scholarly journals Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1584 ◽  
Author(s):  
Cedric Magaway ◽  
Eugene Kim ◽  
Estela Jacinto
Keyword(s):  
Clinical Trials ◽  
Cancer Therapy ◽  
Clinical Studies ◽  
Cancer Metabolism ◽  
Therapeutic Strategies ◽  
Metabolic Reprogramming ◽  
Metabolic Processes ◽  
Mtor Inhibition ◽  
Early Clinical Trial

Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

scholarly journals Role of dendritic cell metabolic reprogramming in tumor immune evasion

2020 ◽  
Vol 32 (7) ◽  
pp. 485-491 ◽  
Author(s):  
Michael P Plebanek ◽  
Michael Sturdivant ◽  
Nicholas C DeVito ◽  
Brent A Hanks
Keyword(s):  
Dendritic Cell ◽  
Metabolic Pathways ◽  
Checkpoint Inhibitor ◽  
Therapeutic Strategies ◽  
Metabolic Reprogramming ◽  
Combination Immunotherapy ◽  
Tumor Immune Evasion ◽  
Effector T Cell ◽  
Cell Responses

Abstract The dendritic cell (DC) is recognized as a vital mediator of anti-tumor immunity. More recent studies have also demonstrated the important role of DCs in the generation of effective responses to checkpoint inhibitor immunotherapy. Metabolic programming of DCs dictates their functionality and can determine which DCs become immunostimulatory versus those that develop a tolerized phenotype capable of actively suppressing effector T-cell responses to cancers. As a result, there is great interest in understanding what mechanisms have evolved in cancers to alter these metabolic pathways, thereby allowing for their continued progression and metastasis. The therapeutic strategies developed to reverse these processes of DC tolerization in the tumor microenvironment represent promising candidates for future testing in combination immunotherapy clinical trials.

scholarly journals Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 404 ◽  
Author(s):  
Guo ◽  
Tan ◽  
Chen ◽  
Wang ◽  
Feng
Keyword(s):  
Chinese Medicine ◽  
Cancer Therapy ◽  
Traditional Chinese Medicine ◽  
Cancer Cells ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Metabolic Reprogramming ◽  
Traditional Chinese Medicines ◽  
Chinese Medicines ◽  
Incidence And Mortality

Cancer is a common and complex disease with high incidence and mortality rates, which causes a severe public health problem worldwide. As one of the standard therapeutic approaches for cancer therapy, the prognosis and outcome of chemotherapy are still far from satisfactory due to the severe side effects and increasingly acquired resistance. The development of novel and effective treatment strategies to overcome chemoresistance is urgent for cancer therapy. Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells could rewire metabolic pathways to facilitate tumorigenesis, tumor progression, and metastasis, as well as chemoresistance. The metabolic reprogramming may serve as a promising therapeutic strategy and rekindle the research enthusiasm for overcoming chemoresistance. This review focuses on emerging mechanisms underlying rewired metabolic pathways for cancer chemoresistance in terms of glucose and energy, lipid, amino acid, and nucleotide metabolisms, as well as other related metabolisms. In particular, we highlight the potential of traditional Chinese medicine as a chemosensitizer for cancer chemotherapy from the metabolic perspective. The perspectives of metabolic targeting to chemoresistance are also discussed. In conclusion, the elucidation of the underlying metabolic reprogramming mechanisms by which cancer cells develop chemoresistance and traditional Chinese medicines resensitize chemotherapy would provide us a new insight into developing promising therapeutics and scientific evidence for clinical use of traditional Chinese medicine as a chemosensitizer for cancer therapy.

scholarly journals Implementing Curcumin in Translational Oncology Research

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5240
Author(s):  
Koraljka Gall Trošelj ◽  
Ivana Samaržija ◽  
Marko Tomljanović ◽  
Renata Novak Kujundžić ◽  
Nikola Đaković ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Studies ◽  
Metabolic Reprogramming ◽  
Current Status ◽  
Strong Indication ◽  
Experimental Animals ◽  
Oncology Research ◽  
Modifying Effect ◽  
Detailed Presentation

