Texas A&M Microphysiological Lead Optimization and Toxicity Screening (MLOTS) Program
Introduction
The Texas A&M Microphysiological Lead Optimization and Toxicity Screening (MLOTS) program is a component of the Gulf Coast Consortia network of drug discovery core facilities offering in vitro pharmacologic lead optimization and pre-clinical toxicity and efficacy profiling services. MLOTS addresses the need of drug discovery researchers for specialized facilities to rapidly and efficiently evaluate the efficacy and potential toxicity of new drugs and drug combinations. This ‘Fail Early’ strategy seeks to de-risk new drugs during the lead optimization stage of development thereby preventing failures that may occur much later in the development pipeline. This approach identifies potential liabilities early in drug development, at a time when liabilities can be effectively addressed and minimized or removed prior to preclinical and clinical testing. MLOTS provides 2D in vitro cellular models of cardiovascular and neuronal toxicity and organ-on-a-chip models of liver toxicity to identify some of the most common toxic liabilities that complicate late-stage clinical development. In addition, MLOTS provides low to medium throughput screening and imaging capabilities to allow for the evaluation of drug efficacy in both 2D and 3D complex in vitro mono- and multi-cellular model systems. The sophisticated cell-based screening systems provided by MLOTS offer efficient, economical, and flexible systems that enable drug discovery researchers to rapidly test multiple drugs and drug combinations at multiple doses and times. Data generated from these studies greatly improve the selection of the best candidates to be advanced to testing in animals and eventually in patients. MLOTS provides academic and commercial cancer researchers with access to a core facility with the complex technologic infrastructure to support biochemical and phenotypic screening research and a multi-disciplinary team of experts in the fields of drug discovery, stem cell, cancer and immune tissue engineering, imaging-based screening, image analysis and data informatics. The MLOTS program is a CPRIT CFSA-supported multi-institutional core facility providing Texas’ cancer researchers with access to critical resources supporting lead optimization and in vitro toxicity screening services.
Methods
The MLOTS core has specialized capabilities for supporting biochemical, bioelectronic, and phenotypic drug screening in a range of standard and bespoke 2D and 3D complex in vitro model systems including monolayer cell cultures, mono- and multicellular spheroids and organoids, and microphysiological chip-based models. The core’s screening platforms include fully automated high throughput confocal and metabolic imaging, multi-modal biochemical and imaging endpoint detection systems, and a multiwell microelectrode array and impedance system. Data analysis services include both traditional statistical methods and advanced machine learning/AI technologies to contextualize pharmacologic, genomic, and transcriptomic interactions. The MLOTS core is fully equipped to run in vitro screens from simple biochemical end points, live cell imaging using fully automated platforms, and the monitoring of the intricate, electrical activity of excitable cells (e.g., neurons and cardiomyocytes), or tracking the growth and death of cancer cells.
Results
The MLOTS core is providing cancer researchers with access to laboratory automation, specialized cell culture capabilities and imaging platforms, technical expertise, and the informatics necessary for lead optimization studies using advanced cellular models of cancer, and “fit for purpose” cell-based and biochemical screening technologies to support the discovery of new and novel therapies for cancer.
Conclusion
The MLOTS program’s value is the support provided to drug discovery projects with promising new drugs and drug combinations that can be advanced to animal testing and subsequent clinical evaluation. The goal of the Program is to support the discovery of novel single agent or combinatorial therapeutics that can be rapidly advanced to animal testing and clinical evaluation.