Targeting the in Vivo Hypoxic Microenvironment of Multiple Myeloma as an Anti-Tumor Strategy

针对多发性骨髓瘤体内缺氧微环境作为抗肿瘤策略

基本信息

批准号：
10266051
负责人：
Patrick J Frost
金额：
--
依托单位：
VA GREATER LOS ANGELES HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10266051
关键词：
Acids Affect African American Aging Alkalinization American Apoptosis Binding Bone Marrow Caring Cell Hypoxia Cell Line Cells Cessation of life Characteristics Chemoresistance Complement Consensus DNA Sequence DNA Sequence Alteration Development Disease Disease Progression Elderly Elements Environment Exhibits Exposure to Gender Genes Growth Gulf War Healthcare Hematologic Neoplasms Hematological Disease Hypoxia Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway In Vitro Incidence Lactic acid Lesion Link Magnetic Resonance Imaging Maintenance Malignant - descriptor Malignant Neoplasms Marrow Mediating Metabolism Mission Monoclonal gammopathy of uncertain significance Morbidity - disease rate Multiple Myeloma Neoplasm Metastasis Nylons Oncogene Activation Organ Osteoblasts Osteoclasts Osteogenesis Osteolytic PET/CT scan Pathologic Pathology Pathway interactions Patients Pesticides Phenotype Plasma Cells Play Process Production Proteins Protons Race Radiation Regulation Research Risk Factors Role Severities Severity of illness Skeleton Smoking Solvents Source Substance abuse problem System Tumor-Derived Up-Regulation Veterans Xenograft Model Xenograft procedure agent orange alkalinity anaerobic glycolysis bHLH-PAS factor HLF base bone bone loss carbonate dehydratase clinically relevant clinically significant extracellular in vivo inhibitor/antagonist male migration military veteran neoplastic cell novel novel therapeutic intervention optical imaging preclinical efficacy preclinical study prevent recruit response transcription factor tumor tumor microenvironment tumor xenograft

项目摘要

Multiple myeloma (MM) is a disease of the hematological system in which plasma cells that have developed malignant characteristics engraft within the bone marrow (BM). There is a consensus that the microenvironment of the BM contains factors and conditions that play a major role in the myeloma survival and proliferation. The BM is known to be hypoxic (pO2~<32mmHg) and low pO2 is theoretically deleterious to the survival of MM and other cells, although myeloma cells have developed adaptive responses that favor their survival and spread in this harsh microenvironment. Chief among these responses is the induction of master genes by hypoxia inducible factors (HIFs) that regulate various pathways protecting MM cells from hypoxia- mediated apoptosis. Many MM tumors exhibit constitutive HIF expression as a result of oncogene activation and/or genetic mutations in the O2-sensing/HIF pathway and we hypothesize that this likely contributes to a more malignant tumor phenotype and facilitates the progression of the disease. Thus, we believe that inhibiting HIF activity and overcoming these adaptive hypoxic responses may have major clinical significance in treating this disease. Indeed, we have shown that targeting HIF activity with a polyamide compound (HIF- PA) that blocks the ability of HIF to bind to its cognate DNA sequence sensitizes MM to hypoxia-mediated killing in vitro and has anti-tumor efficacy against MM xenografts in vivo. The focus of this MERIT is to examine the role of HIF transcription factors in survival and growth of MM cells and its impact on acid/base regulation and the formation of osteolytic bone lesions. To this end, we will examine the responses of established MM cell lines and patient derived tumor cells from myeloma of patients with different severity of diseases. To complement these in vitro studies, we will utilize novel orthotopic xenograft models to study how hypoxia regulates the MM/BM microenvironment and determine the pre-clinical efficacy of targeting HIF in vivo.

多发性骨髓瘤（MM）是血液学系统的疾病，其中已经形成的浆细胞骨髓（BM）内的恶性特征。有一个共识，即 BM的微环境包含在骨髓瘤生存中起主要作用的因素和条件增殖。 BM已知低氧（PO2〜 <32mmHg），而低PO2在理论上是有害的 MM和其他细胞的生存，尽管骨髓瘤细胞已经发展出适应性反应，有利于它们生存并在这种艰难的微环境中传播。这些回应中的主要主要是大师的归纳低氧诱导因子（HIF）的基因调节了保护MM细胞免受缺氧的各种途径介导的凋亡。由于癌基活化，许多MM肿瘤表现出组成型HIF表达和/或O2传感/HIF途径中的遗传突变，我们假设这可能有助于更恶性的肿瘤表型并促进了疾病的进展。因此，我们相信抑制HIF活性并克服这些适应性低氧反应可能具有重要的临床意义治疗这种疾病。确实，我们已经表明，用聚酰胺化合物靶向HIF活性（HIF- PA）阻止了HIF与其同源DNA序列结合的能力，使MM敏感到缺氧介导在体外杀死体外杀死抗肿瘤功效。该优点的重点是检查 HIF转录因子在MM细胞存活和生长中的作用及其对酸/碱调节的影响以及骨骨病变的形成。为此，我们将检查已建立的MM单元的响应疾病严重程度不同的患者的骨髓瘤线和患者衍生出肿瘤细胞。到补充这些体外研究，我们将利用新型的原位异种移植模型来研究缺氧如何调节MM/BM微环境，并确定靶向HIF体内的临床前疗效。