Carney Brandon, Kossatz Susanne, Lok Benjamin H, Schneeberger Valentina, Gangangari Kishore K, Pillarsetty Naga Vara Kishore, Weber Wolfgang A, Rudin Charles M, Poirier John T, Reiner Thomas
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Department of Chemistry, Hunter College and PhD Program in Chemistry, The Graduate Center of the City University of New York, New York, NY, 10018, USA.
Nat Commun. 2018 Jan 12;9(1):176. doi: 10.1038/s41467-017-02096-w.
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.
化疗反应不足和疾病快速进展仍是小细胞肺癌（SCLC）面临的问题。肿瘤学家依靠系列CT扫描来指导治疗决策，但这无法评估治疗药物在体内的靶点结合情况。活检材料中的生物标志物评估无法评估同期靶点表达、肿瘤内药物暴露或药物-靶点结合情况。在此，我们报告了使用PARP1/2靶向成像来测量PARP抑制剂在体内的靶点结合情况。使用一组临床PARP抑制剂，我们表明PARP成像可在体外和体内定量化学结构多样的小分子抑制剂的靶点结合情况。我们测量PARP1/2随时间的抑制情况以计算每种药物的有效剂量。使用患者来源的异种移植模型，我们证明不同的治疗方法在不同给药方案下可实现相似的综合抑制效率。这种用于非侵入性、定量评估肿瘤内动态靶点抑制的成像方法可能通过实时监测药物递送改善患者护理。
