Targeting the Microenvironment for Myeloma Growth Control

针对骨髓瘤生长控制的微环境

• 批准号: 8555169
• 负责人: SHMUEL YACCOBY
• 金额: $ 22.97万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-05 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555169
• 关键词: Address; Affect; Anabolic Agents; Anabolism; Animals; Attenuated; Behavior; Binding; Blood Circulation; Bone Diseases; Bone Marrow; Bone Marrow Cells; Bone remodeling; Bortezomib; CXCR4 gene; Caveolae; Cell Line; Cell Survival; Cells; Clinical; Coculture Techniques; Combined Modality Therapy; Complex; DEXA; Data; Development; Dexamethasone; Dipeptidyl-Peptidase IV; Disease; Disease Progression; Disease remission; Environment; Enzyme-Linked Immunosorbent Assay; Goals; Growth; Hematopoietic stem cells; Homing; Homologous Gene; Homologous Protein; Hormones; Human; Image; Immunohistochemistry; Implant; In complete remission; Individual; Intervention; Lesion; Leucine; Life; Lytic Metastatic Lesion; Malignant Neoplasms; Marrow; Mediating; Melphalan; Modeling; Molecular; Multiple Myeloma; Neoplasm Metastasis; Osteoblasts; Osteoclasts; Osteogenesis; Osteolysis; Osteolytic; Parathyroid gland; Patients; Peptide Hydrolases; Placenta; Play; Prevention; Process; Production; Proteoglycan; Quality of life; Recombinant Proteins; Recurrent disease; Relapse; Reporting; Role; SCID-hu Mice; Sampling; Serine Protease; Signal Transduction; Site; Stromal Cell-Derived Factor 1; Structure; Supporting Cell; System; Testing; Therapeutic; Time; angiogenesis; base; bone; cell growth; chemokine; improved; in vivo; inhibitor/antagonist; interstitial; lenalidomide; mouse model; neutralizing antibody; novel; osteoclastogenesis; osteoprogenitor cell; prevent; programs; response; treatment effect; tumor; tumor growth

The common and typical induction of osteolytic bone disease in multiple myeloma (MM) led to the notion that bone disease is both a consequence and a necessity of MM progression and metastasis. Our reported and preliminary data suggest that osteoclasts support myeloma cell survival and metastasis through production of certain serine proteases known as dipeptidyl peptidase-IV activity and/or structure homolog (DASH) proteins and that inhibiting activity of osteoclasts or DASH proteases suppresses growth of medullary MM. Conversely, we found that osteoblasts reduce growth of myeloma cells through production of certain small leucine-rich proteoglycans and that increased osteoblast activity in myelomatous bones (from treating with osteoblast-activating agents [parathyroid hormone or anti-DKKI] or with cytotherapy [osteoprogenitor cells]) increases bone formation, creating an inhospitable microenvironment that attenuates MM progression in vivo. Based on these findings, we hypothesize that the microenvironment in existing focal lesions is a critical determinant of long-term survival and dissemination of myeloma cells; therefore, simultaneously inhibiting osteoclast activity and stimulating bone formation is critical for sustaining a patient's response to treatment and for preventing metastasis. In Specific Aim 1, we will determine whether increased bone formation by bone-anabolic agents (e.g., PTH, anti-DKKI), with or without exogenous osteoblast precursors, will sustain remission induced by clinical agents (e.g., melphalan, dexamethasone, bortezomib, lenalidomide), and/or prevent tumor metastasis upon relapse. We will also investigate molecular mechanisms associated with these effects. In Specific Aim 2, we will determine whether osteoclast-produced DASH proteases contribute to MM-induced bone disease, support survival of MM in osteolytic lesions, and stimulate metastasis directly by signaling through caveolae and indirectly through reduced retention of myeloma cells by inactivating the central chemokine SDF-1. In Specific Aim 3, we will determine whether combining treatments to increase activity of osteoblasts and inhibit activity of DASH proteases has superior effects on controlling MM growth and dissemination and on preventing relapse than either individual therapeutic approach. Through interactions with all projects and cores, using our SCID-hu model and coculture systems with primary samples and myeloma cell lines, we will unravel antitumor and antimetastatic effects of factors associated with bone anabolism, as well as molecular mechanisms of DASH proteases in MM using gain-and-loss approaches, specific inhibitors, and recombinant proteins.

多发性骨髓瘤 (MM) 中常见且典型的溶骨性骨病诱导导致人们认为骨病既是 MM 进展和转移的结果，也是其必然。我们报告的初步数据表明，破骨细胞通过产生某些丝氨酸蛋白酶（称为二肽基肽酶-IV 活性和/或结构同源物 (DASH) 蛋白）来支持骨髓瘤细胞的存活和转移，并且抑制破骨细胞或 DASH 蛋白酶的活性可抑制髓质 MM 的生长。相反，我们发现成骨细胞通过产生某些富含亮氨酸的小蛋白多糖来减少骨髓瘤细胞的生长，并且增加骨髓瘤骨中的成骨细胞活性（通过用成骨细胞激活剂[甲状旁腺激素或抗DKKI]或细胞疗法[骨祖细胞]治疗）增加骨形成，从而产生不适宜的骨形成。 减弱体内 MM 进展的微环境。基于这些发现，我们假设现有局灶性病变的微环境是骨髓瘤细胞长期存活和传播的关键决定因素。因此，同时抑制破骨细胞活性和刺激骨形成对于维持患者对治疗的反应和预防转移至关重要。在具体目标 1 中，我们将确定骨合成代谢药物（例如 PTH、抗 DKKI）在有或没有外源性成骨细胞前体的情况下增加骨形成是否会维持临床药物（例如美法仑、地塞米松、硼替佐米、来那度胺）诱导的缓解，和/或预防复发时的肿瘤转移。我们还将研究与这些效应相关的分子机制。在具体目标 2 中，我们将确定破骨细胞产生的 DASH 蛋白酶是否会导致 MM 诱导的骨病，支持溶骨性病变中 MM 的存活，并通过小窝信号直接刺激转移，并通过灭活中央趋化因子 SDF-1 减少骨髓瘤细胞的保留来间接刺激转移。在具体目标 3 中，我们将确定增加成骨细胞活性和抑制 DASH 蛋白酶活性的联合治疗在控制 MM 生长和扩散以及预防复发方面是否比任何一种单独治疗方法具有更好的效果。通过与所有项目和核心的互动，使用我们的 SCID-hu 模型以及原始样本和骨髓瘤细胞系的共培养系统，我们将利用得失方法、特异性抑制剂和重组蛋白揭示与骨合成代谢相关的因子的抗肿瘤和抗转移作用，以及 DASH 蛋白酶在 MM 中的分子机制。