scholarly journals Matrix Metalloproteases as Influencers of the Cells’ Social Media

2019 ◽  
Vol 20 (16) ◽  
pp. 3847 ◽  
Author(s):  
Daniel Young ◽  
Nabangshu Das ◽  
Anthonia Anowai ◽  
Antoine Dufour
Keyword(s):  
Inflammatory Diseases ◽  
Matrix Metalloproteases ◽  
Phase Iii ◽  
Biological Functions ◽  
Mmp Inhibitors ◽  
Ecm Remodeling ◽  
Surface Receptors ◽  
Phase Iii Clinical Trials ◽  
The Matrix ◽  
The Impact

Matrix metalloproteinases (MMPs) have been studied in the context of cancer due to their ability to increase cell invasion, and were initially thought to facilitate metastasis solely through the degradation of the extracellular matrix (ECM). MMPs have also been investigated in the context of their ECM remodeling activity in several acute and chronic inflammatory diseases. However, after several MMP inhibitors failed in phase III clinical trials, a global reassessment of their biological functions was undertaken, which has revealed multiple unanticipated functions including the processing of chemokines, cytokines, and cell surface receptors. Despite what their name suggests, the matrix aspect of MMPs could contribute to a lesser part of their physiological functions in inflammatory diseases, as originally anticipated. Here, we present examples of MMP substrates implicated in cell signaling, independent of their ECM functions, and discuss the impact for the use of MMP inhibitors.

scholarly journals The Pharmacological TAILS of Matrix Metalloproteinases and Their Inhibitors

2020 ◽  
Vol 14 (1) ◽  
pp. 31
Author(s):  
Nabangshu Das ◽  
Colette Benko ◽  
Sean E. Gill ◽  
Antoine Dufour
Keyword(s):  
Clinical Trials ◽  
Matrix Metalloproteinases ◽  
Conformational Changes ◽  
Active Sites ◽  
Inflammatory Diseases ◽  
Phase Iii ◽  
Biological Functions ◽  
Mmp Inhibitors ◽  
Allosteric Control ◽  
Phase Iii Clinical Trials

Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches, such as proteomics and N-terminomics, to identify new MMP substrates. We present some examples of new MMP substrates and their implications in regulating biological functions. By characterizing the roles and substrates of individual MMP, MMP inhibitors could be utilized more effectively in the optimal disease context or in diseases never tested before where MMP activity is elevated and contributing to disease progression.

scholarly journals The Pharmacological Tails of Matrix Metalloproteinases and Their Inhibitors

2021 ◽  
Author(s):  
Nabangshu Das ◽  
Colette Benko ◽  
Sean E. Gill ◽  
Antoine Dufour
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Matrix Metalloproteinases ◽  
Conformational Changes ◽  
Active Sites ◽  
Inflammatory Diseases ◽  
Phase Iii ◽  
Mmp Inhibitors ◽  
Allosteric Control ◽  
Phase Iii Clinical Trials

Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites (e.g., exosites, ectosites) through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches such as proteomics and N-terminomics to identify new MMP substrates and achieve a better understanding of the roles of these proteases in diseases.

scholarly journals The Pharmacological Tails of Matrix Metalloproteinases and Their Inhibitors

2020 ◽  
Author(s):  
Nabangshu Das ◽  
Colette Benko ◽  
Sean E. Gill ◽  
Antoine Dufour
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Matrix Metalloproteinases ◽  
Conformational Changes ◽  
Active Sites ◽  
Inflammatory Diseases ◽  
Phase Iii ◽  
Mmp Inhibitors ◽  
Allosteric Control ◽  
Phase Iii Clinical Trials

Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites (e.g., exosites, ectosites) through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches such as proteomics and N-terminomics to identify new MMP substrates and achieve a better understanding of the roles of these proteases in diseases.

scholarly journals Comparison of futility monitoring guidelines using completed phase III oncology trials

2016 ◽  
Vol 14 (1) ◽  
pp. 48-58 ◽  
Author(s):  
Qiang Zhang ◽  
Boris Freidlin ◽  
Edward L Korn ◽  
Susan Halabi ◽  
Sumithra Mandrekar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Sample Size ◽  
Alternative Hypothesis ◽  
Phase Iii ◽  
Interim Result ◽  
Type I ◽  
Conditional Power ◽  
Phase Iii Clinical Trials ◽  
The Impact ◽  
Analytical Approaches

