Dual HER2 Targeting with Trastuzumab and Liposomal-Encapsulated Doxorubicin (MM-302) Demonstrates Synergistic Antitumor Activity in Breast and Gastric Cancer
Dual HER2 Targeting with Trastuzumab and Liposomal-Encapsulated Doxorubicin (MM-302) Demonstrates Synergistic Antitumor Activity in Breast and Gastric Cancer
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DOI：
10.1158/0008-5472.can-15-1518
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发表时间：
2016-03-15
期刊：
影响因子：
11.2
通讯作者：
Hendriks, Bart S.
中科院分区：
文献类型：
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作者：
Espelin, Christopher W.;Leonard, Shannon C.;Hendriks, Bart S.
曲妥珠单抗是HER 2阳性乳腺癌患者的标准治疗，可显著改善无病生存期和总生存期。与化疗结合，它可以改善患者的预后，但曲妥珠单抗治疗引起的心脏毒性会造成严重的不良反应。MM-302是一种HER 2靶向聚乙二醇化脂质体，包裹阿霉素，以促进其递送至HER 2过表达的肿瘤细胞，同时限制暴露于非靶组织（包括心脏）。在这项研究中，我们评估了MM-302与曲妥珠单抗联合治疗的可行性和临床前活性。MM-302和曲妥珠单抗靶向HER 2受体的不同结构域，因此可在体外和体内同时结合HER 2过表达肿瘤细胞。此外，曲妥珠单抗未破坏MM-302将多柔比星递送至核并诱导DNA损伤的作用机制。相反，MM-302不会干扰曲妥珠单抗阻断促生存p-Akt信号传导的能力。有趣的是，两种药物的联合给药急剧增加了MM-302在人异种移植肿瘤中的沉积，随后增加了DNA损伤标志物p-p53的表达。最后，MM-302和曲妥珠单抗的组合在乳腺癌和胃癌的HER 2过表达异种移植物模型中诱导协同抗肿瘤活性。总的来说，我们的研究结果突出了一种新型联合治疗，通过多种机制有效靶向HER 2过表达细胞，并支持在随机II期临床试验中对MM-302/曲妥珠单抗联合治疗HER 2阳性转移性乳腺癌的持续研究。(C)2016年AACR。
Trastuzumab is the standard of care for HER2-positive breast cancer patients, markedly improving disease-free and overall survival. Combined with chemotherapy, it enhances patient outcomes, but cardiotoxicity due to the trastuzumab treatment poses a serious adverse effect. MM-302 is a HER2-targeted PEGylated liposome that encapsulates doxorubicin to facilitate its delivery to HER2-overexpressing tumor cells while limiting exposure to nontarget tissues, including the heart. In this study, we evaluated the feasibility and preclinical activity of combining MM-302 with trastuzumab. MM-302 and trastuzumab target different domains of the HER2 receptor and thus could simultaneously bind HER2-overexpressing tumor cells in vitro and in vivo. Furthermore, trastuzumab did not disrupt the mechanism of action of MM-302 in delivering doxorubicin to the n0ucleus and inducing DNA damage. Reciprocally, MM-302 did not interfere with the ability of trastuzumab to block prosurvival p-Akt signaling. Interestingly, coadministration of the two agents acutely increased the deposition of MM-302 in human xenograft tumors and subsequently increased the expression of the DNA damage marker p-p53. Finally, the combination of MM-302 and trastuzumab induced synergistic antitumor activity in HER2-overexpressing xenograft models of breast and gastric cancer. Collectively, our findings highlight a novel combination therapy that efficiently targets HER2-overexpressing cells through multiple mechanisms and support the ongoing investigation of combined MM-302/trastuzumab therapy for HER2-positive metastatic breast cancer in a randomized phase II clinical trial. (C) 2016 AACR.