Targeting B cell activating factor receptor (BAFF-R) as a novel therapeutic strategy for drug resistant Acute Lymphoblastic Leukemia (ALL)

靶向 B 细胞激活因子受体 (BAFF-R) 作为耐药急性淋巴细胞白血病 (ALL) 的新型治疗策略

• 批准号: 9296098
• 负责人: Reshmi Parameswaran
• 金额: $ 17.24万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296098
• 关键词: Acute Lymphocytic Leukemia; Adult; Adverse effects; Affect; Allogenic; Antibodies; Antigen Targeting; Antigens; Apoptosis; Attenuated; Autologous; B-Lymphocytes; Binding; Biology; Bone Marrow; Cancer Etiology; Cell Death; Cell physiology; Cell surface; Cells; Child; Comparative Study; Cues; Data; Drug resistance; Drug usage; Effectiveness; Exposure to; Fusion Toxin; Glycocalyx; Growth; Human; Immunoglobulins; In Vitro; Injection of therapeutic agent; Interleukin 4 Receptor; Lead; Leukemic Cell; Leukocytes; Malignant - descriptor; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Methods; Molecular; Molecular Abnormality; Monoclonal Antibodies; Mus; Names; Natural Killer Cells; Normal Cell; Outcome; Pathway interactions; Patients; Ph+ ALL; Pharmaceutical Preparations; Philadelphia Chromosome; Phosphotransferases; Play; Pre-B Acute Lymphoblastic Leukemia; Proteins; Publishing; R-factor; Recombinants; Resistance; Resistance development; Role; Sampling; Signal Pathway; Signal Transduction; Stromal Cells; Surface; Testing; Therapeutic; Therapeutic Uses; Transplantation; Tumor Antigens; United States; Vincristine; aged; antibody-dependent cell cytotoxicity; autocrine; base; bcr-abl Fusion Proteins; cancer cell; cancer type; chemotherapy; cytotoxicity; design; drug relapse; experimental study; in vivo; killings; leukemia; lymphoblast; neoplastic cell; novel; novel therapeutics; outcome forecast; paracrine; progenitor; public health relevance; receptor; therapeutic target

Abstract- B-lineage acute lymphoblastic leukemia (B-ALL) arises by malignant transformation of a progenitor (pre-B) cell. Cure rates in adults remain low and treatment is complicated by support provided by the microenvironment to the leukemic cells, indicating an urgent need to better understand the factors that promote their survival. We found that B-cell-activating factor (BAFF) and its receptor BAFF-R are important for ALL survival. Both Philadelphia chromosome (Ph)- positive and Ph-negative ALL samples tested were positive for high BAFF-R cell surface expression. Recombinant BAFF supported survival of the ALL cells in the absence of stroma, and it significantly attenuated the rate of apoptosis caused by exposure to nilotinib, a drug used therapeutically to treat Ph-positive ALLs. In this proposal, we will investigate the signaling pathways elicited by BAFF, role of BAFF in mediating drug resistance and finally how we can target BAFF-R or BAFF signaling for specific killing of ALL cells. We already published the effectiveness of fusion toxin rGel/BLyS in killing ALL cells. We propose to use a novel afucosylated BAFF-R antibody to mediate antibody dependent cytotoxicity (ADCC) using allogenic or autologous natural killer (NK) cells.

摘要-- B系急性淋巴细胞白血病（B-ALL）是由急性淋巴细胞白血病（ALL）的恶性转化引起的。 祖细胞（前B细胞）。成人的治愈率仍然很低，治疗因支持而复杂化 提供的微环境的白血病细胞，表明迫切需要更好地 了解促进其生存的因素。我们发现B细胞活化因子（BAFF） 及其受体BAFF-R对ALL的存活很重要。费城染色体（Ph）- 检测的阳性和Ph阴性ALL样本的高BAFF-R细胞表面呈阳性 表情重组BAFF支持ALL细胞在无基质存在下的存活， 它显著减弱了暴露于尼洛替尼（一种用于治疗糖尿病的药物）引起的细胞凋亡率， 治疗性地治疗Ph阳性ALL。在本提案中，我们将研究 BAFF引起的途径，BAFF在介导耐药性中的作用，以及我们如何 靶向BAFF-R或BAFF信号传导以特异性杀伤ALL细胞。我们已经发布了 融合毒素rGel/BLyS杀伤ALL细胞的有效性。我们打算用一本小说 使用去岩藻糖基化BAFF-R抗体介导抗体依赖性细胞毒性（ADCC） 同种异体或自体自然杀伤（NK）细胞。