Background: Futility (inefficacy) interim monitoring is an important component in the conduct of phase III clinical trials, especially in life-threatening diseases. Desirable futility monitoring guidelines allow timely stopping if the new therapy is harmful or if it is unlikely to demonstrate to be sufficiently effective if the trial were to continue to its final analysis. There are a number of analytical approaches that are used to construct futility monitoring boundaries. The most common approaches are based on conditional power, sequential testing of the alternative hypothesis, or sequential confidence intervals. The resulting futility boundaries vary considerably with respect to the level of evidence required for recommending stopping the study. Purpose: We evaluate the performance of commonly used methods using event histories from completed phase III clinical trials of the Radiation Therapy Oncology Group, Cancer and Leukemia Group B, and North Central Cancer Treatment Group. Methods: We considered published superiority phase III trials with survival endpoints initiated after 1990. There are 52 studies available for this analysis from different disease sites. Total sample size and maximum number of events (statistical information) for each study were calculated using protocol-specified effect size, type I and type II error rates. In addition to the common futility approaches, we considered a recently proposed linear inefficacy boundary approach with an early harm look followed by several lack-of-efficacy analyses. For each futility approach, interim test statistics were generated for three schedules with different analysis frequency, and early stopping was recommended if the interim result crossed a futility stopping boundary. For trials not demonstrating superiority, the impact of each rule is summarized as savings on sample size, study duration, and information time scales. Results: For negative studies, our results show that the futility approaches based on testing the alternative hypothesis and repeated confidence interval rules yielded less savings (compared to the other two rules). These boundaries are too conservative, especially during the first half of the study (<50% of information). The conditional power rules are too aggressive during the second half of the study (>50% of information) and may stop a trial even when there is a clinically meaningful treatment effect. The linear inefficacy boundary with three or more interim analyses provided the best results. For positive studies, we demonstrated that none of the futility rules would have stopped the trials. Conclusion: The linear inefficacy boundary futility approach is attractive from statistical, clinical, and logistical standpoints in clinical trials evaluating new anti-cancer agents.

scholarly journals Recent insights into natural product inhibitors of matrix metalloproteinases

MedChemComm ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 2024-2037 ◽  
Author(s):  
Geetha B. Kumar ◽  
Bipin G. Nair ◽  
J. Jefferson P. Perry ◽  
David B. C. Martin
Keyword(s):  
Cardiovascular Disease ◽  
Matrix Metalloproteinases ◽  
Matrix Metalloproteinase ◽  
Natural Product ◽  
Human Health ◽  
Neurodegenerative Disorders ◽  
Biological Functions ◽  
Mmp Inhibitors ◽  
The Matrix ◽  
Health And Disease

Members of the matrix metalloproteinase (MMP) family have biological functions that are central to human health and disease, and MMP inhibitors have been investigated for the treatment of cardiovascular disease, cancer and neurodegenerative disorders.

A review of clinical endpoints and use of quality-of-life outcomes in phase III metastatic breast cancer clinical trials.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 129-129
Author(s):  
Raman Tatla ◽  
Denis Landaverde ◽  
Charles Victor ◽  
David Miles ◽  
Sunil Verma
Keyword(s):  
Breast Cancer ◽  
Quality Of Life ◽  
Clinical Trials ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Clinical Endpoints ◽  
Phase Iii Clinical Trials ◽  
The Impact

