using a CCK-8 cell counting assay we found that expression of miR-199a-3p was positively correlated with cisplatin sensitivity in cholangiocarcinoma cell lines. MiR-199a-3p overexpression could decrease the proliferation rate and increase apoptosis of cholangiocarcinoma cells in the presence of cisplatin, while miR-199a-3p inhibition had the opposite effect. Further study demonstrated that mTOR was the target gene of miR-199a-3p, and that miR-199a-3p mimics could inhibit expression of mTOR, which consequently reduced the phosphorylation of its downstream proteins 4EBP1 and p70s6k. Rescue experiments proved that miR-199a-3p could increase the cisplatin sensitivity of cholangiocarcinoma cell lines by regulating mTOR expression. Moreover, we also found that miR-199a-3p overexpression could reduce cisplatin induced MDR1 expression by decreasing the synthesis and increasing the degradation of MDR1, thus enhancing the effectiveness of cisplatin in cholangiocarcinoma. In conclusion, miR-199a-3p could increase cisplatin sensitivity of cholangiocarcinoma cell lines by inhibiting the activity of the mTOR signaling pathway and decreasing the expression of MDR1.
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Affiliation(s)
- Qiang Li
- Department of General Surgery, The Afflicted Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Xuefeng Xia
- Department of General Surgery, The Afflicted Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jie Ji
- Nangjing Medical University, Nangjing, China
| | - Jianghui Ma
- Department of General Surgery, The Afflicted Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Liang Tao
- Department of General Surgery, The Afflicted Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Linjun Mo
- School of Surgery, The University of Western Australia, and Western Australia Liver and Kidney Surgical Transplant Service, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Wei Chen
- Institute of Molecular Engineering, University of Chicago, Chicago, Illinois, USA
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Xu J, Wu Y, Lu G, Xie S, Ma Z, Chen Z, Shen HM, Xia D. Importance of ROS-mediated autophagy in determining apoptotic cell death induced by physapubescin B. Redox Biol 2017; 12:198-207. [PMID: 28258023 PMCID: PMC5333534 DOI: 10.1016/j.redox.2017.02.017] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 02/22/2017] [Accepted: 02/23/2017] [Indexed: 10/26/2022] Open
Abstract
Physapubescin B, a steroidal compound extracted from the plant Physalis pubescens L. (Solanaceae), has been reported to possess anti-cancer potential, whereas the molecular mechanism remains elusive. In this study, we first demonstrated that physapubescin B induced autophagy in human cancer cells based on the evidence that physapubescin B increased lipidation of microtubule-associated protein 1 light chain 3 (LC3) as well as number of GFP-LC3 puncta. We further examined the molecular mechanisms and found that physapubescin B enhanced the autophagic flux through promotion of reactive oxygen species (ROS)-mediated suppression of mammalian target of rapamycin complex I (mTORC1), the key negative regulator of autophagy. Additionally, excessive ROS caused by physapubescin B also induced p53-dependent apoptotic cell death. Furthermore, we provided evidence that inhibition of autophagy either by a chemical inhibitor or gene silencing promoted physapubescin B-induced apoptotic cell death, indicating that autophagy serves as a cell survival mechanism to protect cell death. Thus, our data provide a clue that inhibition of autophagy would serve as a novel strategy for enhancing the anti-cancer potential of physapubescin B.
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Affiliation(s)
- Jian Xu
- Department of Toxicology, School of Public Health, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou 310058, PR China
| | - Yihua Wu
- Department of Toxicology, School of Public Health, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou 310058, PR China
| | - Guang Lu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Shujun Xie
- Department of Toxicology, School of Public Health, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou 310058, PR China
| | - Zhongjun Ma
- School of Pharmaceutical Sciences, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou 310058, PR China
| | - Zhe Chen
- Chinese Traditional Medicine Hospital of Zhejiang Province, No. 54 You-Dian Road, Hangzhou 310006, PR China
| | - Han-Ming Shen
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | - Dajing Xia
- Department of Toxicology, School of Public Health, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou 310058, PR China.
