Editors' ChoiceCancer

A GEMA of a personalized medicine strategy

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Science Translational Medicine  24 May 2017:
Vol. 9, Issue 391, eaan4294
DOI: 10.1126/scitranslmed.aan4294

Abstract

A screening method can identify tumors susceptible to synthetic lethality via PARP inhibition.

The ability to treat an individual’s cancer based on features essential to that specific tumor holds great promise for improving patient outcomes. However, the success of this personalized medicine approach is dependent on the methods used to screen for points of fragility and hence guide treatment decisions. This requires understanding the efficacy of any promising personalized therapeutic options against cancer stem cells (CSCs), which can perpetuate the disease by evading treatment-induced cell death. In many cases, CSCs can either be inherently resistant to treatment, despite actively proliferating, or be shielded from drug effects by residing in a quiescent state. The identification of a drug efficacious to one cell state holds no guarantee that it will also target the other. In an effort to identify personalized strategies that inclusively target all CSCs, Nieborowska-Skorska et al. developed a gene expression and mutation analysis (GEMA)–based personalized medicine strategy that centers on the DNA damage response machinery.

The authors focused on leukemia stem cells (LSCs), where altered DNA repair mechanisms have been linked to survival after genotoxic stress and where proliferating versus quiescent LSC populations are well defined. The GEMA process involved a multimodal screening strategy that included microarrays, reverse transcription-quantitative PCR (RT-qPCR), flow cytometry, and mutational screening to identify samples with at least one gene with reduced expression in either BReast CAncer susceptibility gene (BRCA)–based or DNA-dependent protein kinase (DNA-PK)–based DNA damage repair pathways. The next step was to apply the concept of synthetic lethality (obtaining cell death by targeting two genes, where targeting one gene alone is ineffective) to these samples using a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), which mediates an additional DNA repair pathway. This approach was tested on a variety of proliferating and quiescent LSCs and in multiple leukemia mouse models. The authors also queried BRCA/DNA-PK–pathway expression alterations using existing databases as a means to test the potential utility of GEMA for solid tumors. Results from these studies confirmed that PARP inhibition promoted synthetic lethality for both proliferating and quiescent BRCA-deficient and DNA-PK–deficient LSCs.

These studies introduce a personalized medicine screening strategy that allows for the expansion of the proven concept of synthetic lethality seen in breast and ovarian cancers harboring mutations in BRCA1 and BRCA2 to tumors where mutations in these genes are rare. The potential curative impact of this approach is underscored by the efficacy observed for LSCs in this study.

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