Targeting cell trafficking as a new therapeutic modality for Multiple Myeloma

靶向细胞运输作为多发性骨髓瘤的新治疗方式

• 批准号: 7673688
• 负责人: Irene M. Ghobrial
• 金额: $ 35.39万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673688
• 关键词: AMD3100; Activities of Daily Living; Adhesions; Affect; Apoptosis; Apoptotic; Biological; Bioluminescence; Blood; Blood Circulation; Bone Marrow; Bone Marrow Cells; Bone Marrow Involvement; Bortezomib; CXCR4 Receptors; CXCR4 gene; Cells; Chemotactic Factors; Clinical Trials; Confocal Microscopy; Correlative Study; Data; Development; Diagnosis; Disease; Endothelial Cells; Environment; Flow Cytometry; Future; Growth; Hematologic Neoplasms; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Homing; Image; In Vitro; Induction of Apoptosis; Integrin alpha4beta1; Kinetics; Knowledge; Lead; Lymphocyte; Malignant - descriptor; Measures; Mesenchymal; Modality; Modeling; Molecular; Monitor; Mononuclear; Multiple Myeloma; Osteoclasts; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase; Plasma Cells; Plasmacytic Leukemia; Play; Process; Property; Relapse; Resistance; Role; Safety; Signal Pathway; Signal Transduction; Site; Stem cells; Stromal Cell-Derived Factor 1; Stromal Cells; Testing; Thalidomide; Therapeutic; Therapeutic Agents; Therapy Clinical Trials; Time; Tumor Burden; base; cancer cell; cell killing; cell type; chemokine; chemokine receptor; chemotherapy; cytokine; design; in vivo; inhibitor/antagonist; innovation; killings; lenalidomide; migration; neoplastic cell; novel therapeutics; peripheral blood; prevent; public health relevance; research study; response; safety testing; therapy development; trafficking; tumor growth

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.

描述（由申请人提供）：多发性骨髓瘤 (MM) 是第二大常见的血液恶性肿瘤，且仍无法治愈，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使该疾病患者的治疗取得了重大进展。然而，在复发情况下，只有 25-35% 的患者对这些药物有反应。骨髓 (BM) 微环境在 MM 细胞对治疗药物的耐药性中发挥着关键作用。我们提出了一项临床试验，以 MM 细胞的运输过程为目标，通过将 MM 细胞从其保护性微环境中释放到外周循环中，破坏 MM 细胞与其微环境的相互作用，在外周循环中，它们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CXCR4抑制剂AMD3100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，我们还发现，AMD3100 和硼替佐米的组合可以增加凋亡 MM 细胞向外周循环的动员，并减少体内肿瘤负荷。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细胞凋亡的敏感性。我们将在 3 个具体目标中检验这一假设。具体目标 1：通过针对复发 MM 患者的 I/II 期临床试验，确定 AMD3100 和硼替佐米联合用药对 MM 患者的安全性、诱导 MM 细胞动员以及肿瘤反应。具体目标 2：确定与 BM 微环境之外的 MM 细胞相比，局限于 BM 的 MM 细胞中发生的生物学后遗症。具体目标 3：确定 BM 微环境中因 AMD3100 和硼替佐米而发生的生物学后遗症。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加敏感。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专门针对 MM 细胞驻留在其保护环境中的能力的治疗试验至关重要。公共卫生相关性：骨髓微环境会诱导对多发性骨髓瘤细胞的抵抗力，并防止化疗杀死它们的细胞。我们提出了一项临床试验，将骨髓瘤细胞从骨髓中的保护性巢穴中动员出来，使它们在血液中循环，从而很容易被硼替佐米药物杀死。我们将与本次临床试验一起进行相关研究，以了解这些细胞从骨髓中循环的机制。