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Yoshida K, Imamura CK, Hara K, Mochizuki M, Tanigawara Y. Effect of everolimus on the glucose metabolic pathway in mouse skeletal muscle cells (C2C12). Metabolomics 2017; 13:98. [PMID: 28781589 PMCID: PMC5501892 DOI: 10.1007/s11306-017-1236-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 06/24/2017] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Everolimus selectively inhibits mammalian target of rapamycin complex 1 (mTORC1) and exerts an antineoplastic effect. Metabolic disturbance has emerged as a common and unique side effect of everolimus. OBJECTIVES We used targeted metabolomic analysis to investigate the effects of everolimus on the intracellular glycometabolic pathway. METHODS Mouse skeletal muscle cells (C2C12) were exposed to everolimus for 48 h, and changes in intracellular metabolites were determined by capillary electrophoresis time-of-flight mass spectrometry. mRNA abundance, protein expression and activity were measured for enzymes involved in glycometabolism and related pathways. RESULTS Both extracellular and intracellular glucose levels increased with exposure to everolimus. Most intracellular glycometabolites were decreased by everolimus, including those involved in glycolysis and the pentose phosphate pathway, whereas no changes were observed in the tricarboxylic acid cycle. Everolimus suppressed mRNA expression of enzymes related to glycolysis, downstream of mTOR signaling enzymes and adenosine 5'-monophosphate protein kinases. The activity of key enzymes involved in glycolysis and the pentose phosphate pathway were decreased by everolimus. These results show that everolimus impairs glucose utilization in intracellular metabolism. CONCLUSIONS The present metabolomic analysis indicates that everolimus impairs glucose metabolism in muscle cells by lowering the activities of glycolysis and the pentose phosphate pathway.
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Affiliation(s)
- Kayoko Yoshida
- Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo Japan
| | - Chiyo K. Imamura
- Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 Japan
| | - Kanako Hara
- Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 Japan
| | - Mayumi Mochizuki
- Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo Japan
| | - Yusuke Tanigawara
- Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 Japan
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Shah RR. Hyperglycaemia Induced by Novel Anticancer Agents: An Undesirable Complication or a Potential Therapeutic Opportunity? Drug Saf 2016; 40:211-228. [DOI: 10.1007/s40264-016-0485-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Caloric restriction - A promising anti-cancer approach: From molecular mechanisms to clinical trials. Biochim Biophys Acta Rev Cancer 2016; 1867:29-41. [PMID: 27871964 DOI: 10.1016/j.bbcan.2016.11.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 11/17/2016] [Accepted: 11/18/2016] [Indexed: 02/07/2023]
Abstract
Cancer is the second leading cause of death worldwide and the morbidity is growing in developed countries. According to WHO, >14 million people per year are diagnosed with cancer and about 8 million die. Anti-cancer strategy includes chemo-, immune- and radiotherapy or their combination. Unfortunately, these widely used strategies often have insufficient efficacy and significant toxic effects on healthy cells. Consequently, the improvement of treatment approaches is an important goal. One of promising schemes to enhance the effect of therapy is the restriction of calorie intake or some nutrients. The combination of caloric restriction or its chemical mimetics along with anti-cancer drugs may suppress growth of tumor cells and enhance death of cancer cells. That will allow the dose of therapeutic drugs to be decreased and their toxic effects to be reduced. Here the possibility of using this combinatory therapy as well as the molecular mechanisms underlying this approach will be discussed.
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Ong PS, Wang LZ, Dai X, Tseng SH, Loo SJ, Sethi G. Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives. Front Pharmacol 2016; 7:395. [PMID: 27826244 PMCID: PMC5079084 DOI: 10.3389/fphar.2016.00395] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 10/07/2016] [Indexed: 12/16/2022] Open
Abstract
The mechanistic target of rapamycin (mTOR), via its two distinct multiprotein complexes, mTORC1, and mTORC2, plays a central role in the regulation of cellular growth, metabolism, and migration. A dysregulation of the mTOR pathway has in turn been implicated in several pathological conditions including insulin resistance and cancer. Overactivation of mTORC1 and disruption of mTORC2 function have been reported to induce insulin resistance. On the other hand, aberrant mTORC1 and mTORC2 signaling via either genetic alterations or increased expression of proteins regulating mTOR and its downstream targets have contributed to cancer development. These underlined the attractiveness of mTOR as a therapeutic target to overcome both insulin resistance and cancer. This review summarizes the evidence supporting the notion of intermittent, low dose rapamycin for treating insulin resistance. It further highlights recent data on the continuous use of high dose rapamycin analogs and related second generation mTOR inhibitors for cancer eradication, for overcoming chemoresistance and for tumor stem cell suppression. Within these contexts, the potential challenges associated with the use of mTOR inhibitors are also discussed.
