Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma

被引：157

作者：

Bosse, Kristopher R. ^{[1
,2
,3
]}

Raman, Pichai ^{[1
,2
,4
,5
]}

Zhu, Zhongyu ^{[6
]}

Lane, Maria ^{[1
,2
]}

Martinez, Daniel ^{[7
]}

Heitzeneder, Sabine ^{[8
]}

Rathi, Komal S. ^{[1
,2
,4
,5
]}

Kendsersky, Nathan M. ^{[1
,2
]}

Randall, Michael ^{[1
,2
]}

Donovan, Laura ^{[9
,10
]}

Morrissy, Sorana ^{[9
,10
]}

Sussman, Robyn T. ^{[1
,2
,15
,16
]}

Zhelev, Doncho V. ^{[6
]}

Feng, Yang ^{[6
]}

Wang, Yanping ^{[6
]}

Hwang, Jennifer ^{[6
]}

Lopez, Gonzalo ^{[1
,2
]}

Harenza, Jo Lynne ^{[1
,2
]}

Wei, Jun S.

Pawel, Bruce ^{[7
]}

Bhatti, Tricia ^{[7
]}

Santi, Mariarita ^{[7
]}

Ganguly, Arupa ^{[12
]}

Khan, Javed ^{[11
]}

Marra, Marco A. ^{[13
,14
]}

Taylor, Michael D. ^{[9
,10
]}

Dimitrov, Dimiter S. ^{[6
]}

Mackall, Crystal L. ^{[8
]}

Maris, John M. ^{[1
,2
,3
]}

机构：

[1] Childrens Hosp Philadelphia, Div Oncol, Colket Translat Res Bldg,3501 Civ Ctr Blvd, Philadelphia, PA 19104 USA

[2] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Colket Translat Res Bldg,3501 Civ Ctr Blvd, Philadelphia, PA 19104 USA

[3] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA

[4] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA

[5] Childrens Hosp Philadelphia, Ctr Data Driven Discovery Biomed, Philadelphia, PA 19104 USA

[6] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA

[7] Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA 19104 USA

[8] Stanford Univ, Stanford Canc Inst, Stanford, CA 94305 USA

[9] Hosp Sick Children, Div Neurosurg, Toronto, ON M5G 1X8, Canada

[10] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON M5G 1X8, Canada

[11] NCI, Oncogen Sect, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA

[12] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA

[13] Univ British Columbia, Genome Sci Ctr, British Columbia Canc Agcy, Vancouver, BC V6T 1Z4, Canada

[14] Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 1Z4, Canada

[15] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA

[16] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA

来源：

CANCER CELL | 2017年 / 32卷 / 03期

关键词：

RNA-SEQ; ANTIBODY; INHIBITION; DIFFERENTIATION; PATHWAY; CELLS; MAP;

D O I：

10.1016/j.ccell.2017.08.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

We developed an RNA-sequencing-based pipeline to discover differentially expressed cell-surface molecules in neuroblastoma that meet criteria for optimal immunotherapeutic target safety and efficacy. Here, we show that GPC2 is a strong candidate immunotherapeutic target in this childhood cancer. We demonstrate high GPC2 expression in neuroblastoma due to MYCN transcriptional activation and/or somatic gain of the GPC2 locus. We confirm GPC2 to be highly expressed on most neuroblastomas, but not detectable at appreciable levels in normal childhood tissues. In addition, we demonstrate that GPC2 is required for neuroblastoma proliferation. Finally, we develop a GPC2-directed antibody-drug conjugate that is potently cytotoxic to GPC2-expressing neuroblastoma cells. Collectively, these findings validate GPC2 as a non-mutated neuroblastoma oncoprotein and candidate immunotherapeutic target.

引用

页码：295 / +

页数：27

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