scholarly journals What is the prospect of indoleamine 2,3-dioxygenase 1 inhibition in cancer? Extrapolation from the past

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yu Yao ◽  
Heng Liang ◽  
Xin Fang ◽  
Shengnan Zhang ◽  
Zikang Xing ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Kynurenine Pathway ◽  
Phase Iii ◽  
Current Status ◽  
The Past ◽  
Indoleamine 2,3 Dioxygenase ◽  
Negative Results ◽  
Rate Limiting Step ◽  
Pharmacodynamic Markers ◽  
Tumor Types

AbstractIndoleamine 2,3-dioxygenase 1 (IDO1), a monomeric heme-containing enzyme, catalyzes the first and rate-limiting step in the kynurenine pathway of tryptophan metabolism, which plays an important role in immunity and neuronal function. Its implication in different pathophysiologic processes including cancer and neurodegenerative diseases has inspired the development of IDO1 inhibitors in the past decades. However, the negative results of the phase III clinical trial of the would-be first-in-class IDO1 inhibitor (epacadostat) in combination with an anti-PD1 antibody (pembrolizumab) in patients with advanced malignant melanoma call for a better understanding of the role of IDO1 inhibition. In this review, the current status of the clinical development of IDO1 inhibitors will be introduced and the key pre-clinical and clinical data of epacadostat will be summarized. Moreover, based on the cautionary notes obtained from the clinical readout of epacadostat, strategies for the identification of reliable predictive biomarkers and pharmacodynamic markers as well as for the selection of the tumor types to be treated with IDO1inhibitors will be discussed.

scholarly journals New agents on the horizon in hepatocellular carcinoma

2012 ◽  
Vol 5 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Andrew X. Zhu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Iii ◽  
Current Status ◽  
Advanced Hepatocellular Carcinoma ◽  
Targeted Agents ◽  
New Agents ◽  
The Past ◽  
Early Evidence ◽  
Molecularly Targeted Agents ◽  
Active Research

Despite the successful approval and extensive application of sorafenib, the prognosis for patients with advanced hepatocellular carcinoma (HCC) remains poor. Fortunately, there have been renewed and continued interests and active research in developing other molecularly targeted agents in HCC during the past few years. While there is early evidence of antitumor activity of several agents in phase I/II studies, phase III efforts with a few targeted agents have failed, highlighting the challenges of new drug development in HCC. This review summarizes the current status of other molecularly targeted agents under development in advanced HCC.

Learning from the Past: A Review of Clinical Trials Targeting Amyloid, Tau and Neuroinflammation in Alzheimer’s Disease

2020 ◽  
Vol 17 (2) ◽  
pp. 112-125 ◽  
Author(s):  
Kelly Ceyzériat ◽  
Thomas Zilli ◽  
Philippe Millet ◽  
Giovanni B. Frisoni ◽  
Valentina Garibotto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Animal Models ◽  
Phase Iii ◽  
Current Status ◽  
Central Feature ◽  
Phase Iii Trial ◽  
The Past ◽  
Positive Results

Alzheimer’s Disease (AD) is the most common neurodegenerative disease and cause of dementia. Characterized by amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau, AD pathology has been intensively studied during the last century. After a long series of failed trials of drugs targeting amyloid or Tau deposits, currently, hope lies in the positive results of one Phase III trial, highly debated, and on other ongoing trials. In parallel, some approaches target neuroinflammation, another central feature of AD. Therapeutic strategies are initially evaluated on animal models, in which the various drugs have shown effects on the target (decreasing amyloid, Tau and neuroinflammation) and sometimes on cognitive impairment. However, it is important to keep in mind that rodent models have a less complex brain than humans and that the pathology is generally not fully represented. Although they are indispensable tools in the drug discovery process, results obtained from animal models must be viewed with caution. In this review, we focus on the current status of disease-modifying therapies targeting amyloid, Tau and neuroinflammation with particular attention on the discrepancy between positive preclinical results on animal models and failures in clinical trials.