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Affiliation(s)
- Pei Shi Ong
- Department of Pharmacy, Faculty of Science, National University of Singapore Singapore, Singapore
| | - Louis Z Wang
- Department of Pharmacy, Faculty of Science, National University of SingaporeSingapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore
| | - Xiaoyun Dai
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore
| | - Sheng Hsuan Tseng
- Department of Pharmacy, Faculty of Science, National University of Singapore Singapore, Singapore
| | - Shang Jun Loo
- Department of Pharmacy, Faculty of Science, National University of Singapore Singapore, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore
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40
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Weber H, Leal P, Stein S, Kunkel H, García P, Bizama C, Espinoza JA, Riquelme I, Nervi B, Araya JC, Grez M, Roa JC. Rapamycin and WYE-354 suppress human gallbladder cancer xenografts in mice. Oncotarget 2016; 6:31877-88. [PMID: 26397134 PMCID: PMC4741647 DOI: 10.18632/oncotarget.5047] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 09/01/2015] [Indexed: 01/17/2023] Open
Abstract
Gallbladder cancer (GBC) is a highly malignant tumor characterized by a poor response to chemotherapy and radiotherapy. We evaluated the in vitro and in vivo antitumor efficacy of mTOR inhibitors, rapamycin and WYE-354. In vitro assays showed WYE-354 significantly reduced cell viability, migration and invasion and phospho-P70S6K expression in GBC cells. Mice harboring subcutaneous gallbladder tumors, treated with WYE-354 or rapamycin, exhibited a significant reduction in tumor mass. A short-term treatment with a higher dose of WYE-354 decreased the tumor size by 68.6% and 52.4%, in mice harboring G-415 or TGBC-2TKB tumors, respectively, compared to the control group. By contrast, treatment with a prolonged-low-dose regime of rapamycin almost abrogated tumor growth, exhibiting 92.7% and 97.1% reduction in tumor size, respectively, compared to control mice. These results were accompanied by a greater decrease in the phosphorylation status of P70S6K and a lower cell proliferation Ki67 index, compared to WYE-354 treated mice, suggesting a more effective mTOR pathway inhibition. These findings provide a proof of concept for the use of rapamycin or WYE-354 as potentially good candidates to be studied in clinical trials in GBC patients.
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Affiliation(s)
- Helga Weber
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Pamela Leal
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Stefan Stein
- Gene Therapy Unit, Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Hana Kunkel
- Gene Therapy Unit, Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Patricia García
- Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Jaime A Espinoza
- Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ismael Riquelme
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Bruno Nervi
- Department of Hematology Oncology, UC-Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan C Araya
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Manuel Grez
- Gene Therapy Unit, Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Juan C Roa
- Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
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Trelińska J, Dachowska I, Kotulska K, Jóźwiak S, Fendler W, Młynarski W. Everolimus treatment among patients with tuberous sclerosis affects serum lipid profile. Pharmacol Rep 2016; 68:1002-7. [PMID: 27423526 DOI: 10.1016/j.pharep.2016.05.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 05/16/2016] [Accepted: 05/23/2016] [Indexed: 12/29/2022]
Abstract
BACKGROUND The purpose of the study was to evaluate lipid homeostasis before and after treatment of everolimus, the mammalian target of the rapamycin (mTOR) inhibitor, among patients with tuberous sclerosis complex (TSC). METHODS The study group consisted of 15 patients with a diagnosis of subependymal giant cell astrocytoma (SEGA) related to TSC. The following lipid parameters were determined: total serum cholesterol (TCh), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), total serum triglyceride (TG) concentration at baseline, then after three and 12 months of observation. The values were compared with those of age-matched healthy controls. RESULTS In the study group TCh, LDL and HDL levels at baseline were significantly higher than in the control group. TCh and LDL levels were positively correlated with baseline SDS-BMI in TSC patients. Everolimus treatment resulted in significant increases of TCh (from 192.04±40.51mg/dl to 210.74±51.12mg/dl and to 216.69±45.43mg/dl; p=0.0273) and LDL (from 113.21±38.72mg/dl to 133.88±50.71mg/dl and to 141.58±40.67mg/dl; p=0.0006) after three and 12 months respectively. The differences between the TCh and LDL levels at baseline and after 12 months of therapy were negatively correlated with baseline SDS-BMI. The observed increase of BMI after 12 months was correlated with increases in TCh and LDL levels. CONCLUSIONS Patients with TSC have disrupted lipid homeostasis before and during treatment with everolimus, which might be partially connected to the mTOR-dependent nutritional status of the patients. There is a need to develop strategies for children with TSC treated with everolimus, who experience hyperlipidemia.
