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

• 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
• 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

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）：需要新的治疗方法来治疗三阴性乳腺癌（TNBC）。为了响应这一临床需求，本研究将测试一种针对分化的TNBC细胞和TNBC癌起始细胞（CICs）的新型组合策略的有效性。为了“治愈”恶性疾病，必须根除被认定为ALDHbright细胞的后者，因为根据癌症干细胞理论，这些细胞是导致疾病复发和转移的原因。肿瘤抗原选择作为靶标是葡萄糖调节蛋白的94kda （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单抗W9的独特特异性。mAb W9识别癌细胞选择性表达的细胞外Grp94表位，包括分化的TNBC细胞和TNBC CICs，但在正常组织中的分布有限。mAb W9显著抑制TNBC和TNBC CICs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是一种新的Sonic Hedgehog （SHH）通路抑制剂，在TNBC中异常激活，特别是在TNBC CICs中。mAb W9增强了LDE225在体外抑制TNBC细胞生长的能力，并通过抑制TNBC细胞和TNBC CICs参与细胞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：