Regulation of Notch Signaling by ErbB-2: Novel Therapeutic Strategy

ErbB-2 对 Notch 信号传导的调节：新颖的治疗策略

• 批准号: 9096019
• 负责人: Clodia Osipo
• 金额: $ 31.33万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096019
• 关键词: 2-tyrosine; Accounting; Breast; Breast Cancer Cell; Cell Proliferation; Cell Survival; Cell surface; Cells; Cessation of life; Clinical Trials; Data; Development; Diagnosis; Disease Progression; Disease Resistance; Distant; Endocytosis; Epidermal Growth Factor Receptor; Foundations; Future; Goals; Hormones; In Vitro; Ligands; Mammary Neoplasms; Mediating; Mediator of activation protein; Metastatic breast cancer; Molecular; Neoplasm Metastasis; Notch Signaling Pathway; Oncogenes; Organ; Pathway interactions; Phase; Phase II Clinical Trials; Principal Investigator; Recurrence; Regulation; Resistance; Signal Transduction; Solid Neoplasm; Testing; Therapeutic; Time; Trastuzumab; Treatment Efficacy; Tyrosine Kinase Inhibitor; Vesicle Transport Pathway; Woman; Work; base; cancer stem cell; cell growth; chemotherapy; cytotoxic; design; efficacy trial; evidence base; expectation; humanized monoclonal antibodies; improved; in vivo; inhibitor/antagonist; jagged1 protein; lapatinib; malignant breast neoplasm; new therapeutic target; notch protein; novel; novel therapeutics; overexpression; pre-clinical; prevent; prospective; receptor; response; standard of care; targeted agent; targeted treatment; taxane; therapeutic effectiveness; therapy resistant; trafficking; treatment strategy; tumor

DESCRIPTION (provided by applicant): The breast oncogene ErbB-2 is amplified or overexpressed in 15-30% of breast cancers. ErbB-2 overexpression is associated with resistance to cytotoxic and anti-hormone treatment and poor overall survival. Anti-ErbB-2 treatment strategies include the use of trastuzumab, a humanized monoclonal antibody directed against ErbB-2, plus a taxane-based chemotherapy or lapatinib, a dual EGFR and ErbB-2 tyrosine kinase inhibitor-approved for trastuzumab resistant disease. Unfortunately, resistance to trastuzumab and now lapatinib is a major problem in metastatic breast cancer with only 30-50% responding to anti-ErbB-2 therapy. Therefore, the identification of compensatory survival pathways that contribute to anti-ErbB-2 treatment resistance is important in order to design rational targeted treatment options to prevent or reverse resistance and improve overall survival. We have identified that Notch-1, another potent breast oncogene and cell fate determinant, is activated by trastuzumab or a TKI similar to lapatinib in ErbB-2 positive breast cancer cells and served as a novel therapeutic target for anti-ErbB-2 treatment resistance (1). Our findings suggested that there is a compensatory increase in Notch-1-mediated proliferation/survival in trastuzumab or a TKI similar to lapatinib-treated breast cancer (1). The Notch-1 receptor is another potent breast oncogene (2) that is overexpressed with its ligand Jagged-1 in breast cancers associated with the poorest overall survival (3-5). Furthermore, Notch has been shown to be necessary for the proliferation and survival of breast cancer stem cells (6). Therefore, it i critical to identify the mechanism(s) by which ErbB-2 inhibition activates Notch-1 activity and whether suppression of the Notch pathway prevents and/or reverses resistance to trastuzumab or lapatinib in vivo in order to develop the optimal therapy for women with ErbB-2 positive breast cancer. Based on our findings, we propose a central hypothesis that ErbB-2 overexpression and activity de-regulates Jagged- 1 vesicular transport restricting Jagged-1-mediated Notch activation at the cell surface. Thus, resistance to anti-ErbB-2-targeted agents can be prevented and/or reversed by targeting Jagged-1 and/or Notch-1 directly. We have formulated this hypothesis based on our preliminary data suggesting that hyperactive ErbB-2 de- regulates vesicular trafficking of Jagged-1, and that Jagged-1 was required for trastuzumab-induced increase in Notch-1 transcriptional activity. To test our hypothesis and achieve the overall objective, we propose three Specific Aims: Specific Aim 1: Identify the molecular mechanism(s) responsible for Jagged-1-mediated Notch-1 activation in response to ErbB-2 inhibition. Our working hypothesis based on strong preliminary data is, that hyperactive ErbB-2 restricts proper Jagged-1 endocytosis to inhibit Notch activation at the cell surface. ErbB-2 inhibition rescues this effect, resulting in re-activation of Jagged-1-mediated Notch signaling. Specific Aim 2: Determine if Jagged-1 is the critical mediator of Notch Signalling to confer resistance to anti-ErbB-2 treatment in vitro. Our working hypothesis is that availability of cell surface Jagged-1 is critical to activating Notch-1 and thus promoting cell proliferation, survival, and resistance to anti-ErbB-2 treatment in vitro. Specific Aim 3: Evaluate the therapeutic efficacy of targeting Jagged-1 to prevent tumor recurrence and reverse resistance in vivo. Our working hypothesis is that simultaneous targeting of both ErbB-2 and Jagged-1-mediated Notch signaling pathways will prevent and/or reverse trastuzumab or lapatinib resistant ErbB-2 positive breast cancer in vivo providing pre-clinical evidence for a future prospective efficacy trial. Upon successful completion of these studies, we will begin a clinical trial to test our pre-clinical results. Our gal is development of scientifically-based evidence to support a therapeutic benefit of combining anti- ErbB-2 treatment with Notch pathway inhibition which provides a foundation for Phase I/Phase 2 clinical trials to test benefits in women with ErbB-2 positive breast cancer with the goal of preventing or reversing resistance.