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Affiliation(s)
- Joanna Trelińska
- Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lódź, Poland.
| | - Iwona Dachowska
- Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lódź, Poland
| | - Katarzyna Kotulska
- Department of Neurology & Epileptology and Pediatric Rehabilitation, The Children's Memorial Health Institute,Warszawa, Poland
| | - Sergiusz Jóźwiak
- Department of Neurology & Epileptology and Pediatric Rehabilitation, The Children's Memorial Health Institute,Warszawa, Poland; Department of Child Neurology, Medical University of Warsaw, Warszawa, Poland
| | - Wojciech Fendler
- Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lódź, Poland; Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lódź, Poland
| | - Wojciech Młynarski
- Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lódź, Poland
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Študentová H, Vitásková D, Melichar B. Safety of mTOR inhibitors in breast cancer. Expert Opin Drug Saf 2016; 15:1075-85. [DOI: 10.1080/14740338.2016.1192604] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Hana Študentová
- Department of Oncology, Palacký University Medical School & Teaching Hospital, Olomouc, Czech Republic
| | - Denisa Vitásková
- Department of Oncology, Palacký University Medical School & Teaching Hospital, Olomouc, Czech Republic
| | - Bohuslav Melichar
- Department of Oncology, Palacký University Medical School & Teaching Hospital, Olomouc, Czech Republic
- Institute of Molecular and Translational Medicine, Palacký University Medical School & Teaching Hospital, Olomouc, Czech Republic
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Ghobrial IM, Siegel DS, Vij R, Berdeja JG, Richardson PG, Neuwirth R, Patel CG, Zohren F, Wolf JL. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia. Am J Hematol 2016; 91:400-5. [PMID: 26800393 DOI: 10.1002/ajh.24300] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 01/08/2016] [Accepted: 01/12/2016] [Indexed: 12/13/2022]
Abstract
The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies.
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Affiliation(s)
- Irene M. Ghobrial
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston Massachusetts
| | - David S. Siegel
- John Theurer Cancer Center at Hackensack University Medical Center; Hackensack New Jersey
| | - Ravi Vij
- Division of Hematology and Oncology, Washington University School of Medicine; St. Louis Missouri
| | | | - Paul G. Richardson
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston Massachusetts
| | - Rachel Neuwirth
- Global Biostatistics, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USA, a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited
| | - Chirag G. Patel
- Clinical Pharmacology, Millennium Pharmaceuticals, Inc; Cambridge Massachusetts USA, a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited
| | - Fabian Zohren
- Oncology Clinical Research, Millennium Pharmaceuticals, Inc; Cambridge Massachusetts USA, a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited
| | - Jeffrey L. Wolf
- Department of Medicine; University of California San Francisco; San Francisco California
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Stepanenko AA, Andreieva SV, Korets KV, Mykytenko DO, Baklaushev VP, Chekhonin VP, Dmitrenko VV. mTOR inhibitor temsirolimus and MEK1/2 inhibitor U0126 promote chromosomal instability and cell type-dependent phenotype changes of glioblastoma cells. Gene 2016; 579:58-68. [PMID: 26748241 DOI: 10.1016/j.gene.2015.12.064] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 12/14/2015] [Accepted: 12/26/2015] [Indexed: 01/22/2023]
Abstract
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and the RAF/mitogen-activated and extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways are frequently deregulated in cancer. Temsirolimus (TEM) and its primary active metabolite rapamycin allosterically block mTOR complex 1 substrate recruitment. The context-/experimental setup-dependent opposite effects of rapamycin on the multiple centrosome formation, aneuploidy, DNA damage/repair, proliferation, and invasion were reported. Similarly, the context-dependent either tumor-promoting or suppressing effects of RAF-MEK-ERK pathway and its inhibitors were demonstrated. Drug treatment-mediated stress may promote chromosomal instability (CIN), accelerating changes in the genomic landscape and phenotype diversity. Here, we characterized the genomic and phenotypic changes of U251 and T98G glioblastoma cell lines long-term treated with TEM or U0126, an inhibitor of MEK1/2. TEM significantly increased clonal and non-clonal chromosome