Target engagement imaging of PARP inhibitors in small-cell lung cancer

被引：75

作者：

Carney, Brandon ^{[1
,2
,3
]}

Kossatz, Susanne ^{[1
]}

Lok, Benjamin H. ^{[4
,5
]}

Schneeberger, Valentina ^{[5
]}

Gangangari, Kishore K. ^{[1
,2
,3
]}

Pillarsetty, Naga Vara Kishore ^{[1
,6
]}

Weber, Wolfgang A. ^{[1
,5
,6
]}

Rudin, Charles M. ^{[5
,7
]}

Poirier, John T. ^{[5
,7
]}

Reiner, Thomas ^{[1
,6
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA

[2] CUNY, Grad Ctr, Hunter Coll, Dept Chem, New York, NY 10018 USA

[3] CUNY, Grad Ctr, PhD Program Chem, New York, NY 10018 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, New York, NY 10065 USA

[6] Weill Cornell Med Coll, Dept Radiol, New York, NY 10065 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

POLY(ADP-RIBOSE) POLYMERASE-1; HIGHLY POTENT; IN-VITRO; BMN; 673; PET; EXPRESSION; APOPTOSIS; INIPARIB; EFFICACY; MODELS;

D O I：

10.1038/s41467-017-02096-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Insufficient chemotherapy response and rapid disease progression remain concerns for small-cell lung cancer (SCLC). Oncologists rely on serial CT scanning to guide treatment decisions, but this cannot assess in vivo target engagement of therapeutic agents. Biomarker assessments in biopsy material do not assess contemporaneous target expression, intratumoral drug exposure, or drug-target engagement. Here, we report the use of PARP1/2-targeted imaging to measure target engagement of PARP inhibitors in vivo. Using a panel of clinical PARP inhibitors, we show that PARP imaging can quantify target engagement of chemically diverse small molecule inhibitors in vitro and in vivo. We measure PARP1/2 inhibition over time to calculate effective doses for individual drugs. Using patient-derived xenografts, we demonstrate that different therapeutics achieve similar integrated inhibition efficiencies under different dosing regimens. This imaging approach to non-invasive, quantitative assessment of dynamic intratumoral target inhibition may improve patient care through real-time monitoring of drug delivery.

引用

页数：13

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