scholarly journals Bridging in vitro and in vivo research via an agent-based modelling approach: predicting tumour responses to an ATR-inhibiting drug

2019 ◽  
Author(s):  
Sara Hamis ◽  
James Yates ◽  
Mark AJ Chaplain ◽  
Gibin G Powathil
Keyword(s):  
Drug Development ◽  
Quantitative Information ◽  
Agent Based Model ◽  
Agent Based ◽  
Lovo Cells ◽  
Preclinical Drug Development ◽  
Development Processes ◽  
Modelling Approach

AbstractTranslating quantitative information between in vitro and in vivo research remains a scientifically and financially challenging step in preclinical drug development processes. However, well-developed in silico tools can be used to facilitate this in vitro to in vivo translation, and we here propose using a data-driven, agent-based model to bridge the gap between in vitro and in vivo research. The agent-based model used in this study is governed by a set of empirically observable rules, and by adjusting only the rules when moving between in vitro and in vivo simulations, whilst keeping the fundamental mathematical model and parameters intact, the agent-based model can first be parameterised by in vitro data and thereafter be used to predict in vivo treatment responses.As a proof-of-concept, this modelling approach is here validated against data pertaining to LoVo cells subjected to the ATR (ataxia telangiectasia mutated and rad3-related kinase) inhibiting drug AZD6738, but the modelling approach has the potential to be expanded to other applications. In this article we also highlight how agent-based models, that are currently underutilised in pharmaceutical contexts, can be used in preclinical drug development.

scholarly journals Targeting Cellular DNA Damage Responses in Cancer: An In Vitro-Calibrated Agent-Based Model Simulating Monolayer and Spheroid Treatment Responses to ATR-Inhibiting Drugs

2021 ◽  
Vol 83 (10) ◽  
Author(s):  
Sara Hamis ◽  
James Yates ◽  
Mark A. J. Chaplain ◽  
Gibin G. Powathil
Keyword(s):  
Dna Damage ◽  
Drug Development ◽  
Agent Based Model ◽  
Agent Based ◽  
Preclinical Drug Development ◽  
Dna Damage Responses ◽  
Treatment Responses ◽  
Cellular Dna

AbstractWe combine a systems pharmacology approach with an agent-based modelling approach to simulate LoVo cells subjected to AZD6738, an ATR (ataxia–telangiectasia-mutated and rad3-related kinase) inhibiting anti-cancer drug that can hinder tumour proliferation by targeting cellular DNA damage responses. The agent-based model used in this study is governed by a set of empirically observable rules. By adjusting only the rules when moving between monolayer and multi-cellular tumour spheroid simulations, whilst keeping the fundamental mathematical model and parameters intact, the agent-based model is first parameterised by monolayer in vitro data and is thereafter used to simulate treatment responses in in vitro tumour spheroids subjected to dynamic drug delivery. Spheroid simulations are subsequently compared to in vivo data from xenografts in mice. The spheroid simulations are able to capture the dynamics of in vivo tumour growth and regression for approximately 8 days post-tumour injection. Translating quantitative information between in vitro and in vivo research remains a scientifically and financially challenging step in preclinical drug development processes. However, well-developed in silico tools can be used to facilitate this in vitro to in vivo translation, and in this article, we exemplify how data-driven, agent-based models can be used to bridge the gap between in vitro and in vivo research. We further highlight how agent-based models, that are currently underutilised in pharmaceutical contexts, can be used in preclinical drug development.

Technological Advances in Preclinical Drug Evaluation: The Role of -Omics Methods

2020 ◽  
Vol 27 (8) ◽  
pp. 1337-1349 ◽  
Author(s):  
Sandra Kraljević Pavelić ◽  
Elitza Markova-Car ◽  
Marko Klobučar ◽  
Lana Sappe ◽  
Radan Spaventi
Keyword(s):  
Drug Development ◽  
Drug Evaluation ◽  
Legal Aspects ◽  
Drug Candidates ◽  
Technological Advances ◽  
Preclinical Drug Development ◽  
New Chemical Entities ◽  
Speed Up