aberrations. Both TEM and U0126 affected copy number alterations (CNAs) pattern. A proliferation rate of U251TEM and U251U0126 cells was lower and higher, respectively, than control cells. Colony formation efficiency of U251TEM significantly decreased, whereas U251U0126 did not change. U251TEM and U251U0126 cells decreased migration. In contrast, T98GTEM and T98GU0126 cells did not change proliferation, colony formation efficiency, and migration. Changes in the sensitivity of inhibitor-treated cells to the reduction of the glucose concentration were observed. Our results suggest that CIN and adaptive reprogramming of signal transduction pathways may be responsible for the cell type-dependent phenotype changes of long-term TEM- or U0126-treated tumor cells.
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Affiliation(s)
- A A Stepanenko
- Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, Zabolotnogo Str. 150, Kyiv 03680, Ukraine.
| | - S V Andreieva
- Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, Zabolotnogo Str. 150, Kyiv 03680, Ukraine
| | - K V Korets
- Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, Zabolotnogo Str. 150, Kyiv 03680, Ukraine
| | - D O Mykytenko
- Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, Zabolotnogo Str. 150, Kyiv 03680, Ukraine
| | - V P Baklaushev
- Department of Medicinal Nanobiotechnology, Pirogov Russian State Medical University, Ostrovitianov str. 1, Moscow 117997, Russia; Federal Research and Clinical Centre, FMBA of Russia, Orekhoviy bulvar str. 28, Moscow 115682, Russia
| | - V P Chekhonin
- Department of Medicinal Nanobiotechnology, Pirogov Russian State Medical University, Ostrovitianov str. 1, Moscow 117997, Russia
| | - V V Dmitrenko
- Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, Zabolotnogo Str. 150, Kyiv 03680, Ukraine
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Simone V, D'Avenia M, Argentiero A, Felici C, Rizzo FM, De Pergola G, Silvestris F. Obesity and Breast Cancer: Molecular Interconnections and Potential Clinical Applications. Oncologist 2016; 21:404-17. [PMID: 26865587 DOI: 10.1634/theoncologist.2015-0351] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 11/23/2015] [Indexed: 01/22/2023] Open
Abstract
UNLABELLED Obesity is an important risk factor for breast cancer (BC) in postmenopausal women; interlinked molecular mechanisms might be involved in the pathogenesis. Increased levels of estrogens due to aromatization of the adipose tissue, inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and prostaglandin E2, insulin resistance and hyperactivation of insulin-like growth factors pathways, adipokines, and oxidative stress are all abnormally regulated in obese women and contribute to cancerogenesis. These molecular factors interfere with intracellular signaling in the mitogen-activated protein kinase and phosphatydilinositol-3-phosphate/mammalian target of rapamycin (mTOR) pathways, which regulate the progression of the cell cycle, apoptosis, and protein synthesis. In this context, structural defects of typical genes related to both BC and obesity, such as leptin, leptin receptor, serum paraoxonase/arylesterase 1, the fat mass and obesity-associated gene and melanocortin receptor 4, have been associated with a high or low risk of BC development. The early detection of these gene alterations might be useful as risk predictors in obese women, and targeting these pathways involved in the BC pathogenesis in obese women is a potential therapeutic tool. In particular, mTOR pathway deregulation concurs in both obesity and BC, and inhibition of this might disrupt the molecular interlinks in a similar manner to that of metformin, which exerts definite anticancer activity and is currently used as an antidiabetic drug with a weight-reducing property. The identification of both genetic and pharmacological implications on the prevention and management of BC is the ultimate aim of these studies. IMPLICATIONS FOR PRACTICE Obese women are at risk of breast cancer, but clinicians lack concrete tools for the prevention or early diagnosis of this risk. The present study, starting from the biology and the molecular defects characterizing both obesity and breast cancer, analyzed the potential molecules and genetic defects whose early identification could delineate a risk profile. Three steps are proposed that are potentially achievable in the clinical assessment of obese women, namely the evaluation of altered levels of serum molecules, the identification of genetic polymorphisms, and the study of the transcriptomic profile of premalignant lesions. Finally, the therapeutic implications of this molecular assessment were evaluated.
