Therapeutic targeting of SPINK1-positive prostate cancer.
Therapeutic targeting of SPINK1-positive prostate cancer.
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DOI：
10.1126/scitranslmed.3001498
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发表时间：
2011-03-02
影响因子：
17.1
通讯作者：
Chinnaiyan AM
中科院分区：
文献类型：
--
作者：
Ateeq B;Tomlins SA;Laxman B;Asangani IA;Cao Q;Cao X;Li Y;Wang X;Feng FY;Pienta KJ;Varambally S;Chinnaiyan AM
在大约 50% 的前列腺癌中发现了涉及成红细胞增多症病毒 E26 转化特异性 (ETS) 家族转录因子的反复基因融合，这为前列腺癌的分子亚分类提供了基础。此前，我们发现，编码分泌型丝氨酸蛋白酶抑制剂的 SPINK1（丝氨酸肽酶抑制剂，Kazal 1 型）的显着过度表达定义了 ETS 融合阴性前列腺癌的侵袭性分子亚型（SPINK1+/ETS-，约占所有前列腺癌的 10%）。在这里，我们研究了 SPINK1 作为前列腺癌细胞外治疗靶点的潜力。我们证明重组 SPINK1 蛋白 (rSPINK1) 可刺激良性 RWPE 和癌性前列腺细胞的细胞增殖。用 rSPINK1 或来自 22RV1 前列腺癌细胞 (SPINK1+/ETS-) 的条件培养基处理的 RWPE 细胞显示出细胞侵袭和内渗显着增加。在异种移植试验中，22RV1 细胞中 SPINK1 的敲除抑制了细胞增殖、细胞侵袭和肿瘤生长。重要的是，抗 SPINK1 单克隆抗体 (mAb) 减弱了 22RV1 细胞增殖、侵袭和内渗。我们还证明 SPINK1 通过与表皮生长因子受体 (EGFR) 相互作用部分介导其肿瘤效应。向携带 22RV1 异种移植物的小鼠施用抗 SPINK1 mAb 或抗 EGFR mAb（西妥昔单抗），单独使用时可分别抑制超过 60% 和 40% 的肿瘤生长，联合使用时可抑制约 75%，且不影响 PC3 异种移植物 (SPINK1-/ETS-) 的生长。总而言之，这项研究使 SPINK1 成为 SPINK1+/ETS- 前列腺癌患者子集的治疗靶点。与乳腺癌子集中针对 ERBB2 的抗体类似，我们的结果为人源化抗 SPINK1 单克隆抗体的开发和 SPINK1+/ETS- 前列腺癌中 EGFR 抑制的评估提供了理论依据。
The discovery of recurrent gene fusions involving Erythroblastosis virus E26 transformation-specific (ETS) family transcription factors in approximately 50% of prostate cancers provides a basis for the molecular subclassification of prostate cancer. Previously, we showed that marked over-expression of SPINK1 (serine peptidase inhibitor, Kazal type 1), which encodes a secreted serine protease inhibitor, defines an aggressive molecular subtype of ETS fusion-negative prostate cancers (SPINK1+/ETS-, ~10% of all prostate cancers). Here, we examined the potential of SPINK1 as an extracellular therapeutic target in prostate cancer. We demonstrate that recombinant SPINK1 protein (rSPINK1) stimulates cell proliferation in benign RWPE and cancerous prostate cells. RWPE cells treated with rSPINK1 or conditioned medium from 22RV1 prostate cancer cells (SPINK1+/ETS-) showed significantly increased cell invasion and intravasation. Knockdown of SPINK1 in 22RV1 cells inhibited cell proliferation, cell invasion, and tumor growth in xenograft assays. Importantly, 22RV1 cell proliferation, invasion and intravasation were attenuated by an anti-SPINK1 monoclonal antibody (mAb). We also demonstrate that SPINK1 partially mediates its neoplastic effects through interaction with the epidermal growth factor receptor (EGFR). Administration of anti-SPINK1 mAb or anti-EGFR mAb (cetuximab) to mice bearing 22RV1 xenografts attenuated tumor growth by over 60% and 40% alone, respectively, and approximately 75% when combined, without affecting PC3 xenograft (SPINK1-/ETS-) growth. Taken together, this study qualifies SPINK1 as a therapeutic target in a subset of patients with SPINK1+/ETS- prostate cancer. Similar to antibody targeting of ERBB2 in a subset of breast cancers, our results provide rationale for both the development of humanized anti-SPINK1 monoclonal antibodies and evaluation of EGFR inhibition in SPINK1+/ETS- prostate cancers.
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影响因子：
30.8
作者：
Carver, Brett S.;Tran, Jennifer;Gopalan, Anuradha;Chen, Zhenbang;Shaikh, Safa;Carracedo, Arkaitz;Alimonti, Andrea;Nardella, Caterina;Varmeh, Shohreh;Scardino, Peter T.;Cordon-Cardo, Carlos;Gerald, William;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo
影响因子：
3.9
作者：
SCHEVING, LA
通讯作者：
SCHEVING, LA
DOI：
10.1158/1078-0432.ccr-08-0979
发表时间：
2008-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dagvadorj A;Tan SH;Liao Z;Cavalli LR;Haddad BR;Nevalainen MT
通讯作者：
Nevalainen MT
影响因子：
6.4
作者：
HUHTALA, ML;KAHANPAA, K;STENMAN, UH
通讯作者：
STENMAN, UH
影响因子：
30.8
作者：
King, Jennifer C.;Xu, Jin;Wongvipat, John;Hieronymus, Haley;Carver, Brett S.;Leung, David H.;Taylor, Barry S.;Sander, Chris;Cardiff, Robert D.;Couto, Suzana S.;Gerald, William L.;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.