Most data published on curcumin and curcumin-based formulations are very promising. In cancer research, the majority of data has been obtained in vitro. Less frequently, researchers used experimental animals. The results of several clinical studies are conclusive, and these studies have established a good foundation for further research focusing on implementing curcumin in clinical oncology. However, the issues regarding timely data reporting and lack of disclosure of the exact curcumin formulations used in these studies should not be neglected. This article is a snapshot of the current status of publicly available data on curcumin clinical trials and a detailed presentation of results obtained so far with some curcumin formulations. Phenomena related to the observed effects of curcumin shown in clinical trials are presented, and its modifying effect on gut microbiota and metabolic reprogramming is discussed. Based on available data, there is a strong indication that curcumin and its metabolites present molecules that do not necessarily need to be abundant in order to act locally and benefit systemically. Future clinical studies should be designed in a way that will take that fact into consideration.

scholarly journals Wnt Signaling in Cancer Metabolism and Immunity

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 904 ◽  
Author(s):  
Sara El-Sahli ◽  
Ying Xie ◽  
Lisheng Wang ◽  
Sheng Liu
Keyword(s):  
Wnt Signaling ◽  
Cancer Cells ◽  
Cancer Metabolism ◽  
Metabolic Reprogramming ◽  
Tumor Initiating Cells ◽  
Tumor Plasticity ◽  
Anti Cancer ◽  
Wnt Ligands ◽  
Canonical Wnt

The Wingless (Wnt)/β-catenin pathway has long been associated with tumorigenesis, tumor plasticity, and tumor-initiating cells called cancer stem cells (CSCs). Wnt signaling has recently been implicated in the metabolic reprogramming of cancer cells. Aberrant Wnt signaling is considered to be a driver of metabolic alterations of glycolysis, glutaminolysis, and lipogenesis, processes essential to the survival of bulk and CSC populations. Over the past decade, the Wnt pathway has also been shown to regulate the tumor microenvironment (TME) and anti-cancer immunity. Wnt ligands released by tumor cells in the TME facilitate the immune evasion of cancer cells and hamper immunotherapy. In this review, we illustrate the role of the canonical Wnt/β-catenin pathway in cancer metabolism and immunity to explore the potential therapeutic approach of targeting Wnt signaling from a metabolic and immunological perspective.

Controversies on neuroprotection therapy in non-arteritic anterior ischaemic optic neuropathy

2019 ◽  
Vol 104 (2) ◽  
pp. 153-156
Author(s):  
Sohan Singh Hayreh
Keyword(s):  
Clinical Trials ◽  
Ischaemic Stroke ◽  
Optic Neuropathy ◽  
Experimental Studies ◽  
Therapeutic Strategies ◽  
Ischaemic Optic Neuropathy ◽  
Pubmed Search ◽  
Anterior Ischaemic Optic Neuropathy ◽  
Study Designs

ObjectiveThere has long been a great interest in neuroprotection therapy for ischaemic stroke and various types of optic neuropathies. In view of that, I reviewed the literature on the role of neuroprotection for non-arteritic anterior ischaemic optic neuropathy (NA-AION).MethodsThe review is based on a PubMed search of literature about the use of neuroprotectors in stroke and optic neuropathies and about current clinical trials of RPh201 and QPI-1007 in NA-AION.ResultsSeveral neuroprotection agents for ischaemic stroke and various types of optic neuropathies have been evaluated extensively in experimental studies in animals and benefits claimed. However, translation of therapeutic strategies for neuroprotection from experimental research to humans has invariably been fraught with failure. Two currently ongoing studies dealing with neuroprotection by RPh201 and QPI-1007 in NA-AION may have limitations in their rationale and study designs.ConclusionsUnfortunately, in spite of all the experimental and clinical research on neuroprotection agents in NA-AION so far, we have no scientifically proven evidence of neuroprotection agents showing any benefit in the human clinical studies so far.

scholarly journals Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies

Biomedicines ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 270 ◽  
Author(s):  
Gabriela Reyes-Castellanos ◽  
Rawand Masoud ◽  
Alice Carrier
Keyword(s):  
Cancer Therapy ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Mitochondrial Metabolism ◽  
Metabolic Reprogramming ◽  
Ductal Adenocarcinoma ◽  
Current View ◽  
Pancreatic Cancer Cells

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

scholarly journals The role of a data manager at a clinical trial center: the experience of the Alessandria hospital, Italy

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Fabio Giacchero ◽  
Carolina Pelazza ◽  
Serena Panpa ◽  
Marinella Bertolotti ◽  
Tatiana Bolgeo ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Research ◽  
Clinical Studies ◽  
Reference Period ◽  
Job Description ◽  
Data Manager

