Drug repositioning for personalized medicine

Yvonne Y Li,Steven Jm Jones

doi:10.1186/gm326

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.

Highlights

Human diseases can be caused by complex mechanisms involving aberrations in numerous proteins and pathways
Personalized medicine takes into account the fact that 30% of drugs investigated in clinical trials fail because of lack of efficacy [3], and its premise is that stratifying patients and diseases into molecular subtypes and treating with subtype-specific drugs will improve drug efficacy. e recent approval of crizotinib for non-small-cell lung cancer (NSCLC) provides a proof of concept for linking these two strategies: crizotinib was repositioned from anaplastic large-cell lymphoma treatment and is accompanied by a diagnostic test to identify the subset of NSCLC patients it is effective for [7]
It can be an efficient approach to discovery because many existing drugs have 1) established formulations and manufacturing methods, 2) extensive absorption distribution, metabolism, excre tion and toxicity (ADMET) data, 3) previously passed clinical trial safety endpoints and are less likely to fail future clinical trials owing to adverse effects [2], and 4) phase IV safety data, which are expensive and time consuming to obtain [8]

Summary

Conclusions and future directions

The field of medicine has always been personalized as doctors endeavor to determine the underlying causes of disease for each patient. Human diseases are hetero geneous and complex, and sequencing methods have the potential to characterize an individual’s disease at a molecular resolution in clinically relevant time frames This can lead to treatments that take into account the specific molecular mechanisms underlying disease as well as the known pharmacogenomic variants in the patient. Given the considerable time and cost of developing new drugs, a much more efficient option is to reposition drugs from other disease indications when possible These drugs are already approved for use in humans and are more likely to be safe than drugs still undergoing trials. Competing interests The authors declare that they have no competing interests

Lawrence S

Findings

95. Tambuyzer E