Evaluation of the DLL3-targeting antibody-drug conjugate rovalpituzumab tesirine in preclinical models of neuroblastoma.
Evaluation of the DLL3-targeting antibody-drug conjugate rovalpituzumab tesirine in preclinical models of neuroblastoma.
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DLL 3靶向抗体-药物缀合物罗伐匹珠单抗tesirine在神经母细胞瘤临床前模型中的评价。
DOI：
10.1158/2767-9764.crc-22-0137
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发表时间：
2022-07
期刊：
影响因子：
--
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中科院分区：
文献类型：
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Neuroblastomas have neuroendocrine features and often show similar gene expression patterns to small cell lung cancer including high expression of delta-like ligand 3 (DLL3). Here we determine the efficacy of rovalpituzumab tesirine (Rova-T), an antibody drug conjugated (ADC) with a pyrrolobenzodiazepine (PBD) dimer toxin targeting DLL3, in preclinical models of human neuroblastoma. We evaluated DLL3 expression in RNA sequencing data sets and performed immunohistochemistry (IHC) on neuroblastoma patient derived xenograft (PDX), human neuroblastoma primary tumor and normal childhood tissue microarrays (TMAs). We then evaluated the activity of Rova-T against 11 neuroblastoma PDX models using varying doses and schedules and compared anti-tumor activity to expression levels. DLL3 mRNA was differentially overexpressed in neuroblastoma at comparable levels to small cell lung cancer, as well as Wilms and rhabdoid tumors. DLL3 protein was robustly expressed across the neuroblastoma PDX array, but membranous staining was variable. The human neuroblastoma array, however, showed staining in only 44% of cases, whereas no significant staining was observed in the normal childhood tissue array. Rova-T showed a clear dose response effect across the 11 models tested, with a single dose inducing a complete or partial response in 3/11 and stable disease in another 3/11 models. No overt signs of toxicity were observed, and there was no treatment-related mortality. Strong membranous staining was necessary, but not sufficient, for anti-tumor activity. Rova-T has activity in a subset of neuroblastoma preclinical models, but heterogeneous expression in these models and the near absence of expression seen in human tumors suggests that any DLL3-targeting clinical trial should be only performed with a robust companion diagnostic to evaluate DLL3 expression for patient selection.
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DOI：
10.1016/s1470-2045(16)30565-4
发表时间：
2017-01
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Rudin CM;Pietanza MC;Bauer TM;Ready N;Morgensztern D;Glisson BS;Byers LA;Johnson ML;Burris HA 3rd;Robert F;Han TH;Bheddah S;Theiss N;Watson S;Mathur D;Vennapusa B;Zayed H;Lally S;Strickland DK;Govindan R;Dylla SJ;Peng SL;Spigel DR;SCRX16-001 investigators
通讯作者：
SCRX16-001 investigators
影响因子：
82.9
作者：
Kononen, J;Bubendorf, L;Kallioniemi, OP
通讯作者：
Kallioniemi, OP
影响因子：
11.5
作者：
Morgensztern, Daniel;Besse, Benjamin;Carbone, David P.
通讯作者：
Carbone, David P.
影响因子：
8.8
作者：
Rokita, Jo Lynne;Rathi, Komal S.;Maris, John M.
通讯作者：
Maris, John M.
影响因子：
20.4
作者：
Malhotra, Jyoti;Nikolinakos, Petros;Besse, Benjamin
通讯作者：
Besse, Benjamin