PTEN Deficiency and Trastuzumab Resistance

PTEN 缺乏和曲妥珠单抗耐药

• 批准号: 7906040
• 负责人: Dihua Yu
• 金额: $ 26.93万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906040
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Address; Antibodies; Antisense Oligonucleotides; Breast Cancer Cell; Cancer Patient; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Development; Disease; ERBB2 gene; Epithelial Cells; Genes; Human; Immunohistochemistry; In Vitro; Life; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Mus; Outcome; PTEN gene; Pathway interactions; Patients; Phase; Phenotype; Phosphorylation; Primary Neoplasm; Reproduction spores; Resistance; Retrospective Studies; Roche brand of trastuzumab; Role; Sampling; Signal Pathway; Site; Taxane Compound; Testing; Therapeutic; Transgenic Mice; Trastuzumab; Treatment Efficacy; Treatment Protocols; Xenograft Model; base; cancer type; cohort; improved; in vivo; inhibitor/antagonist; mTOR Inhibitor; malignant breast neoplasm; molecular marker; mouse model; neoplastic cell; novel; novel therapeutics; overexpression; recombinase; response; taxane; tumor; wortmannin

ErbB2 overexpression is found in ~ 30% of human breast cancers and many other cancer types. ErbB2 overexpression leads to a very aggressive, highly metastatic breast cancer phenotype and poor patient survival. The ErbB2-targeting antibody, trastuzumab (Herceptin) has shown remarkable therapeutic efficacy in some patients with ErbB2-overexpressing breast cancer. The overall trastuzumab response rate, however, is limited and the causes of trastuzumab resistance are poorly understood. We have recently found that a rapid PTEN activation in ErbB2-overexpressing breast cancer cells by trastuzumab contributes to the anti-tumor activity of trastuzumab. Reducing PTEN expression in ErbB2-overexpressing human breast cancer cells by PTEN antisense oligonucleotides (PTEN-AS) conferred trastuzumab resistance in vitro and in xenograft models. More importantly, among a small cohort of patients having ErbB2- overexpressing breast cancers treated with trastuzumab plus taxanes, those with PTEN-deficient cancers had significantly worse responses to trastuzumab-based therapy than those with normal PTEN (p<0.01). We also found that PI3K inhibitors LY294002 and wortmannin rescued trastuzumab resistance induced by PTEN loss in vitro and in xenograft models. Thus, we hypothesize that a) PTEN deficiency in an ErbB2- overexpressing breast tumor is a sensitive and specific predictor for trastuzumab resistance, and b) Combination therapies with trastuzumab and agents targeting PI3K pathways can be developed to overcome the trastuzumab resistance mediated by PTEN loss. To test our hypotheses, we will first determine whether PTEN deficiency predicts trastuzumab resistance in a large-scale (200 patients) retrospective study (Aim 1). To investigate effective combination therapies that overcome the PTEN loss mediated trastuzumab resistance, we will establish mice models bearing PTEN-deficient and ErbB2- overexpressing mammary tumors and mammary epithelial cell (MEC) strains from the tumors (Aim 2). We will then test therapeutics that reverses PTEN deficiency-mediated trastuzumab resistance in vitro and in vivo using the mice models and the MEC strains (Aim 3). Finally, we will test whether combination therapy of trastuzumab and inhibitors of the PI3K signaling pathway overcome the PTEN loss-mediated trastuzumab resistance in patients (Aim 4). PTEN deficiency has been found in approximately 50% of breast cancer patients, our proposed studies will define the role of this deficiency in trastuzumab resistance. More importantly, the proposed studies will investigate novel treatment regimens for trastuzumab-resistant patients and may provide new therapeutic options that dramatically improve the clinical outcomes for these patients.

ErbB 2过表达见于约30%的人类乳腺癌和许多其他癌症类型。ERBB2 过度表达导致非常侵袭性的、高转移性的乳腺癌表型和较差的患者预后。 生存ErbB 2靶向抗体曲妥珠单抗（赫赛汀）已显示出显著的治疗效果， ErbB 2过度表达乳腺癌患者的疗效。曲妥珠单抗的总体缓解率， 然而，这种方法是有限的，曲妥珠单抗耐药的原因知之甚少。我们最近 发现曲妥珠单抗在ErbB 2过表达乳腺癌细胞中快速激活PTEN有助于 曲妥珠单抗的抗肿瘤活性。在ErbB 2过表达的人中降低PTEN表达 乳腺癌细胞通过PTEN反义寡核苷酸（PTEN-AS）赋予曲妥珠单抗耐药， 体外和异种移植模型中。更重要的是，在一小群ErbB 2- 用曲妥珠单抗加紫杉烷治疗的过表达乳腺癌， 对曲妥珠单抗治疗的反应明显差于PTEN正常的患者（p<0.01）。 我们还发现PI 3 K抑制剂LY 294002和渥曼青霉素可挽救由PI 3 K诱导的曲妥珠单抗耐药。 体外和异种移植模型中的PTEN损失。因此，我们假设a）ErbB 2 - 3中的PTEN缺陷， 过表达乳腺肿瘤是曲妥珠单抗耐药的敏感和特异性预测因子，和B） 可以开发曲妥珠单抗和靶向PI 3 K通路的药物的联合疗法， 克服由PTEN缺失介导的曲妥珠单抗抗性。为了验证我们的假设，我们将首先 在大规模（200例患者）中确定PTEN缺陷是否预测曲妥珠单抗耐药 回顾性研究（目标1）。为了研究克服PTEN缺失介导的细胞凋亡的有效联合疗法， 我们将建立携带PTEN缺陷和ErbB 2的小鼠模型， 过表达乳腺肿瘤和来自肿瘤的乳腺上皮细胞（MEC）株（Aim 2）。我们 然后将在体外和体内测试逆转PTEN缺陷介导的曲妥珠单抗耐药性的治疗方法。 体内使用小鼠模型和MEC株（Aim 3）。最后，我们将测试联合治疗是否 曲妥珠单抗和PI 3 K信号通路抑制剂克服了PTEN丢失介导的 患者的曲妥珠单抗耐药（目的4）。在大约50%的人中发现了PTEN缺陷。 乳腺癌患者，我们提出的研究将确定这种缺陷在曲妥珠单抗耐药中的作用。 更重要的是，拟议的研究将研究曲妥珠单抗耐药的新治疗方案。 患者，并可能提供新的治疗选择，显着改善这些临床结果 患者