Department of Nuclear Medicine, TUM School of Medicine and Health, University Hospital Klinikum Rechts Der Isar, and Central Institute for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany.
Comparative Experimental Pathology (CEP), Institute of Pathology, School of Medicine and Health, Technical University of Munich, Munich, Germany.
Eur J Nucl Med Mol Imaging. 2024 Nov;51(13):4099-4110. doi: 10.1007/s00259-024-06844-1. Epub 2024 Jul 18.
Small cell lung cancer (SCLC) is a highly aggressive tumor with neuroendocrine origin. Although SCLC frequently express somatostatin receptor type 2 (SSTR2), a significant clinical benefit of SSTR2-targeted radionuclide therapies of SCLC was not observed so far. We hypothesize that combination treatment with a PARP inhibitor (PARPi) could lead to radiosensitization and increase the effectiveness of SSTR2-targeted therapy in SCLC.
SSTR2-ligand uptake of the SCLC cell lines H69 and H446 was evaluated in vitro using flow cytometry, and in vivo using SPECT imaging and cut-and-count biodistribution. Single-agent (Olaparib, Rucaparib, [Lu]Lu-DOTA-TOC) and combination treatment responses were determined in vitro via cell viability, clonogenic survival and γH2AX DNA damage assays. In vivo, we treated athymic nude mice bearing H69 or H446 xenografts with Olaparib, Rucaparib, or [Lu]Lu-DOTA-TOC alone or with combination treatment regimens to assess the impact on tumor growth and survival of the treated mice.
H446 and H69 cells exhibited low SSTR2 expression, i.e. 60 to 90% lower uptake of SSTR2-ligands compared to AR42J cells. In vitro, combination treatment of [Lu]Lu-DOTA-TOC with PARPi resulted in 2.9- to 67-fold increased potency relative to [Lu]Lu-DOTA-TOC alone. We observed decreased clonogenic survival and higher amounts of persistent DNA damage compared to single-agent treatment for both Olaparib and Rucaparib. In vivo, tumor doubling times increased to 1.6-fold (H446) and 2.2-fold (H69) under combination treatment, and 1.0 to 1.1-fold (H446) and 1.1 to 1.7-fold (H69) in monotherapies compared to untreated animals. Concurrently, median survival was higher in the combination treatment groups in both models compared to monotherapy and untreated mice. Fractionating the PRRT dose did not lead to further improvement of therapeutic outcome.
The addition of PARPi can markedly improve the potency of SSTR2-targeted PRRT in SCLC models in SSTR2 low-expressing tumors. Further evaluation in humans seems justified based on the results as novel treatment options for SCLC are urgently needed.
小细胞肺癌（SCLC）是一种具有神经内分泌起源的高度侵袭性肿瘤。尽管 SCLC 经常表达生长抑素受体 2（SSTR2），但迄今为止，SSTR2 靶向放射性核素治疗 SCLC 的显著临床获益尚未得到观察。我们假设与 PARP 抑制剂（PARPi）联合治疗可能导致放射增敏，并增加 SSTR2 靶向治疗在 SCLC 中的有效性。
通过流式细胞术评估 SCLC 细胞系 H69 和 H446 的 SSTR2 配体摄取，并通过 SPECT 成像和切分计数生物分布进行体内评估。通过细胞活力、集落形成存活和 γH2AX DNA 损伤测定，在体外确定单药（奥拉帕利、鲁卡帕利、[Lu]Lu-DOTA-TOC）和联合治疗反应。在体内，我们用奥拉帕利、鲁卡帕利或[Lu]Lu-DOTA-TOC 单独或联合治疗方案治疗荷瘤裸鼠，以评估其对肿瘤生长和存活的影响。
H446 和 H69 细胞表现出低 SSTR2 表达，即与 AR42J 细胞相比，SSTR2 配体的摄取低 60-90%。在体外，[Lu]Lu-DOTA-TOC 与 PARPi 的联合治疗导致与单独使用[Lu]Lu-DOTA-TOC 相比，效力增加 2.9 至 67 倍。与单药治疗相比，我们观察到奥拉帕利和鲁卡帕利的集落形成存活降低和持续 DNA 损伤增加。在体内，与未治疗动物相比，联合治疗时肿瘤倍增时间增加 1.6 倍（H446）和 2.2 倍（H69），单药治疗时增加 1.0 至 1.1 倍（H446）和 1.1 至 1.7 倍（H69）。同时，在两种模型中，与单药治疗和未治疗的小鼠相比，联合治疗组的中位生存期更高。分割 PRRT 剂量并没有导致治疗结果的进一步改善。
在 SSTR2 低表达肿瘤的 SCLC 模型中，添加 PARPi 可以显著提高 SSTR2 靶向 PRRT 的效力。鉴于迫切需要新的 SCLC 治疗方法，基于这些结果，进一步在人类中进行评估似乎是合理的。