Preclinical drug development is an essential step in the drug development process where the evaluation of new chemical entities occurs. In particular, preclinical drug development phases include deep analysis of drug candidates’ interactions with biomolecules/targets, their safety, toxicity, pharmacokinetics, metabolism by use of assays in vitro and in vivo animal assays. Legal aspects of the required procedures are well-established. Herein, we present a comprehensive summary of current state-of-the art approaches and techniques used in preclinical studies. In particular, we will review the potential of new, -omics methods and platforms for mechanistic evaluation of drug candidates and speed-up of the preclinical evaluation steps.

scholarly journals In Silico Modeling of Biofilm Formation by Nontypeable Haemophilus influenzae In Vivo

mSphere ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Jonathan R. Brown ◽  
Joseph Jurcisek ◽  
Vinal Lakhani ◽  
Ali Snedden ◽  
William C. Ray ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
In Silico ◽  
Biofilm Formation ◽  
Host Responses ◽  
Model Parameters ◽  
Agent Based Model ◽  
Content Type ◽  
Agent Based

ABSTRACT Biofilms formed by nontypeable Haemophilus influenzae (NTHI) bacteria play an important role in multiple respiratory tract diseases. Visual inspection of the morphology of biofilms formed during chronic infections shows distinct differences from biofilms formed in vitro. To better understand these differences, we analyzed images of NTHI biofilms formed in the middle ears of Chinchilla lanigera and developed an in silico agent-based model of the formation of NTHI biofilms in vivo. We found that, as in vitro, NTHI bacteria are organized in self-similar patterns; however, the sizes of NTHI clusters in vivo are more than 10-fold smaller than their in vitro counterparts. The agent-based model reproduced these patterns and suggested that smaller clusters occur due to elimination of planktonic NTHI cells by the host responses. Estimation of model parameters by fitting simulation results to imaging data showed that the effects of several processes in the model change during the course of the infection. IMPORTANCE Multiple respiratory illnesses are associated with formation of biofilms within the human airway by NTHI. However, a substantial amount of our understanding of the mechanisms that underlie NTHI biofilm formation is obtained from in vitro studies. Our in silico model that describes biofilm formation by NTHI within the middle ears of Chinchilla lanigera will help isolate processes potentially responsible for the differences between the morphologies of biofilms formed in vivo versus those formed in vitro. Thus, the in silico model can be used to glean mechanisms that underlie biofilm formation in vivo and connect those mechanisms to those obtained from in vitro experiments. The in silico model developed here can be extended to investigate potential roles of specific host responses (e.g., mucociliary clearance) on NTHI biofilm formation in vivo. The developed computational tools can also be used to analyze and describe biofilm formation by other bacterial species in vivo.

scholarly journals Detecting apoptosis as a clinical endpoint for proof of a clinical principle

2020 ◽  
Author(s):  
Piero Zollet ◽  
Timothy E.Yap ◽  
M Francesca Cordeiro
Keyword(s):  
Drug Development ◽  
Therapeutic Response ◽  
Imaging Techniques ◽  
Brain Diseases ◽  
Promising Strategy ◽  
Sight Loss ◽  
Apoptosis Detection ◽  
Novel Therapeutic Strategies

The transparent eye media represent a window through which to observe changes occurring in the retina during pathological processes. In contrast to visualising the extent of neurodegenerative damage that has already occurred, imaging an active process such as apoptosis has the potential to report on disease progression and therefore the threat of irreversible functional loss in various eye and brain diseases. Early diagnosis in these conditions is an important unmet clinical need to avoid or delay irreversible sight loss. In this setting, apoptosis detection is a promising strategy with which to diagnose, provide prognosis, and monitor therapeutic response. Additionally, monitoring apoptosis in vitro and in vivo has been shown to be valuable for drug development in order to assess the efficacy of novel therapeutic strategies both in the pre-clinical and clinical setting. Detection of Apoptosing Retinal Cells (DARC) technology is to date the only tool of its kind to have been tested in clinical trials, with other new imaging techniques under investigation in the fields of neuroscience, ophthalmology and drug development. We summarize the transitioning of techniques detecting apoptosis from bench to bedside, along with the future possibilities they encase.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Wei-Jin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Cathepsin L ◽  
Human Cells ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals Adipose and Muscle Cell Co-Culture System: A Novel In Vitro Tool to Mimic the In Vivo Cellular Environment

