Drug development in the era of precision medicine

Abstract

For the past three decades, the use of genomics to inform drug discovery and development pipelines has generated both excitement and scepticism. Although earlier efforts successfully identified some new drug targets, the overall clinical efficacy of developed drugs has remained unimpressive, owing in large part to the heterogeneous causes of disease. Recent technological and analytical advances in genomics, however, have now made it possible to rapidly identify and interpret the genetic variation underlying a single patient's disease, thereby providing a window into patient-specific mechanisms that cause or contribute to disease, which could ultimately enable the 'precise' targeting of these mechanisms. Here, we first examine and highlight the successes and limitations of the earlier phases of genomics in drug discovery and development. We then review the current major efforts in precision medicine and discuss the potential broader utility of mechanistically guided treatments going forward.

Figure 1 |. Precision therapy approaches in oncology.

Precision therapies in cancer generally use two primary approaches: pathway-based targeted therapies and immunotherapies. For both approaches, access to tumour cells (through resection or biopsy of solid tumours, or blood sample for haematological cancers or circulating tumour cells) enables an investigation into tumour biomarkers using various tools, including companion diagnostics, next-generation sequencing, gene expression profiling and proteomics. For pathway-based targeted treatments, these biomarker studies are used for the discovery of key drivers and master regulators of networks and pathways that promote tumour proliferation and survival. US Food and Drug Administration (FDA)-approved drugs that target these particular pathways can then be identified, or opportunities for drug repurposing or development may be explored for new targets. Alternatively, precision immunotherapy approaches include cell-based therapies, vaccines and biologics. Autologous (patient-derived) tumour cell and dendritic cell vaccines are generated from extracted tumours and dendritic cells, respectively. Extracted tumours may also be used to isolate tumour-infiltrating lymphocytes (TILs). This, in combination with tumour antigen data obtained from biomarker studies, has given rise to TIL-based adoptive cell therapies and chimeric antigen receptor (CAR) T cell therapies. The identification of tumour antigens, such as tumour-specific neoantigens or tumour-associated antigens, is also important for other personalized therapies, including antigen vaccines, programmed cell death 1 ligand 1 (PDL1)–PD1 checkpoint inhibitors and other monoclonal antibodies aimed at targeting tumour-promoting antigens.

Figure 2 |. Precision medicine for highly genetic diseases — epileptic encephalopathy as a model.

A patient with epileptic encephalopathy can undergo genetic testing, including screening of an epilepsy gene panel or whole-exome sequencing for detection of single nucleotide variants, or microarray analysis for identification of copy number variants (CNVs) (right panel). Novel variants are interpreted using existing variant annotation tools and gene-level intolerance scores to determine likely pathogenicity. Patient registries have been established to house the data on disease-causing mutations and their associated phenotypes for future diagnostic efforts. Advances in gene-editing technologies have revolutionized the ability to generate functional models of pathogenic variants (bottom panel). In vivo modelling of whole organisms and in vitro modelling of neural networks along with individual neurons (derived from mouse or human induced pluripotent stem cells) and heterologous cell models can be thoroughly evaluated for pro-epileptic states using a variety of electrophysiological platforms, including electroencephalography, electroconvulsive threshold studies, multielectrode arrays and patch–clamp studies. Additional molecular and cellular studies, such as those assessing protein–protein interactions, protein localization or gene expression, can also be performed to further dissect disease pathogenesis and identify potential drug targets. These drug targets can be used as the basis for drug repositioning or drug development efforts (left panel). The efficacy of candidate compounds can then be tested using the previously established electrophysiological screening platforms. Compounds that are already US Food and Drug Administration (FDA)-approved and demonstrate amelioration of the disease phenotype in functional models may be considered for use in the patient under the care and surveillance of their physician. Efforts in epilepsy precision medicine have been thoroughly reviewed by the EpiPM Consortium. NME, new molecular entity; SUDEP, Sudden Unexplained Death in Epilepsy.