129 Background: The management of metastatic breast cancer (MBC) is often considered to be palliative, with most interventions intended to relieve disease symptoms, minimize treatment effects and prolong patient survival. The impact of disease and treatment on a patient's funcitonal abilities has led to an emphasis of incorporating quality of life (QoL) measures into clinical trials. The main objective of this study is to evaluate phase III clinical trials in MBC, and assess the inclusion of QOL as an endpoint, in addition to conventional efficacy endpoints. Methods: A structured PubMed search was conducted to identify phase III clinical trials published between Jan. 1990 and Aug. 2011, evaluating systemic treatment in MBC patients. Data pertaining to treatment regimens, study endpoints and clinical findings were collected, with a particular focus on progression-based (PB), overall survival (OS), and QoL endpoints. Results: Of 520 publications identified, 122 phase III MBC clinical trials met the inclusion criteria. Of these studies, 98.4% and 95.9% included PB and OS respectively, as clinical endpoints, while QoL was assessed in only 46 (37.7%) studies. While the inclusion of QoL was not associated with the significance of PB results, there was an association between the inclusion of QoL and OS results, with 59% of significant OS studies and 32% of non-significant OS studies including QoL as a clinical endpoint (p=0.016). When stratified by treatment arm, it was found that studies favouring standard therapy were more likely to include QoL (75%, p=0.045), compared to those favouring the intervention (56%), and those without significant differences (32%). Conclusions: Although the importance of QoL is often emphasized in MBC management and treatment decisions, only one-third of identified phase III clinical trials included an assessment of QoL. About half of these trials showed no statistically significant differences in the QoL endpoint; of not, instruments of varying validity were utilized. There needs to be a greater emphasis on the evaluation of QoL, with the use of standard and validated QoL tools in MBC clinical trials, especially as we increasingly focus on progression-based endpoints.

scholarly journals Ovulation is Inhibited by an Environmentally Relevant Phthalate Mixture in Mouse Antral Follicles in Vitro

2020 ◽  
Author(s):  
Katie L Land ◽  
Madison E Lane ◽  
Ava C Fugate ◽  
Patrick R Hannon
Keyword(s):  
Endocrine Disrupting Chemicals ◽  
Consumer Products ◽  
Matrix Metalloproteases ◽  
Dependent Manner ◽  
Ecm Remodeling ◽  
Antral Follicles ◽  
The Matrix ◽  
Housing Materials ◽  
Ovulatory Period

Abstract Phthalates are solvents and plasticizers found in consumer products including cosmetics, food/beverage containers, housing materials, etc. Phthalates are known endocrine-disrupting chemicals that can directly target the ovary, potentially causing defects in ovulation and fertility. Women are exposed to multiple different phthalates daily, therefore this study investigated the effects of an environmentally relevant phthalate mixture (PHTmix) on ovulation. Ovulation is initiated by the luteinizing hormone (LH) surge, which induces prostaglandin (PG) production, progesterone (P4)/progesterone receptor (PGR) signaling, and extra-cellular matrix (ECM) remodeling. We hypothesized that the PHTmix would directly inhibit ovulation by altering the levels of PGs, P4/PGR, and enzymes involved in ECM remodeling. Antral follicles from CD-1 mice were treated with vehicle control alone (dimethylsulfoxide, DMSO), hCG alone (LH analog), and hCG+PHTmix (1-500μg/ml), and samples were collected across the ovulatory period. The PHTmix decreased ovulation rates at all doses tested in a dose dependent manner when compared to hCG. PG levels were decreased by the PHTmix when compared to hCG, which was potentially mediated by altered levels of PG synthesis (Ptgs2) and transport (Slco2a1) genes. The PHTmix altered P4 and Pgr levels when compared to hCG, leading to decreases in downstream PGR-mediated genes (Edn2, Il6, Adamts1). ECM remodeling was potentially dysregulated by altered levels of ovulatory mediators belonging to the matrix metalloproteases and plasminogen activator families. These data suggest that phthalate exposure inhibits ovulation by altering PG levels, P4/PGR action, and ECM remodeling.

A review of clinical endpoints and use of quality of life outcomes in phase III metastatic breast cancer clinical trials.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e16547-e16547
Author(s):  
Raman Tatla ◽  
Denis Landaverde ◽  
Charles Victor ◽  
David Miles ◽  
Sunil Verma
Keyword(s):  
Breast Cancer ◽  
Quality Of Life ◽  
Clinical Trials ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Clinical Endpoints ◽  
Phase Iii Clinical Trials ◽  
The Impact

