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HSP based combinatorial immunotherapy in triple negative breast cancer

基于 HSP 的三阴性乳腺癌组合免疫疗法

基本信息

批准号：
8854051
负责人：
SOLDANO FERRONE
金额：
$ 8.48万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8854051
关键词：
Address Aldehydes Animal Model Antibodies Apoptosis Biological Models Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Carbohydrates Cell Migration Induction Cell Proliferation Cell Survival Cells Client Clinical Conduct Clinical Trials Data Disease Epitopes Family Goals Growth Health Heat shock proteins Heat-Shock Proteins 90 Human Immunotherapeutic agent Immunotherapy In Vitro Individual Induction of Apoptosis Libraries Light Literature MDA MB 231 Malignant - descriptor Malignant Neoplasms Mediating Monoclonal Antibodies Mus Neoplasm Metastasis Normal Cell Normal tissue morphology Oral Pathway interactions Patients Phage Display Proteins Proto-Oncogene Proteins c-akt Recurrence Role Severe Combined Immunodeficiency Signal Pathway Sonic Hedgehog Pathway Specificity Testing Therapeutic Translations Treatment Efficacy Tumor Antigens Tumor Cell Biology base cancer cell cancer stem cell clinically relevant clinically significant combinatorial dalton design efficacy testing extracellular glucose-regulated protein 94 glucose-regulated proteins human SHH protein human monoclonal antibodies improved in vivo inhibitor/antagonist member migration neoplastic cell novel novel therapeutics research study response selective expression skills small molecule smoothened signaling pathway theories triple-negative invasive breast carcinoma tumor

项目摘要

DESCRIPTION (provided by applicant): Novel therapies are need for the treatment of triple negative breast cancer (TNBC). In response to this clinical need, this proposal will test the efficacy of a novel combinatorial strategy which targets differentiated TNBC cells and TNBC cancer initiating cells (CICs). The latter identified as ALDHbright cells have to be eradicated in order to "cure" a malignant disease, since according to cancer stem cell theory these cells are responsible for disease recurrence and metastases. The tumor antigen selected as a target is the glucose-regulated protein of 94 kDa (Grp94). Grp94 regulates the activation of signaling pathways associated with cell proliferation, survival and migration. To target Grp94, we will take advantage of the unique specificity of the human mAb W9 we have recently characterized. mAb W9 recognizes an extracellular Grp94 epitope selectively expressed on cancer cells, including differentiated TNBC cells and TNBC CICs, but with a restricted distribution in normal tissues. mAb W9 markedly inhibits TNBC and TNBC CICs in vitro proliferation. To enhance its anti-proliferative activity we have combined mAb W9 with LDE225, a novel inhibitor of the Sonic Hedgehog (SHH) pathway which is aberrantly activated in TNBC and especially in TNBC CICs. mAb W9 enhances the ability of LDE225 in inhibiting TNBC cell in vitro growth, and in eliminating TNBC CICs by inhibiting signaling pathways involved in cell proliferation and survival of TNBC cells and TNBC CICs. The in vivo and potential clinical relevance of the in vitro results will be assessed by the following specific aims: i) mAb W9 and LDE225 combination is more effective than the individual agents in eradicating TNBC tumors established in Severe Combined Immunodeficiency (SCID) mice orthotopically grafted with the TNBC cell line MDA-MB-231-Luc-D3H1; ii) the results obtained with the TNBC cell line MDA-MB-231-Luc-D3H1 have clinical significance, as they are reproduced in SCID mice orthotopically grafted with TNBC tumors surgically removed from patients. The results generated by the outlined experiments will contribute to determine whether mAb W9 should be moved to a clinical setting. Its translation will be facilitated by the fact that the mAb W9 is a fully human antibody and does not require any major manipulation for use in patients. Furthermore, the clinical implementation of this novel combinatorial strategy will be facilitated b Dr. Isakoff's access to his patients with TNBC and his skills in conducting clinical trials.

描述(申请人提供)：三阴性乳腺癌(TNBC)的治疗需要新的治疗方法。为了回应这一临床需求，这项建议将测试一种针对分化的TNBC细胞和TNBC癌症起始细胞(CICs)的新组合策略的有效性。后者被认为是ALDHbright细胞，必须根除才能“治愈”一种恶性疾病，因为根据癌症干细胞理论，这些细胞负责疾病的复发和转移。作为靶点的肿瘤抗原是94 kDa的葡萄糖调节蛋白(Grp94)。Grp94调节与细胞增殖、存活和迁移相关的信号通路的激活。为了针对Grp94，我们将利用我们最近鉴定的人mAbW9的独特特异性。MAb W9识别细胞外Grp94表位，选择性地表达在癌细胞上，包括分化的TNBC细胞和TNBC CIC，但在正常组织中分布有限。MAb W9在体外对TNBC和TNBC CICs的增殖有明显的抑制作用。为了增强其抗增殖活性，我们将单抗W9与LDE225结合，LDE225是一种新的Sonic Hedgehog(SHH)途径的抑制剂，在TNBC中，特别是在TNBC CICs中被异常激活。MAb W9可增强LDE225抑制TNBC细胞体外生长的能力，并通过抑制参与TNBC细胞和TNBC CICs增殖和存活的信号通路来消除TNBC CICs。体外结果的体内和潜在临床相关性将通过以下具体目标进行评估： 1)单抗W9和LDE225联合用药能更有效地消除严重联合免疫缺陷(SCID)小鼠原位移植的TNBC细胞株MDA-MB-231-Luc-D3H1的肿瘤； Ii)用TNBC细胞系MDA-MB-231-Luc-D3H1获得的结果具有临床意义，因为它们是在原位移植的SCID小鼠身上复制的，这些肿瘤是从患者身上切除的TNBC肿瘤。概述的实验产生的结果将有助于确定是否应该将mAbW9转移到临床环境中。它的翻译将因为mAb的事实而变得更容易 W9是一种完全的人类抗体，不需要任何重大操作就可以在患者身上使用。此外，由于Isakoff博士接触到他的TNBC患者以及他进行临床试验的技能，这种新的组合策略的临床实施将得到促进。