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

Brandon Carney, Susanne Kossatz, Benjamin H. Lok, Valentina Schneeberger, Kishore K. Gangangari, Naga Vara Kishore Pillarsetty, Wolfgang A. Weber, Charles M. Rudin, John T. Poirier and Thomas Reiner ()
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Brandon Carney: Memorial Sloan Kettering Cancer Center
Susanne Kossatz: Memorial Sloan Kettering Cancer Center
Benjamin H. Lok: Memorial Sloan Kettering Cancer Center
Valentina Schneeberger: Memorial Sloan Kettering Cancer Center
Kishore K. Gangangari: Memorial Sloan Kettering Cancer Center
Naga Vara Kishore Pillarsetty: Memorial Sloan Kettering Cancer Center
Wolfgang A. Weber: Memorial Sloan Kettering Cancer Center
Charles M. Rudin: Memorial Sloan Kettering Cancer Center
John T. Poirier: Memorial Sloan Kettering Cancer Center
Thomas Reiner: Memorial Sloan Kettering Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02096-w

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