Objectives: To define the Data Manager (DM) job description within the Clinical Trial Center (CTC) of the Alessandria Hospital (AO AL). To identify the number of authorized clinical studies after the implementation of three DMs in the CTC of the AO AL. Methods: The activities of the DM within the CTC of the AO AL take place in the activation, management and conclusion of clinical trials. The activities were monitored through specific indicators from June 01st, 2019 to May 31st, 2020. Results: During the reference period, an increased authorized studies were observed. Conclusion: The implementation of DMs in the CTC of AO AL has been demonstrated the importance of the figure itself, which, although it has not professionally recognized yet, is found to be fundamental in clinical research.

scholarly journals Extracellular Vesicles in Cancer Metabolism: Implications for Cancer Diagnosis and Treatment

2021 ◽  
Vol 20 ◽  
pp. 153303382110378
Author(s):  
Qian Zhang ◽  
Xiangling Yang ◽  
Huanliang Liu
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cancer Diagnosis ◽  
Cancer Metabolism ◽  
Metabolic Reprogramming ◽  
Bioactive Molecules ◽  
Diagnosis And Treatment ◽  
Existing Problems ◽  
Non Coding Rnas

Metabolic reprogramming is one of the most common characteristics of cancer cells. The metabolic alterations of glucose, amino acids and lipids can support the aggressive phenotype of cancer cells. Exosomes, a kind of extracellular vesicles, participate in the intercellular communication through transferring bioactive molecules. Increasing evidence has demonstrated that enzymes, metabolites and non-coding RNAs in exosomes are responsible for the metabolic alteration of cancer cells. In this review, we summarize the past and recent findings of exosomes in altering cancer metabolism and elaborate on the role of the specific enzymes, metabolites and non-coding RNAs transferred by exosomes. Moreover, we give evidence of the role of exosomes in cancer diagnosis and treatment. Finally, we discuss the existing problems in the study and application of exosomes in cancer diagnosis and treatment.

The Therapeutic Impact of New Migraine Discoveries

2019 ◽  
Vol 26 (34) ◽  
pp. 6261-6281 ◽  
Author(s):  
László Vécsei ◽  
Melinda Lukács ◽  
János Tajti ◽  
Ferenc Fülöp ◽  
József Toldi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Preventive Treatment ◽  
Therapeutic Strategies ◽  
Migraine Treatment ◽  
Preclinical Studies ◽  
Therapeutic Approaches ◽  
Trigeminovascular System ◽  
Glutamate Receptor Antagonists

Background: Migraine is one of the most disabling neurological conditions and associated with high socio-economic costs. Though certain aspects of the pathomechanism of migraine are still incompletely understood, the leading hypothesis implicates the role of the activation of the trigeminovascular system. Triptans are considered to be the current gold standard therapy for migraine attacks; however, their use in clinical practice is limited. Prophylactic treatment includes non-specific approaches for migraine prevention. All these support the need for future studies in order to develop innovative anti-migraine drugs. Objective: The present study is a review of the current literature regarding new therapeutic lines in migraine research. Methods: A systematic literature search in the database of PUBMED was conducted concerning therapeutic strategies in a migraine published until July 2017. Results: Ongoing clinical trials with 5-HT1F receptor agonists and glutamate receptor antagonists offer promising new aspects for acute migraine treatment. Monoclonal antibodies against CGRP and the CGRP receptor are revolutionary in preventive treatment; however, further long-term studies are needed to test their tolerability. Preclinical studies show positive results with PACAP- and kynurenic acid-related treatments. Other promising therapeutic strategies (such as those targeting TRPV1, substance P, NOS, or orexin) have failed to show efficacy in clinical trials. Conclusion: Due to their side-effects, current therapeutic approaches are not suitable for all migraine patients. Especially frequent episodic and chronic migraine represents a therapeutic challenge for researchers. Clinical and preclinical studies are needed to untangle the pathophysiology of migraine in order to develop new and migraine-specific therapies.

