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，在这种疾病中，浆细胞已经发育 恶性特征植入骨髓(BM)。有一个共识是， 骨髓微环境包含在骨髓瘤存活和转移中起主要作用的因素和条件。 扩散。众所周知，BM是低氧的(PO2~&lt；32 mm Hg)，低PO2理论上对 MM和其他细胞的存活，尽管骨髓瘤细胞已经形成了有利于其 在这种恶劣的微环境中生存和传播。在这些回应中，最主要的是师父的诱导 通过低氧诱导因子(HIF)调节保护MM细胞免受低氧损伤的各种途径的基因。 介导的细胞凋亡。许多多发性骨髓瘤由于癌基因激活而表现出结构性的HIF表达 和/或O2感知/HIF途径中的基因突变，我们假设这可能有助于 更多的恶性肿瘤表型和促进疾病的进展。因此，我们认为 抑制HIF活性和克服这些适应性低氧反应可能具有重要的临床意义 在治疗这种疾病方面。事实上，我们已经证明，靶向HIF活性的聚酰胺化合物(HIF- PA)，阻断HIF与其同源DNA序列结合的能力，使MM对低氧中介敏感 体外杀伤作用，体内对MM移植瘤有抗肿瘤作用。这一优点的重点是审查 HIF转录因子在多发性骨髓瘤细胞存活和生长中的作用及其对酸碱调节的影响 并形成溶骨性骨损。为此，我们将检查已建立的MM细胞的反应 不同病情的骨髓瘤患者的肿瘤细胞株和患者来源的肿瘤细胞。至 作为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是如何 调节MM/BM微环境，确定体内靶向HIF的临床前疗效。

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.