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Affiliation(s)
- Valeria Simone
- Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy
| | - Morena D'Avenia
- Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy
| | - Antonella Argentiero
- Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy
| | - Claudia Felici
- Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy
| | - Francesca Maria Rizzo
- Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy
| | - Giovanni De Pergola
- Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy
| | - Franco Silvestris
- Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy
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Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials. Br J Cancer 2015; 113:1541-7. [PMID: 26554652 PMCID: PMC4705886 DOI: 10.1038/bjc.2015.373] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 09/16/2015] [Accepted: 10/05/2015] [Indexed: 01/17/2023] Open
Abstract
Background: PI3K–AKT–mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and is becoming increasingly important with their use in larger numbers of patients. Methods: Retrospective case-control study comparing incidence and severity of hyperglycaemia (all grades) between a case group of 387 patients treated on 18 phase I clinical trials with PAMi (78 patients with PI3Ki, 138 with mTORi, 144 with AKTi and 27 with PI3K/mTORi) and a control group of 109 patients treated on 10 phase I clinical trials with agents not directly targeting the PAM pathway. Diabetic patients were excluded in both groups. Results: The incidence of hyperglycaemia was not significantly different between cases and controls (86.6% vs 80.7%, respectively, P=0.129). However, high grade (grade 3–4) hyperglycaemia was more frequent in the PAMi group than in controls (6.7% vs 0%, respectively, P=0.005). The incidence of grade 3–4 hyperglycaemia was greater with AKT and multikinase inhibitors compared with other PAMi (P<0.001). All patients with high-grade hyperglycaemia received antihyperglycemic treatment and none developed severe metabolic complications (diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic state). High-grade hyperglycaemia was the cause of permanent PAMi discontinuation in nine patients. Conclusions: PI3K–AKT–mTOR inhibitors are associated with small (6.7%) but statistically significant increased risk of high-grade hyperglycaemia compared with non-PAM targeting agents. However, PAMi-induced hyperglycaemia was not found to be associated with severe metabolic complications in this non-diabetic population of patients with advanced cancers.
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Abstract
The mammalian target of rapamycin (mTOR) inhibitors are drugs, primarily used as immunosuppressors that are now frequently used as antineoplastic therapies in various cancers (such as advanced renal cell carcinoma, advanced breast cancer, progressive pancreatic neuroendocrine tumors). They act on mTOR signaling pathway which plays a key role in regulating cell growth as well as lipid and glucose metabolism. Treatment with mTOR inhibitors is associated with a high incidence of hyperglycemia and new-onset diabetes, ranging from 13% to 50% in the clinical trials in which they have been used as anticancer therapies. The rate of severe hyperglycemia is also increased, ranging from 4 to 12% in the main phase III clinical trials. Due to limited human studies, the pathophysiology of mTOR inhibitor-induced hyperglycemia has not yet been totally clarified. However, data from animal studies suggest that the mechanisms responsible for hyperglycemia with mTOR inhibitors are likely due to the combination of impaired insulin secretion and insulin resistance. Due to the high rate of hyperglycemia associated with the use of mTOR inhibitors, a close and personalized follow-up of blood glucose is recommended in all patients.