Unraveling The Molecular and Metabolic Basis For Glutamine Addiction In Leukemias

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 606-606
Author(s):  
Polina Matre ◽  
Ismael Samudio ◽  
Rodrigo Jacamo ◽  
Ying Wang ◽  
Jing Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prolonged Exposure ◽  
Conflicts Of Interest ◽  
Leukemia Cell ◽  
Cell Number ◽  
Metabolic Reprogramming ◽  
Leukemic Cells ◽  
Viable Cell Number ◽  
Metabolic Processes

Abstract The bone marrow (BM) microenvironment is characterized by hypoxia and the presence of supporting mesenchymal stromal cells (MSC) that promote leukemia cell survival and resistance to therapy, in part by metabolic reprogramming. However mechanisms that couple leukemic cells survival to metabolic processes under different microenvironment conditions have not been elucidated. Glutamine (Gln) provides cells with carbon skeletons to the Krebs cycle (KC) via anaplerosis, sustains cell proliferation, regulates redox homeostasis and modulates activity of signal transduction pathways. Recent data suggests that leukemia cells reduce molecular oxygen utilizing electrons from carbon sources other than pyruvate, and we hypothesize that these electrons could be provided at least in part by glutaminolysis. Our recent studies utilizing gene expression profiling indicate that MSC co-culture under hypoxia promoted glycolytic gene expression in AML cells, as well as genes regulating oxidative phosphorylation (OXPHOS), KC cycle and Gln utilization (GLS1, GOT) (Matre et al., AACR 2013:1887). Here we report studies aimed to unravel metabolic changes in proliferating leukemic cells under hypoxia and upon interaction with MSC and determine the role of Gln as a contributor. First, we performed GC-MS metabolic profiling of OCI-AML3 leukemic cells alone or in co-cultured with MSC under hypoxic or normoxic conditions and observed significant changes in the core metabolic processes. Our data demonstrates that microenvironment promotes glucose-independent OXPHOS to meet bioenergetics needs of leukemic cells. Interaction with MSC propels a glucose-independent oxidative KC through Gln and asparagine catabolism even under conditions where oxygen concentration is limited. Under hypoxia, concentrations of KC intermediates were lower compared to normoxia, however the accumulation of 2-hydroxyglutarate suggests reverse KC activity with glutamate-derived 2-oxoglutarate being converted to citrate via reductive carboxylation pathway. In addition, consumption of glucogenic amino acids was upregulated by MSCs. Glycolytic intermediates accumulated under hypoxia and coculture accompanied by excretion of pyruvate as lactate, suggesting increased availability of carbon skeletons for biomass generation provided, in part, by glutaminolysis. Next, oxygen consumption rates (OCR) and extra-cellular acidification rates (ECAR) in OCI-AML3 and REH cells were assayed using Seahorse Bioscience XF96 EF Analyzer (Billerica, MA). Glutaminase (GLS) inhibition by BPTES or shRNA caused a decrease in basal OCR, reduced ATP production and decreased maximal respiratory capacity of leukemic cells (Fig. 1). Both acute and prolonged exposure to BPTES resulted in a compensatory increase in glycolytic activity as shown by increase in ECAR and confirmed by media lactate levels.Fig. 1OCR in AML and ALL after BPTES treatment.Fig. 1. OCR in AML and ALL after BPTES treatment. Analysis of a panel of acute leukemia cell lines (n=12) showed that subset of leukemia (75%) markedly dependent on Gln for growth with Gln deprivation causing steep decrease in viable cell number via induction of apoptosis. In addition, in the corresponding subset, inhibition of GLS (GLS1) with BPTES decreased cell growth and increased apoptosis under both normoxia and hypoxia. Notably, MSC co-culture failed to protect firmly attached hypoxic AML cells, which are otherwise resistant to chemotherapy-induced cytotoxicity. Finally, the expression of GLS1 gene splice variants, Glutaminase C (GAC) and kidney glutaminase (KGA), was determined using oligonucleotide microarrays (HG U133 Plus 2.0, Affymetrix) in 288 AML and in 103 normal samples (healthy BM and non-leukemia conditions, Haferlach, JCO 2010). GAC transcript was found to be significantly overexpressed in several AML subtypes, including AML with FLT3 gene mutations and complex cytogenetics. In turn, KGA expression was not different between AML and normal samples. In summary, our results indicate that Gln is a major source of carbon skeletons for KC activity in AML cells, and demonstrate the key role of Gln utilization pathway for the survival of hypoxic BM-resident leukemic cells and “Glutamine-dependent OXPHOS subset” of leukemia. These findings support the notion of targeting microenvironment-fueled leukemia metabolism through pharmacological inhibition of GLS with novel selective GLS1/2 inhibitors entering clinical arena. Disclosures: No relevant conflicts of interest to declare.

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