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：
8638639
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 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638639
关键词：
Address Aldehydes Animal Model Antibodies Apoptosis Biological Models Breast Cancer Cell Cancer Patient Cancer cell line Carbohydrates Cell Migration Induction Cell Proliferation Cell Survival Cells Client Clinical Conduct Clinical Trials Data Disease Epitopes Family Goals Growth 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 public health relevance 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（由申请人提供）：治疗三阴性乳腺癌（TNBC）需要新的疗法。为了满足这一临床需求，该提案将测试一种针对分化 TNBC 细胞和 TNBC 癌症起始细胞 (CIC) 的新型组合策略的功效。后者被确定为 ALDHbright 细胞，必须被根除才能“治愈”恶性疾病，因为根据癌症干细胞理论，这些细胞是疾病复发和转移的原因。选择作为靶标的肿瘤抗原是 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。为了靶向 Grp94，我们将利用我们最近表征的人类 mAb W9 的独特特异性。 mAb W9 可识别在癌细胞（包括分化的 TNBC 细胞和 TNBC CIC）上选择性表达的细胞外 Grp94 表位，但在正常组织中的分布有限。 mAb W9 显着抑制 TNBC 和 TNBC CIC 的体外增殖。为了增强其抗增殖活性，我们将 mAb W9 与 LDE225 联合使用，LDE225 是 Sonic Hedgehog (SHH) 通路的新型抑制剂，该通路在 TNBC，尤其是 TNBC CIC 中异常激活。 mAb W9 增强了 LDE225 抑制 TNBC 细胞体外生长的能力，并通过抑制涉及 TNBC 细胞和 TNBC CIC 的细胞增殖和存活的信号通路来消除 TNBC CIC。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： i) mAb W9 和 LDE225 组合比单独使用药物更有效地根除在原位移植 TNBC 细胞系 MDA-MB-231-Luc-D3H1 的严重联合免疫缺陷 (SCID) 小鼠中建立的 TNBC 肿瘤； ii) 用 TNBC 细胞系 MDA-MB-231-Luc-D3H1 获得的结果具有临床意义，因为它们在原位移植有从患者身上切除的 TNBC 肿瘤的 SCID 小鼠中重现。概述的实验产生的结果将有助于确定 mAb W9 是否应转移到临床环境。 mAb 的翻译将更加便利 W9 是一种完全人源抗体，无需任何重大操作即可用于患者。此外，Isakoff 博士接触 TNBC 患者的机会及其进行临床试验的技能将有助于这种新颖组合策略的临床实施。