描述（由申请人提供）：乳腺癌ERBB-2在15-30％的乳腺癌中被放大或过表达。 ERBB-2过表达与对细胞毒性和抗激素治疗的抗性和总生存率差有关。抗ARBB-2治疗策略包括使用曲妥珠单抗，一种针对ERBB-2的人源化单克隆抗体，以及基于紫杉烷的化学疗法或Lapatinib，双重EGFR和ERBB-2酪氨酸激酶抑制剂对Trastuzumab耐药疾病的批准。不幸的是，对曲妥珠单抗和现在拉帕替尼的抵抗是转移性乳腺癌的主要问题，只有30-50％对抗ARBB-2疗法有反应。因此，为了设计合理的目标治疗方案以防止或逆转抗性并改善总体生存率，鉴定有助于抗ERBB-2治疗耐药性的补偿性生存途径很重要。我们已经确定，Notch-1是另一种有效的乳腺癌和细胞命运决定因素，被曲妥珠单抗或类似于lapatinib在ERBB-2阳性乳腺癌细胞中的TKI激活，并作为抗erbbb-2治疗耐药性的新型治疗靶标（1）。我们的发现表明，在曲妥珠单抗或类似于Lapatinib处理的乳腺癌类似的TKI中，Notch-1介导的增殖/存活率有补偿性增加（1）。 Notch-1受体是另一种有效的乳腺癌（2），其在乳腺癌中的配体锯齿状1过表达与最差的总生存期相关的乳腺癌（3-5）。此外，已经证明Notch对于乳腺癌干细胞的增殖和存活是必要的（6）。因此，我要确定ERBB-2抑制激活Notch-1活性的机制，以及对Notch途径的抑制是否可以防止和/或逆转体内抗trastuzumab或Lapatinib的抵抗力，以开发患有ERBB-2阳性乳腺癌女性的最佳治疗。根据我们的发现，我们提出了一个中心假设，即ERBB-2的过表达和活性会脱离锯齿状的1囊泡转运，从而限制了细胞表面的锯齿状1介导的凹槽凹入的凹槽激活。因此，可以通过直接靶向锯齿状1和/或Notch-1来防止和/或反转对抗ARBB-2靶向剂的耐药性。我们根据我们的初步数据提出了这一假设，表明过度活跃的ERBB-2调节锯齿状1的囊泡运输，并且曲妥珠单抗诱导的NotCH-1转录活性的增加需要JAGGED-1。为了检验我们的假设并实现总体目标，我们提出了三个具体目标：具体目标1：确定负责响应ERBB-2抑制作用的锯齿状1介导的Notch-1激活的分子机制。我们基于强初步数据的工作假设是，过度活跃的ERBB-2限制了适当的锯齿状1内吞作用，以抑制细胞表面的Notch激活。 ERBB-2抑制作用挽救了这种效果，从而导致锯齿状1介导的Notch信号转导。具体目标2：确定锯齿状1是否是Notch信号传导的关键介体，可以在体外赋予对抗ARBB-2治疗的耐药性。我们的工作假设是，细胞表面锯齿状-1的可用性对于激活Notch-1并在体外促进细胞增殖，存活和对抗ERBB-2治疗的耐药性至关重要。具体目标3：评估靶向锯齿状1以防止体内肿瘤复发和反向抗性的治疗功效。我们的工作假设是，同时靶向ERBB-2和JAGGED-1介导的Notch信号传导途径将预防和/或反向曲妥珠单抗或抗Lapatinib耐药的ERBB-2阳性乳腺癌在体内为未来的前瞻性疗效试验提供前临床证据。 成功完成这些研究后，我们将开始一项临床试验，以测试我们的临床前结果。我们的GAL是基于科学的证据的发展，以支持将抗ERBB-2治疗与Notch途径抑制相结合的治疗益处，这为I/第2期临床试验提供了基础，以测试ERBB-2阳性乳腺癌女性的益处，以防止或逆转抵抗力。

项目成果

Cancer stem cells and HER2 positive breast cancer: The story so far.

• DOI: 10.1016/j.gendis.2016.02.002
• 发表时间: 2016-06
• 期刊: Genes & diseases
• 影响因子: 6.8
• 作者: Shah D;Osipo C
• 通讯作者: Osipo C

PKCα Attenuates Jagged-1-Mediated Notch Signaling in ErbB-2-Positive Breast Cancer to Reverse Trastuzumab Resistance.

• DOI: 10.1158/1078-0432.ccr-15-0179
• 发表时间: 2016-01-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Pandya K;Wyatt D;Gallagher B;Shah D;Baker A;Bloodworth J;Zlobin A;Pannuti A;Green A;Ellis IO;Filipovic A;Sagert J;Rana A;Albain KS;Miele L;Denning MF;Osipo C
• 通讯作者: Osipo C

Inhibition of HER2 Increases JAGGED1-dependent Breast Cancer Stem Cells: Role for Membrane JAGGED1.

• DOI: 10.1158/1078-0432.ccr-17-1952
• 发表时间: 2018-09-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Shah D;Wyatt D;Baker AT;Simms P;Peiffer DS;Fernandez M;Rakha E;Green A;Filipovic A;Miele L;Osipo C
• 通讯作者: Osipo C