Target engagement imaging of PARP inhibitors in small-cell lung cancer Journal Article
| Authors: | Carney, B.; Kossatz, S.; Lok, B. H.; Schneeberger, V.; Gangangari, K. K.; Pillarsetty, N. V. K.; Weber, W. A.; Rudin, C. M.; Poirier, J. T.; Reiner, T. |
| Article Title: | Target engagement imaging of PARP inhibitors in small-cell lung cancer |
| 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. © 2018 The Author(s). |
| Keywords: | immunohistochemistry; controlled study; protein expression; dose response; nonhuman; chemotherapy; mouse; animal; metabolism; animals; mice, knockout; animal tissue; tumor volume; lung neoplasms; animal experiment; animal model; in vivo study; in vitro study; tumor xenograft; drug screening; enzymology; dose-response relationship, drug; mice, scid; xenograft model antitumor assays; cell line, tumor; diagnostic imaging; inhibitor; lung tumor; quantitative analysis; biomarker; tumor cell line; fluorodeoxyglucose f 18; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; piperazines; tissue microarray; piperazine derivative; mice, inbred nod; drug binding site; nonobese diabetic mouse; non invasive procedure; scid mouse; autoradiography; knockout mouse; olaparib; small cell lung cancer; small cell lung carcinoma; disease; inhibition; cell; molecularly targeted therapy; phthalazine derivative; phthalazines; drug; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 2; molecular targeted therapy; procedures; veliparib; binding kinetics; niraparib; rucaparib; cancer; humans; human; female; article; antagonists and inhibitors; poly(adp-ribose) polymerase inhibitors; positron emission tomography-computed tomography; positron emission tomography computed tomography; single photon emission computed tomography-computed tomography; talazoparib; jhu-lx22 cell line; jhu-lx48 cell line; lung small cell carcinoma cell line; poly (adp-ribose) polymerase-1 |
| Journal Title: | Nature Communications |
| Volume: | 9 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-01-12 |
| Start Page: | 176 |
| Language: | English |
| DOI: | 10.1038/s41467-017-02096-w |
| PUBMED: | 29330466 |
| PROVIDER: | scopus |
| PMCID: | PMC5766608 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 April 2018 -- Source: Scopus |
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MSK Authors
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133Pillarsetty -
63Lok -
136Reiner -
173Weber -
489Rudin -
82Poirier -
40Kossatz -
20Carney -
11Gangangari
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