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

多发性骨髓瘤（MM）是一种血液系统疾病，其中浆细胞已经发展为 恶性特征植入骨髓（BM）。有一个共识是， BM的微环境包含在骨髓瘤存活中起主要作用的因子和条件， 增殖已知BM缺氧（pO 2 ~<32 mmHg），低pO 2理论上对BM有害。 MM和其他细胞的存活，尽管骨髓瘤细胞已经发展出适应性反应， 在这个恶劣的微环境中生存和传播。其中最主要的反应是师父的感应 低氧诱导因子（HIF）调节各种保护MM细胞免受缺氧的途径， 介导的凋亡。许多MM肿瘤由于癌基因激活而表现出组成型HIF表达 和/或基因突变的O2传感/HIF途径，我们假设这可能有助于 更多恶性肿瘤表型并促进疾病的进展。因此，我们认为， 抑制HIF活性和克服这些适应性缺氧反应可能具有重要的临床意义 治疗这种疾病。事实上，我们已经证明，用聚酰胺化合物（HIF-1）靶向HIF活性， PA）阻断HIF与其同源DNA序列结合的能力，使MM对缺氧介导的 体外杀伤，体内对MM异种移植物具有抗肿瘤功效。本MERIT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 和溶骨性骨损伤的形成。为此，我们将检查已建立的MM细胞的反应， 细胞系和来自具有不同疾病严重程度的患者的骨髓瘤的患者来源的肿瘤细胞。到 作为对这些体外研究的补充，我们将利用新的原位异种移植模型来研究缺氧如何影响移植物的存活。 调节MM/BM微环境并确定体内靶向HIF的临床前功效。

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.