Targeting cell trafficking as a new therapeutic modality for Multiple Myeloma

描述（由申请人提供）：多发性骨髓瘤（MM）是第二大最常见的血液恶性肿瘤，它仍然无法治愈，中位生存期为3-5年。包括硼替佐米、沙利度胺和来那度胺在内的新型治疗药物已经导致患有这种疾病的患者的治疗的显著进步。然而，只有25-35%的患者在复发情况下对这些药物有反应。骨髓（BM）微环境在MM细胞对治疗剂的抗性中起关键作用。我们提出了一项临床试验，目标是MM细胞的运输过程，并通过将MM细胞从其保护性龛释放到外周循环中来破坏MM细胞与其微环境的相互作用，在外周循环中，MM细胞对其他治疗药物的凋亡更敏感。在我们的初步数据中，我们证明了CXCR 4抑制剂AMD 3100导致MM细胞从BM动员到体内外周血中，并且该过程的动力学在MM细胞和干细胞之间是不同的。此外，我们发现，AMD 3100和硼替佐米的组合导致凋亡MM细胞进入外周循环的动员增加和体内肿瘤负荷降低。我们假设破坏MM细胞与其微环境的相互作用将改变其生物学特性并诱导对凋亡的敏感性。我们将在三个具体目标中检验这一假设。具体目标1：通过在复发性MM患者中进行的I/II期临床试验，确定AMD 3100和硼替佐米联合治疗MM患者的安全性、MM细胞动员诱导和肿瘤缓解。具体目的2：确定与BM微环境外的MM细胞相比，局限于BM的MM细胞中发生的生物学后遗症。具体目的3：确定BM微环境中对AMD 3100和硼替佐米的反应所产生的生物学后遗症。这些研究具有创新性，因为它们代表了第一个调节患者MM细胞运输的体内试验，以破坏它们与BM微环境的相互作用并使它们对细胞凋亡更敏感。通过这项临床试验，我们将研究调节MM细胞和BM的其他细胞和体液成分的细胞运输的生物学效应。了解调节MM细胞运输的途径对于合理设计未来的治疗试验至关重要，这些试验专门针对MM细胞驻留在其保护环境中的能力。公共卫生相关性：骨髓微环境诱导对多发性骨髓瘤细胞的抗性，并防止其细胞被化疗杀死。我们提出了一项临床试验，我们将骨髓瘤细胞从骨髓中的保护性龛中动员出来，使它们在血液中循环，在那里它们可以很容易地被药物硼替佐米杀死。我们将沿着这项临床试验进行相关研究，以了解这些细胞从骨髓中循环出来的机制。

DESCRIPTION (provided by applicant): Multiple Myeloma (MM) is the second most prevalent hematological malignancy and it remains incurable with a median survival of 3-5 years. Novel therapeutic agents including bortezomib, thalidomide and lenalidomide have led to a significant advancement in the treatment of patients with this disease. However, only 25-35% of patients respond to these agents in the relapsed setting. The bone marrow (BM) microenvironment plays a pivotal role in the resistance of MM cells to therapeutic agents. We propose a clinical trial that targets the process of trafficking of MM cells and disrupt the interaction of MM cells with their microenvironment by releasing them from their protective niches into the peripheral circulation where they are more sensitive to apoptosis by other therapeutic agents. In our preliminary data, we demonstrate that the CXCR4 inhibitor AMD3100 leads to mobilization of MM cells from the BM into the peripheral blood in vivo, and that the kinetics of this process are different between MM cells and stem cells. In addition, we show that the combination of AMD3100 and bortezomib leads to an increase in mobilization of apoptotic MM cells into the peripheral circulation and a decrease in tumor burden in vivo. We hypothesize that disruption of the interaction of MM cells with their microenvironment will change their biologic properties and induce sensitivity to apoptosis. We will test this hypothesis in 3 specific aims. Specific Aim 1: To determine the safety, induction of mobilization of MM cells, and tumor response of the combination of AMD3100 and bortezomib in patients with MM through a phase I/II clinical trial in patients with relapsed MM. Specific Aim 2: To determine the biological sequelae that occur in MM cells confined to the BM compared to those outside of the BM microenvironment. Specific Aim 3: To determine the biological sequelae which occur in the BM microenvironment in response to AMD3100 and bortezomib. These studies are innovative as they represent the first in vivo trials that modulate trafficking of MM cells in patients in order to disrupt their interaction with the BM microenvironment and render them more sensitive to apoptosis. Through this clinical trial, we will investigate the biological effects of modulating cell trafficking of MM cells and other cellular and humoral components of the BM. Understanding the pathways that regulate MM cells' trafficking are critical to rationally design future therapeutic trials that specifically target the capacity of MM cells to reside in their protective environment. PUBLIC HEALTH RELEVANCE: The bone marrow microenvironment induces resistance to multiple myeloma cells and prevents their cell killing by chemotherapies. We propose a clinical trial where we will mobilize the myeloma cells out of their protective niches in the bone marrow and make them circulate in the blood where they can be easily killed by the drug bortezomib. We will perform correlative studies along with this clinical trial to understand the mechanisms of circulation of these cells out of the bone marrow.