Drug repositioning for personalized medicine

Abstract

Human diseases can be caused by complex mechanisms involving aberrations in numerous proteins and pathways. With recent advances in genomics, elucidating the molecular basis of disease on a personalized level has become an attainable goal. In many cases, relevant molecular targets will be identified for which approved drugs already exist, and the potential repositioning of these drugs to a new indication can be investigated. Repositioning is an accelerated route for drug discovery because existing drugs have established clinical and pharmacokinetic data. Personalized medicine and repositioning both aim to improve the productivity of current drug discovery pipelines, which expend enormous time and cost to develop new drugs, only to have them fail in clinical trials because of lack of efficacy or toxicity. Here, we discuss the current state of research in these two fields, focusing on recent large-scale efforts to systematically find repositioning candidates and elucidate individual disease mechanisms in cancer. We also discuss scenarios in which personalized drug repositioning could be particularly rewarding, such as for diseases that are rare or have specific mutations, as well as current challenges in this field. With an increasing number of drugs being approved for rare cancer subtypes, personalized medicine and repositioning approaches are poised to significantly alter the way we diagnose diseases, infer treatments and develop new drugs.

Keywords: Personalized medicine; cancer; computational drug design; drug discovery; high-throughput screening; orphan diseases; repositioning; repurposing.

Figure 1

Potential avenues of drug repositioning. Most repositioned drugs so far have been discovered through serendipitous treatment or unexpected side effects observed during clinical trials (path 1, path 6). More rational approaches to the identification of drug repositioning candidates involve finding existing drugs that can modulate specific disease phenotypes (path 2), finding new drug-target interactions (path 3), finding new roles for existing targets (path 4), or finding new pathways in disease (path 5). One or two examples of successfully repositioned drugs are listed for each method.

Figure 2

Personalized genomic medicine at molecular-level resolution. Whole genome and transcriptome sequencing of the different sets of the patient's cells provides different types of information. Sequencing the primary tumor and normal cells of a patient can identify potential oncogenes, tumor suppressors, structural variations and somatic aberrations (for example, single nucleotide polymorphisms (SNPs), insertions or deletions (indels), copy number variations (CNVs), or structural variations) involved in tumor formation, as well as significantly altered biological pathways. Sequencing metastatic cells can also provide insight into clonal selection, metastatic-specific aberrations, and other valuable information. Together, information from all three cellular sources can help determine targets for therapy. Verifying whether the target, chemoresistance and drug metabolism genes have functionally relevant polymorphisms will further enable tailoring of the treatment to the patient. LOH, loss of heterozygosity.