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JNCI:靶向整合素αvβ6治疗乳腺癌

来源:生物谷 2014-07-07 09:33

2014年7月7日讯 /生物谷BIOON/--近日,伦敦大学玛丽皇后学院(QMUL)研究人员揭示了整合素αvβ6在帮助乳腺癌细胞生长和扩散的基础性作用。这项研究发表在Journal of the National Cancer Institute杂志上,精确定位了这个分子可作为治疗最积极类型乳腺癌的一个可行的新靶标。

有五分之一的乳腺癌患者是HER2阳性,HER2阳性是一个特别积极类型的乳腺癌,其中HER2蛋白水平升高促使癌细胞生长和扩散。目前,一线治疗HER2阳性乳腺癌药物是靶向治疗药物赫赛汀,也称为曲妥珠单抗。赫赛汀阻止HER2发送信号,阻止癌细胞生长和扩散。然而,据估计,高达70%患者要么不回应赫赛汀,要么发展耐药抵抗,使得每年英国7000名妇女治疗选择很有限。

该研究不仅揭示了高水平整合素αvβ6如何有助确定生存差的乳腺癌患者以及发展继发性肿瘤风险较高的患者,同时也揭示整合素αvβ6可作为治疗新靶标。

Kate Moore医生解释说:在我们以前的研究中,αvβ6靶向抗体264RAD已被证明减少肿瘤的大小和蔓延,但并未与其他药物一起进行测试。我们发现,同时靶向整合素αvβ6和HER2治疗乳腺癌小鼠,大大提高了赫赛汀(曲妥珠单抗)的效力,甚至消除对赫赛汀单独治疗无响应的肿瘤。

整合素αvβ6通常在健康细胞中是不可检测到的。但有研究表明,αvβ6在癌症细胞中促进癌症的迁移,侵袭和生存,但到现在为止它与乳腺癌的生长和扩散的相关性作用是未知的。研究人员分析了超过2000名患者乳腺癌样本,结果发现虽然正常乳腺组织没有αvβ6,高水平的αvβ6被发现在40%的HER2阳性患者肿瘤中存在,而这是与不良预后相关。即使对其他肿瘤特征进行调整后,高水平素αvβ6的HER2阳性患者在五年内更容易死亡。

为了探讨HER2和整合素αvβ6之间的联系,科学家们研究HER2阳性乳腺癌细胞系,其中包括赫赛汀耐药株。利用实验抗体264RAD阻断蛋白αvβ6,团队能够确认癌细胞的侵袭能力依赖于αvβ6的存在。在进一步的抗性小鼠肿瘤实验中,264RAD和赫赛汀组合能完全根除小鼠肿瘤,而264RAD单独治疗或曲妥珠单抗治疗的小鼠肿瘤继续生长。

与未处理的对照组进行比较,对赫赛汀敏感肿瘤的小鼠,只需两个星期组合治疗就能最终导致肿瘤尺寸降低94.8%。相比之下,赫赛汀造成的肿瘤尺寸减少77.8%,这表明联合治疗可以改善赫赛汀功效。医生John Marshall补充说:这个临床前研究的结果表明,针对αvβ6分子可增强赫赛汀的效力,而且联合治疗将可以对那些对单独赫赛汀治疗没有响应的患者有效。(生物谷Bioon.com)

Therapeutic Targeting of Integrin αvβ6 in Breast Cancer

Kate M. Moore, Gareth J. Thomas, Stephen W. Duffy, Jane Warwick, Rhian Gabe, Patrick Chou, Ian O. Ellis, Andrew R. Green, Syed Haider, Kellie Brouilette, Antonio Saha, Sabari Vallath, Rebecca Bowen, Claude Chelala, Diana Eccles, William J. Tapper, Alastair M. Thompson, Phillip Quinlan, Lee Jordan, Cheryl Gillett, Adam Brentnall, Shelia Violette, Paul H. Weinreb, Jane Kendrew, Simon T. Barry, Ian R. Hart, J. Louise Jones* and John F. Marshall*

Background Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.

Methods Protein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student’s t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni’s Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.

Results High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.

Conclusions Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.

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