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Affiliation(s)
- Bruno Vergès
- Endocrinology-Diabetology Department, University-Hospital, and, Medicine University, Dijon, France; INSERM CRI 866, Medicine University, Dijon, France; Faculté de Médecine, Université de Nantes, Nantes, France.
| | - Bertrand Cariou
- INSERM CRI 866, Medicine University, Dijon, France; Clinique d'Endocrinologie, l'institut du thorax, CHU de Nantes, Nantes, France; INSERM, UMR1087, l'institut du thorax, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France
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Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance. Proc Natl Acad Sci U S A 2015; 112:9406-11. [PMID: 26170313 DOI: 10.1073/pnas.1511759112] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cancer cells adapt their signaling in response to nutrient availability. To uncover the mechanisms regulating this process and its functional consequences, we interrogated cell lines, mouse tumor models, and clinical samples of glioblastoma (GBM), the highly lethal brain cancer. We discovered that glucose or acetate is required for epidermal growth factor receptor vIII (EGFRvIII), the most common growth factor receptor mutation in GBM, to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote tumor growth. Glucose or acetate promoted growth factor receptor signaling through acetyl-CoA-dependent acetylation of Rictor, a core component of the mTORC2 signaling complex. Remarkably, in the presence of elevated glucose levels, Rictor acetylation is maintained to form an autoactivation loop of mTORC2 even when the upstream components of the growth factor receptor signaling pathway are no longer active, thus rendering GBMs resistant to EGFR-, PI3K (phosphoinositide 3-kinase)-, or AKT (v-akt murine thymoma viral oncogene homolog)-targeted therapies. These results demonstrate that elevated nutrient levels can drive resistance to targeted cancer treatments and nominate mTORC2 as a central node for integrating growth factor signaling with nutrient availability in GBM.
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Fischer-Cartlidge EA. Assessment and management of gastrointestinal toxicities and lab abnormalities related to targeted therapy. Semin Oncol Nurs 2015; 30:183-9. [PMID: 25085030 DOI: 10.1016/j.soncn.2014.05.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVES To identify the most common gastrointestinal toxicities and laboratory abnormalities associated with targeted therapies, as well as the assessment and management necessary to minimize adverse events related to these side effects. DATA SOURCES Peer-reviewed articles and national guidelines for oncology practice. CONCLUSION Common toxicities of diarrhea, mucositis, and laboratory abnormalities are often associated with the use of targeted agents and require skilled assessment and early management interventions to prevent severe complications or treatment interruption. IMPLICATIONS FOR NURSING PRACTICE Emerging trends focused on targeted therapy increase the importance of the oncology nurse's role in assessment, education, and evidenced-based recommendations to meet patient needs.
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Abdel-Rahman O, Fouad M. Risk of fatigue and hepatic and metabolic toxicities in patients with solid tumors treated with everolimus: a meta-analysis. Future Oncol 2015; 11:79-90. [DOI: 10.2217/fon.14.136] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
ABSTRACT Background: We performed a systematic review and meta-analysis of fatigue, hepatic and metabolic toxicities associated with everolimus intake in patients with solid tumors. Methods: Eligible studies included randomized trials of patients with solid tumors on everolimus describing events of fatigue, hyperlipidemia, hyperglycemia and elevated alanine aminotransferase (ALT). Results: After the exclusion of ineligible studies, a total of ten clinical trials were considered eligible for the meta-analysis. The relative risks of all-grade fatigue, hyperglycemia, hyperlipidemia and elevated ALT were 1.31 (p < 0.002), 3.06 (p < 0.0001), 2.54 (p = 0.0001) and 2.96 (p < 0.003), respectively. Conclusion: Our meta-analysis demonstrates that everolimus is associated with a significantly increased risk of all-grade fatigue, hyperglycemia, hyperlipidemia and elevated ALT.
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Affiliation(s)
- Omar Abdel-Rahman
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Lotfy Elsayed Street, Cairo 11665, Egypt
| | - Mona Fouad
- Medical Microbiology & Immunology Department, Faculty of Medicine, Ain Shams University, Lotfy Elsayed Street, Cairo, Egypt
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