A novel multi-targeted therapy for breast cancer resistance

一种新型多靶点乳腺癌耐药疗法

基本信息

批准号：
9111810
负责人：
Sabine M Brouxhon
金额：
$ 15.42万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9111810
关键词：
Address Adjuvant Chemotherapy Antibodies Antigens Antineoplastic Agents Apoptosis Apoptotic Applications Grants Binding Breast Cancer Cell Breast Oncology Cell Death Cell Proliferation Cells Complement Data Disease Disease-Free Survival Down-Regulation E-Cadherin ERBB2 gene Endocytosis Ensure Epidermal Growth Factor Receptor Exhibits FRAP1 gene Family member Growth Factor Receptors Health Hormone Receptor Host resistance Human In Vitro Innovative Therapy Length Ligands Link MAP Kinase Gene MCF7 cell MEKs Mammary Neoplasms Mediating Monoclonal Antibodies Monoclonal Antibody Therapy Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Normal Cell Normal tissue morphology Oncogenes Oncogenic Organ Outcome PTEN gene Pathway interactions Patients Pharmaceutical Preparations Predisposition Progression-Free Survivals Proteins Ras/Raf Receptor Protein-Tyrosine Kinases Recurrence Relapse Resistance Resistance development SKBR3 Safety Signal Transduction Signaling Protein Site Specimen TP53 gene Tamoxifen Testing Transgenic Mice Transmembrane Domain Trastuzumab Tumor Burden Xenograft procedure base cancer cell combinatorial conventional therapy crosslink cytotoxicity extracellular hormone therapy in vivo ineffective therapies inhibitor/antagonist innovation killings lapatinib mTOR Inhibitor malignant breast neoplasm migration neoplastic cell new therapeutic target novel novel anticancer drug pro-apoptotic protein receptor response targeted treatment therapeutic development therapeutic effectiveness tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Over the last decade, the most significant revolutionary advances in breast oncology have been the FDA approval of targeted therapies against growth factor receptors, including the human epidermal growth factor receptors (HER1 and HER2) and drugs for hormone-receptor-positive disease. However, despite such encouraging results, patients that are initially responsive to these drugs eventually become resistant within one year of therapy. Multiple mechanisms responsible for resistance have been proposed, including compensatory crosstalk with alternate receptor tyrosine kinases (i.e. HER1-4, IGF-1R), hyper-activation of downstream MAPK-PI3K/Akt/mTOR signaling, activation of the inhibitor of apoptotic proteins (IAPs) and inactivation of PTEN and p53. We have identified soluble E-cadherin (sEcad) as a novel therapeutic target and have developed monoclonal antibodies targeting sEcad as an innovative therapy that directly kills cancer cells, spares normal cells and overcomes these host resistance pathways. Therefore, in this grant application we propose to first narrow down which HER or non-HER receptors (or combinations) are involved in the efficacy of our antibody- based therapy. We then will test whether combinatorial strategies involving HER or non-HER inhibitors, that act via different mechanism(s) of action than our antibody, may act additively or synergistically to suppress tumor growth and dissect some of the mechanism(s) involved. Lastly, we propose to complement our antibody with a panel of PD markers so as to ensure that the antibody is exerting its intended biologic outcome and perform preliminary studies to confirm no off-target effects. Altogether, we believe that our innovative therapy will make substantial strides in cure rates and in progression-free survival of patients with HER and non-HER-positive breast cancers that progress beyond targeted or other conventional therapies.

描述（由申请人提供）：在过去的十年中，乳腺肿瘤学最显着的进展是 FDA 批准了针对生长因子受体的疗法，包括人表皮靶向生长因子受体（HER1 和 HER2）和激素受体药物然而，尽管有这些令人鼓舞的结果，最初对这些药物有反应的患者最终在治疗后一年内变得耐药，已经提出了多种导致耐药的机制，包括与替代受体的补偿性串扰。我们已经确定了酪氨酸激酶（即 HER1-4、IGF-1R）、下游 MAPK-PI3K/Akt/mTOR 信号传导的过度激活、凋亡蛋白抑制剂 (IAP) 的激活以及 PTEN 和 p53 的失活。钙粘蛋白（sEcad）作为一种新型治疗靶点，并开发了针对 sEcad 的单克隆抗体作为一种创新疗法，可直接杀死癌细胞，备用因此，在本次拨款申请中，我们建议首先缩小哪些 HER 或非 HER 受体（或组合）参与我们基于抗体的疗法的功效，然后我们将测试组合疗法是否有效。 HER 或非 HER 抑制剂通过与我们的抗体建议不同的作用机制发挥作用，可能会叠加或协同作用来抑制肿瘤生长并剖析一些涉及的机制最后，我们补充我们的抗体。和一组 PD 标记物，以确保抗体发挥其预期的生物学结果，并进行初步研究以确认没有脱靶效应。总之，我们相信我们的创新疗法将在治愈率和无进展方面取得重大进展。 HER 和非 HER 阳性乳腺癌患者的生存率超出了靶向治疗或其他常规治疗的范围。