Oxidation of L-tryptophan in biology: a comparison between tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase

2009 ◽  
Vol 37 (2) ◽  
pp. 408-412 ◽  
Author(s):  
Sara A. Rafice ◽  
Nishma Chauhan ◽  
Igor Efimov ◽  
Jaswir Basran ◽  
Emma Lloyd Raven
Keyword(s):  
Structural Information ◽  
Recombinant Expression ◽  
Kynurenine Pathway ◽  
Expression Systems ◽  
Indoleamine 2,3 Dioxygenase ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
The Family ◽  
And Function ◽  
Rate Limiting

The family of haem dioxygenases catalyse the initial oxidative cleavage of L-tryptophan to N-formylkynurenine, which is the first, rate-limiting, step in the L-kynurenine pathway. In the present paper, we discuss and compare structure and function across the family of haem dioxygenases by focusing on TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase), including a review of recent structural information for both enzymes. The present paper describes how the recent development of recombinant expression systems has informed our more detailed understanding of the substrate binding, catalytic activity and mechanistic properties of these haem dioxygenases.

scholarly journals Characterization of apo-form selective inhibition of indoleamine 2,3-dioxygenase

2018 ◽  
Author(s):  
Rodrigo Ortiz-Meoz ◽  
Liping Wang ◽  
Rosalie Matico ◽  
Anna Rutkowska ◽  
Martha De la Rosa ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Inhibitory Effect ◽  
Kynurenine Pathway ◽  
Cellular Systems ◽  
Inhibition Mechanism ◽  
Pharmacokinetic Parameters ◽  
Indoleamine 2,3 Dioxygenase ◽  
Disease States ◽  
Rate Limiting Step

ABSTRACTIndoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of established and novel IDO1 inhibitors remains of great interest. Comparison of a newly-developed IDO1 inhibitor (GSK5628) to the existing best-in-class compound, epacadostat (Incyte), allows us to report on a unique inhibition mechanism for IDO1. Here, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1) while epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition may help design superior inhibitors or may confer a unique competitive advantage over other IDO1 inhibitors vis-à-vis specificity and pharmacokinetic parameters.

scholarly journals Exploring the mechanism of tryptophan 2,3-dioxygenase

2008 ◽  
Vol 36 (6) ◽  
pp. 1120-1123 ◽  
Author(s):  
Sarah J. Thackray ◽  
Christopher G. Mowat ◽  
Stephen K. Chapman
Keyword(s):  
Catalytic Mechanism ◽  
Kynurenine Pathway ◽  
Oxidation Catalysts ◽  
Function Structure ◽  
Indoleamine 2,3 Dioxygenase ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Biochemical Analyses ◽  
Rate Limiting ◽  
Haem Proteins

The haem proteins TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase) are specific and powerful oxidation catalysts that insert one molecule of dioxygen into L-tryptophan in the first and rate-limiting step in the kynurenine pathway. Recent crystallographic and biochemical analyses of TDO and IDO have greatly aided our understanding of the mechanisms employed by these enzymes in the binding and activation of dioxygen and tryptophan. In the present paper, we briefly discuss the function, structure and possible catalytic mechanism of these enzymes.

Advances In Asthma Care

2003 ◽  
Vol 1 (1) ◽  
pp. 87-90 ◽  
Author(s):  
Chris Garvey
Keyword(s):  
Healthcare Costs ◽  
Professional Organizations ◽  
Current Status ◽  
Asthma Care ◽  
Advanced Level ◽  
Clinical Criteria ◽  
Asthma Knowledge ◽  
The Past ◽  
The Us ◽  
Examination Process

Asthma rates in the US have risen during the past 25 years, as have asthma-related morbidity and healthcare costs. Professional organizations involved in asthma care have identified the need to assure that an advanced level of asthma knowledge and skill is available to patients with asthma, their families, and insurers. This need led to development of the certification for asthma educators. The Certified Asthma Educator (AE-C) must meet specific clinical criteria and pass a standardized examination designed to evaluate knowledge and skill for providing competent asthma education and coordination. The development and current status of the Certified Asthma Educator examination process and content are discussed, as are goals of the certification

Water resources management in Greece: current status and prospective outlook

1995 ◽  
Vol 32 (9-10) ◽  
pp. 267-272 ◽  
Author(s):  
A. Angelakis ◽  
E. Diamadopoulos
Keyword(s):  
Water Resources ◽  
Water Resources Management ◽  
Water Demand ◽  
Treatment Plant ◽  
Current Status ◽  
Reclaimed Wastewater ◽  
Resources Management ◽  
The Past ◽  
Precipitation Water ◽  
Pollution Loads

The basic aim of this paper is to present the existing conditions and problems of water resources management in Greece. Water demand has increased tremendously over the past 30 years. Despite adequate precipitation, water imbalance is often experienced, due to temporal and regional variations of the precipitation, the increased water demand during the summer months and the difficulty of transporting water due to the mountainous terrain. Integration of reclaimed wastewater originating from the wastewater treatment plant effluents into the water resources management is proposed. This plan exhibits the potential for reducing the pollution loads entering sea or inland waters, while at the same time providing water for irrigation.