e16547 Background: The management of metastatic breast cancer (MBC) is often considered to be palliative, with therapy used to relieve disease symptoms, minimize treatment effects and prolong survival. The impact of disease and treatment on patients has led to an emphasis of quality of life (QoL) measures in clinical trials. This study’s primary objective is to evaluate phase III clinical trials in MBC, and assess the inclusion of QoL as an endpoint. Methods: A PubMed search was conducted to identify phase III clinical trials published from Jan 1990 to Aug 2011, which evaluated systemic therapy in MBC patients. Data pertaining to treatment regimens, study endpoints and clinical findings were collected, with a focus on progression-based (PB), overall survival (OS), and QoL endpoints. The instrument(s) used to evaluate QoL were also noted (if applicable). Results: Of 520 publications identified, 122 phase III MBC clinical trials met the inclusion criteria. Of these studies, 98.4% and 95.9% included PB and OS respectively, as clinical endpoints, while QoL was assessed in only 46 (37.7%) studies. 14 instruments were identified as QoL tools among the studies, with EORTC QLQ-C30 and FACT-B accounting for 54.7% of the instruments used. While the inclusion of QoL was not related to the significance of PB results, there was an association between the inclusion of QoL and OS results, with 59% of significant OS studies and 32% of non-significant OS studies including QoL as an endpoint (p=0.016). Stratification by treatment arm found that studies favouring standard therapy were more likely to include QoL (75%, p=0.045), compared to those favouring the intervention (56%), and those without significant differences (32%). Conclusions: Although the importance of QoL is often emphasized in MBC management, only one-third of identified phase III clinical trials included its assessment. Half of these trials showed no statistically significant differences in QoL endpoint; of note, instruments of varying validity were utilized. There needs to be greater emphasis on the evaluation of QoL, with the use of standard and validated QoL tools in MBC clinical trials, especially as we increasingly focus on progression-based endpoints.

Biosimilars

Lupus ◽  
2020 ◽  
Vol 29 (6) ◽  
pp. 525-532
Author(s):  
Christopher J Edwards ◽  
Salvatore Bellinvia
Keyword(s):  
Lupus Erythematosus ◽  
Inflammatory Diseases ◽  
Treatment Options ◽  
Mechanisms Of Action ◽  
Phase Iii ◽  
Biological Therapies ◽  
Systemic Lupus ◽  
Safety And Efficacy ◽  
Phase Iii Clinical Trials ◽  
Immune Mediated

Biological therapies have widened the therapeutic armamentarium for immune-mediated inflammatory diseases, providing in many cases a broad range of treatment options with different mechanisms of action. The widespread use of biological agents in systemic lupus erythematosus is currently limited to belimumab and rituximab, although results of promising larger Phase III clinical trials are awaited or have been recently circulated, especially for anti-cytokine therapies. The loss of exclusivity over the last years for several originator biologics has started the successful introduction of biosimilar products into clinical practice. There is an abbreviated pathway to biosimilar approval, but this is underpinned by the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines. Nevertheless, there are unique reasons why development of biosimilars may be particularly challenging in lupus.

scholarly journals HIF2α regulates the synthesis and release of epinephrine in the adrenal medulla

2021 ◽  
Author(s):  
Deepika Watts ◽  
Nicole Bechmann ◽  
Ana Meneses ◽  
Ioanna K. Poutakidou ◽  
Denise Kaden ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Adrenal Medulla ◽  
Phase Iii ◽  
List Type ◽  
Phase Iii Clinical Trials ◽  
Consequent Reduction ◽  
Simultaneous Loss ◽  
Necessary And Sufficient ◽  
The Impact ◽  
Mediated Reduction

Abstract The adrenal gland and its hormones regulate numerous fundamental biological processes; however, the impact of hypoxia signaling on adrenal function remains poorly understood. Here, we reveal that deficiency of HIF (hypoxia inducible factors) prolyl hydroxylase domain protein-2 (PHD2) in the adrenal medulla of mice results in HIF2α-mediated reduction in phenylethanolamine N-methyltransferase (PNMT) expression, and consequent reduction in epinephrine synthesis. Simultaneous loss of PHD2 in renal erythropoietin (EPO)-producing cells (REPCs) stimulated HIF2α-driven EPO overproduction, excessive RBC formation (erythrocytosis), and systemic hypoglycemia, which is necessary and sufficient to enhance exocytosis of epinephrine from the adrenal medulla. Based on these results, we propose that the PHD2-HIF2α axis in the adrenal medulla regulates the synthesis of epinephrine, whereas in REPCs, it indirectly induces the release of this hormone. Our findings are also highly relevant to the testing of small molecule PHD inhibitors in phase III clinical trials for patients with renal anemia. Key messages HIF2α and not HIF1α modulates PNMT during epinephrine synthesis in chromaffin cells. The PHD2-HIF2α-EPO axis induces erythrocytosis and hypoglycemia. Reduced systemic glucose facilitates exocytosis of epinephrine from adrenal gland.

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