Biology ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 6
Author(s):  
Palaniselvam Kuppusamy ◽  
Dahye Kim ◽  
Ilavenil Soundharrajan ◽  
Inho Hwang ◽  
Ki Choon Choi
Keyword(s):  
Drug Development ◽  
Culture System ◽  
Cell Types ◽  
Culture Cell ◽  
In Vitro Techniques ◽  
Culture Systems ◽  
Complex Interactions ◽  
Cellular Environment

A co-culture system allows researchers to investigate the complex interactions between two cell types under various environments, such as those that promote differentiation and growth as well as those that mimic healthy and diseased states, in vitro. In this paper, we review the most common co-culture systems for myocytes and adipocytes. The in vitro techniques mimic the in vivo environment and are used to investigate the causal relationships between different cell lines. Here, we briefly discuss mono-culture and co-culture cell systems and their applicability to the study of communication between two or more cell types, including adipocytes and myocytes. Also, we provide details about the different types of co-culture systems and their applicability to the study of metabolic disease, drug development, and the role of secretory factors in cell signaling cascades. Therefore, this review provides details about the co-culture systems used to study the complex interactions between adipose and muscle cells in various environments, such as those that promote cell differentiation and growth and those used for drug development.

Prevascularized, Co-Culture Model for Breast Cancer Drug Development

2012 ◽  
Author(s):  
Lauren Marshall ◽  
Isabel Löwstedt ◽  
Paul Gatenholm ◽  
Joel Berry
Keyword(s):  
Breast Cancer ◽  
Drug Development ◽  
Three Dimensional ◽  
Human Tumor ◽  
3D Models ◽  
Cancer Drug ◽  
Cancer Therapies ◽  
Anti Cancer

The objective of this study was to create 3D engineered tissue models to accelerate identification of safe and efficacious breast cancer drug therapies. It is expected that this platform will dramatically reduce the time and costs associated with development and regulatory approval of anti-cancer therapies, currently a multi-billion dollar endeavor [1]. Existing two-dimensional (2D) in vitro and in vivo animal studies required for identification of effective cancer therapies account for much of the high costs of anti-cancer medications and health insurance premiums borne by patients, many of whom cannot afford it. An emerging paradigm in pharmaceutical drug development is the use of three-dimensional (3D) cell/biomaterial models that will accurately screen novel therapeutic compounds, repurpose existing compounds and terminate ineffective ones. In particular, identification of effective chemotherapies for breast cancer are anticipated to occur more quickly in 3D in vitro models than 2D in vitro environments and in vivo animal models, neither of which accurately mimic natural human tumor environments [2]. Moreover, these 3D models can be multi-cellular and designed with extracellular matrix (ECM) function and mechanical properties similar to that of natural in vivo cancer environments [3].

scholarly journals Characterization and applications of chimeric mice with humanized livers for preclinical drug development

2020 ◽  
Vol 36 (1) ◽  
Author(s):  
Chise Tateno ◽  
Yuha Kojima
Keyword(s):  
Liver Function ◽  
Drug Development ◽  
Mass Production ◽  
Human Hepatocytes ◽  
In Vitro Studies ◽  
New Drugs ◽  
Pharmaceutical Companies ◽  
Chimeric Mice ◽  
Preclinical Drug Development

AbstractWe have succeeded in stable mass production of chimeric PXB-mice, whose liver is repopulated by human hepatocytes at a ratio of more than 70%, and we are providing these mice to academia and pharmaceutical companies to support the development of new drugs or studies of liver function. Furthermore, we isolated human hepatocytes, called PXB-cells, from the chimeric mice, and provide them for clients weekly for in vitro studies. In this review, we summarize the existing characterizations of PXB-mice and PXB-cells and their present and future applications.

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