Upcoming Drifts In Bio-Similars

2020 ◽  
Vol 15 ◽  
Author(s):  
Geeta Aggarwal ◽  
Manju Nagpal ◽  
Ameya Sharma ◽  
Vivek Puri ◽  
Gitika Arora Dhingra
Keyword(s):  
Metabolic Diseases ◽  
Market Competition ◽  
Current Status ◽  
Medicinal Products ◽  
The Past ◽  
Biologic Activity ◽  
Emerging Trends ◽  
Regulatory Guidelines ◽  
Food Drug Administration ◽  
Insight Into

Background: Biopharmaceuticals such as Biologic medicinal products have been in clinical use over the past three decades and have benefited towards the therapy of degenerative and critical metabolic diseases. It is forecasted that market of biologics will be going to increase at a rate of 20% per year, and by 2025, more than ˃ 50% of new drug approvals may be biological products. The increasing utilization of the biologics necessitates for cost control, especially for innovators products that have enjoyed a lengthy period of exclusive use. As the first wave of biopharmaceuticals is expired or set to expire, it has led to various opportunities for the expansion of bio-similars i.e. copied versions of original biologics with same biologic activity. Development of biosimilars is expected to promote market competition, meet worldwide demand, sustain the healthcare systems and maintain the incentives for innovation. Methods: Appraisal of published articles from peer reviewed journals, PubMed literature, latest news and guidelines from European Medicine Agency, US Food Drug Administration (FDA) and India are used to identify data for review. Results: Main insight into the quality requirements concerning biologics, current status of regulation of biosimilars and upcoming challenges lying ahead for the upgrading of marketing authorization of bio-similars has been incorporated. Compiled literature on therapeutic status, regulatory guidelines and the emerging trends and opportunities of biosimilars has been thoroughly stated. Conclusion: Updates on biosimilars will support to investigate the possible impact of bio-similars on healthcare market.

scholarly journals Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1715
Author(s):  
Robin Park ◽  
Laercio Lopes ◽  
Anwaar Saeed
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Gastroesophageal Cancer ◽  
Programmed Death ◽  
Phase Iii Trials ◽  
Tumor Mutational Burden ◽  
Large Phase ◽  
Programmed Death 1

Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

scholarly journals Changes in Neutrophil–Lymphocyte or Platelet–Lymphocyte Ratios and Their Associations with Clinical Outcomes in Idiopathic Pulmonary Fibrosis

2021 ◽  
Vol 10 (7) ◽  
pp. 1427
Author(s):  
Steven D. Nathan ◽  
Jayesh Mehta ◽  
John Stauffer ◽  
Elizabeth Morgenthien ◽  
Ming Yang ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Clinical Outcomes ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Response To Treatment ◽  
Reference Ranges ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
The Relationship

Identification of prognostic and predictive biomarkers in idiopathic pulmonary fibrosis (IPF) could aid assessment of disease severity and prediction of progression and response to treatment. This analysis examined reference ranges for neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) in IPF, and the relationship between NLR or PLR changes and clinical outcomes over 12 months. This post hoc analysis included patients with IPF from the Phase III, double-blind trials of pirfenidone, ASCEND (NCT01366209) and CAPACITY (NCT00287716 and NCT00287729). The relationship between change from baseline to Month 12 in NLR or PLR (divided into quartiles (Q1–Q4)) and outcomes (mortality, respiratory hospitalization, declines in lung function, exercise capacity and quality of life) was assessed. Estimated reference ranges at baseline for all patients analyzed (n = 1334) were 1.1–6.4 for NLR and 56.8–250.5 for PLR. Significant trends were observed across NLR and PLR quartiles for all outcomes in placebo-treated patients, with patients manifesting the greatest NLR or PLR changes experiencing the worst outcomes. These results suggest that the greatest NLR or PLR changes over 12 months were associated with worse clinical outcomes. Further research is needed to determine the utility of NLR and PLR as prognostic biomarkers in IPF.

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