Animal models and in vivo investigations for drug repurposing in lung cancer

Introduction

Lung cancer is one of the most common and serious types of cancer, which causes the highest cancer mortality among men and women worldwide. The two major types of lung cancers are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), based on histological differentiation. NSCLCs are further divided into squamous cell carcinomas (SCCs), pulmonary adenocarcinomas (ADC), and large cell carcinomas. Lung ADC is the most prevalent form of NSCLC [ ]. Lung cancer has a dismal prognosis of 15%, mainly attributed to ineffective early detection strategies and lack of therapeutic options for metastatic diseases [ ]. This has spurred efforts for the development of molecularly targeted therapies.

Drug repurposing relates to determining new targets for existing drugs and identifying new indications for known diseases. In addition to being time- and cost-efficient, drug repurposing offers a more favorable risk–return tradeoff than other available drug development strategies. Because the existing drugs have already been tested in terms of safety, dosage, and toxicity, they can often enter clinical trials much more rapidly than newly developed drugs [ ]. Computational drug repurposing is deemed an effective alternative method for identifying novel connections between diseases and existing drugs [ ]. The increase in drug–target information and the advances in systems pharmacology approaches have led to an increase in the success of in silico drug repurposing.

As summarized by Jegga et al. approaches for computational drug repurposing can be broadly categorized into knowledge-based and signature-based approaches [ ]. Knowledge-based drug repurposing usually involves utilizing available information on genome-wide association studies and omics data such as genetic markers, structures, targets, and pathways to predict prospective disease mechanisms [ , ].

Signature-based drug repurposing involves comparing the drug-treated gene expression profile with its disease counterpart to construct a detailed map of connections between diseases and drug actions. In particular, large-scale chemical genomics databases, such as the Connectivity Map or the National Institutes of Health Library of Integrated Network-Based Cellular Signatures program's highly expanded chemical genomics data set, provide abundant information on the modes of action of drugs, which are reflected in the transcriptomic responses to chemical perturbation. Additionally, transcriptome-level expression profiles of approximately 20,000 genes have been computationally inferred using 1000 landmark genes (L1000) [ ].

A literature-based approach was also used to identify licensed noncancer drugs with published evidence of anticancer activity. The Repurposing Drugs in Oncology project is an ongoing collaborative project that has focused exclusively on the potential use of licensed noncancer medications as sources of new cancer therapeutics [ ].

By utilizing these computer-aided drug repurposing strategies, abundant amounts of data can be obtained. However, successful translation of repurposed drugs to high efficacy for its new indications (i.e., lung cancer) requires a detailed investigation of the underlying biology. To achieve the goal, target validation should be performed through intervention studies in human lung cancer cell lines. Because in vitro cell culture studies cannot fully mimic the complexity of lung carcinogenesis in vivo, developing mouse lung cancer models will provide insight into lung tumorigenesis. In the next section, we summarize related mouse models and their applications in repurposed lung cancer treatments.

Animal models and in vivo applications in drug repurposing

The importance of drug repurposing lies in the high costs and the prolonged time from target selection to regulatory approval of traditional drug development. Cell-based studies have limitations in terms of fully mimicking the complexity of the onset and development of tumorigenesis in living animals. In vivo evaluation is a key component in the drug discovery process, suggesting that evaluations based on small animal model offer a convenient platform to perform drug repurposing. Testing in an in vivo system allows the evaluation of multiple signaling mechanisms and tissue cross talk that cannot be studied in a cell-based system. This is still the only available platform for safety and efficacy studies with a high biomedical applicability to human use. A small molecule identified in an in vivo system has a higher likelihood of having bioactivity and clinical relevance.