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.

Integrative Omics for Informed Drug Repurposing: Targeting CNS Disorders

“…Possibilities exist to integrate the aforementioned-drug repurposing resources and approaches along with an individual's genomic profile for a "precise-repurposing." Thus far the major push in biomedical research at large for precise repurposing is from cancer genomics, where reference genomic profiles from cancer cell lines, solid tumors, leukemias, and stem cells are available and can be sequenced with relative ease [117]. In contrast, in psychiatry it is difficult to get brain tissues for obvious reasons, limiting access to the source of the pathophysiology for non-malignant, CNS disorders.…”

Integrated Genomic Medicine

“…Thus, outside of compassionate use settings, therapeutic choices that may result from individual integrated genomic medicine and patient-oriented research of the type described here may require repurposing a particular drug or compound rather than attempting to use a drug that has not been approved for use in humans. [78–80] Other barriers to the use of a particular compound may involve simple access to the compound (i.e., through the group that created it) as well as costs. In this light, partnerships between research groups pursuing studies of individual patients for optimizing therapeutic interventions and the pharmaceutical industry may be of mutual benefit, as focused therapeutic assessment studies and repurposing efforts could help justify new markets for a compound.…”

“…Third, as noted, unless one is considering the conduct of a phase I study or a compassionate therapeutic use trial for a particular unapproved compound – which typically come with recommended or accepted guidelines – the design of a therapeutic intervention trial for an individual patient will probably have to be pursued in the context of repurposing an approved drug. [78] Fourth, there is precedent for clinical trials involving a focused study on a unique patient population in the investigation of treatments for rare and orphan diseases that can easily be extended, or at least motivate, studies of individual patients with those diseases. [89–91]…”

A drug‐repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6‐thioguanine as an effective therapeutic agent for TPMT‐low cancer cells

“…Drug-repositioning screening has been increasingly performed to identify therapeutic agents for complex diseases (Li and Jones, 2012) because of the high cost and long time required for the development of novel therapeutic agents. For pancreatic cancer, ritonavir, an HIV inhibitor, was identified as an antitumor agent inhibiting cell cycle progression (Batchu et al, 2014).…”