Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Endocr Relat Cancer. 2019 Apr 1;26(4):437-449. doi: 10.1530/ERC-18-0509. Epub 2019 Feb 1.
177Lu-octreotate is an FDA-approved radionuclide therapy for patients with gastroenteropancreatic neuroendocrine tumours (NETs) expressing somatostatin receptors. The 177Lu-octreotate therapy has shown promising results in clinical trials by prolonging progression-free survival, but complete responses are still uncommon. The aim of this study was to improve the 177Lu-octreotate therapy by means of combination therapy. To identify radiosensitising inhibitors, two cell lines, GOT1 and P-STS, derived from small intestinal neuroendocrine tumours (SINETs), were screened with 1,224 inhibitors alone or in combination with external radiation. The screening revealed that inhibitors of Hsp90 can potentiate the tumour cell-killing effect of radiation in a synergistic fashion (GOT1; false discovery rate <3.2×10-11). The potential for Hsp90 inhibitor ganetespib to enhance the anti-tumour effect of 177Lu-octreotate in an in vivo setting was studied in the somatostatin receptor-expressing GOT1 xenograft model. The combination led to a larger decrease in tumour volume relative to monotherapies and the tumour-reducing effect was shown to be synergistic. Using patient-derived tumour cells from eight metastatic SINETs, we could show that ganetespib enhanced the effect of 177Lu-octreotate therapy for all investigated patient tumours. Levels of Hsp90 protein expression were evaluated in 767 SINETs from 379 patients. We found that Hsp90 expression was upregulated in tumour cells relative to tumour stroma in the vast majority of SINETs. We conclude that Hsp90 inhibitors enhance the tumour-killing effect of 177Lu-octreotate therapy synergistically in SINET tumour models and suggest that this potentially promising combination should be further evaluated.
177Lu-奥曲肽是一种经美国食品药品监督管理局批准的用于治疗表达生长抑素受体的胃肠胰神经内分泌肿瘤（NETs）的放射性核素治疗药物。177Lu-奥曲肽治疗在临床试验中显示出了延长无进展生存期的良好效果，但完全缓解仍不常见。本研究旨在通过联合治疗来改善 177Lu-奥曲肽治疗。为了鉴定放射增敏抑制剂，我们用单独或联合外照射筛选了两种源自小肠神经内分泌肿瘤（SINETs）的细胞系 GOT1 和 P-STS。筛选结果表明，Hsp90 的抑制剂可以以协同的方式增强肿瘤细胞对辐射的杀伤作用（GOT1；假发现率<3.2×10-11）。我们在表达生长抑素受体的 GOT1 异种移植模型中研究了 Hsp90 抑制剂 ganetespib 在体内增强 177Lu-奥曲肽抗瘤作用的潜力。与单药治疗相比，联合治疗导致肿瘤体积明显减小，且肿瘤减少效果呈协同作用。使用 8 例转移性 SINET 患者来源的肿瘤细胞，我们可以证明 ganetespib 增强了所有研究患者肿瘤的 177Lu-奥曲肽治疗效果。在 379 名患者的 767 例 SINET 中评估了 Hsp90 蛋白表达水平。我们发现绝大多数 SINET 中肿瘤细胞中的 Hsp90 表达相对肿瘤基质上调。我们得出结论，Hsp90 抑制剂在 SINET 肿瘤模型中协同增强了 177Lu-奥曲肽治疗的肿瘤杀伤作用，并提示应进一步评估这种有潜力的联合治疗方法。
