Novel targeted therapeutics for multiple myeloma

多发性骨髓瘤的新型靶向治疗

• 批准号: 8100095
• 负责人: JOSEPH Kofi AGYIN
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-09 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100095
• 关键词: Adverse effects; Affinity; Alendronate; Amides; Antineoplastic Agents; Apoptosis; Biological; Biological Assay; Bone Diseases; Bone Marrow; Bone Resorption; Bone neoplasms; Bone remodeling; Bortezomib; Carbon; Cell Cycle Progression; Cell Line; Cells; Charge; Chemical Structure; Cleaved cell; Clinical Research; Cytotoxic agent; Deposition; Development; Disadvantaged; Disease; Dose; Dose-Limiting; Drug Kinetics; Enzymes; Evaluation; Exhibits; Family; Gelatinase A; Gelatinase B; Goals; High Pressure Liquid Chromatography; Human; In Vitro; Inhibitory Concentration 50; Label; Leu-Gly; Link; Lytic Lesion; Malignant Neoplasms; Mass Spectrum Analysis; Matrix Metalloproteinases; Measures; Metastatic Neoplasm to the Bone; Methods; Minerals; Modality; Modeling; Multiple Myeloma; Mus; NMR Spectroscopy; Neoplasms; Non-Hodgkin' s Lymphoma; Normal tissue morphology; Organ; Patient Agents; Patients; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Plant Resins; Plasma; Play; Prodrugs; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Protons; Publishing; Radio; Relapse; Relative (related person); Resistance; Role; Series; Site; Solid; Solutions; Spectrum Analysis; Spleen; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Tumor Cell Invasion; Validation; Xenograft procedure; alanylalanine; analog; angiogenesis; bisphosphonate; bone; cancer therapy; chemical synthesis; chemotherapeutic agent; clinical efficacy; cytotoxicity; design; drug distribution; effective therapy; in vivo; innovation; killings; multicatalytic endopeptidase complex; neoplastic cell; new therapeutic target; novel; overexpression; prevent; protein expression; research study; skeletal; targeted delivery; therapeutic target; tumor; uptake

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is an incurable neoplasm characterized by devastating and progressive bone destruction. Despite recent advances in the first-line treatment of MM, almost all patients eventually relapse, become chemoresistant, and die of the disease. Clinical studies with Bortezomib have validated the proteasome as a therapeutic target for the treatment of MM and non-Hodgkin's lymphoma. However, significant toxicities have restricted the intensity of Bortezomib dosing and its clinical efficacy has been hampered by the emergence of resistance. There is great need for methods to target the delivery of novel, effective cytotoxic agents specifically to bone, where myeloma cells reside. The long-term goal of this proposal is to develop novel and innovative strategies aimed at selectively delivering therapeutic agents to the bone microenvironment for effective management of MM. Our recent studies of the bisphosphonate-proteasome inhibitor (BP-PI) conjugates indicate that the stability of the amide linkage does not permit efficient release of the drug and that the presence of the highly charged bisphosphonate moiety prevents cellular uptake of the conjugates, resulting in diminished cytotoxicity. In this application, our goal is to synthesize and evaluate the efficacy of a new series of tumor-activated bone-targeted proteasome inhibitors using a dual targeting strategy that targets matrix metalloproteinases (MMPs) produced by myeloma cells in the bone microenvironment to cleave a unique bisphosphonate-heptapeptide linker. It will enable us to investigate the potential of exploiting MMP-9 to activate prodrugs rationally designed to target MM cells as a new tumor-specific therapy. Our hypothesis is that by linking bisphosphonates to proteasome inhibitors through an MMP-cleavable heptapeptide, 1) we can target these compounds to deposits of myeloma cells in the bone microenvironment, 2) MMPs produced by the tumor cells will effectively cleave the bisphosphonate to release the "warhead" and achieve more effective concentrations of proteasome inhibitors locally, and 3) the tumor-activated prodrugs will selectively kill tumor cells and prevent or reduce dose-limiting systemic toxicity of pharmaceuticals. The specific aims of the proposal are i) To design and synthesize novel MMP-9 cleavable BP-heptapeptide-PI conjugates as a means of selective delivery of PS-341 to MM cell in bone microenvironment, and ii) To study the proposed compounds in vitro and in vivo. Together, these screens will provide validation for bone-targeted tumor-activated prodrugs as an effective treatment modality for treatment of MM and other bone metastatic cancers. PUBLIC HEALTH RELEVANCE: Multiple myeloma (MM) is an incurable neoplasm characterized by devastating and progressive bone destruction. Standard chemotherapeutic agents have not been effective at significantly prolonging the survival of MM patients and these agents are typically associated with often severe, dose-limiting side effects. There is great need for methods to target the delivery of novel, effective cytotoxic agents specifically to bone, where myeloma cells reside.

描述（由申请人提供）：多发性骨髓瘤（MM）是一种无法治愈的肿瘤，其特征是破坏性和进行性骨破坏。尽管最近MM的一线治疗取得了进展，但几乎所有患者最终都会复发，产生化疗耐药性，并死于该疾病。硼替佐米的临床研究已经证实蛋白酶体是治疗MM和非霍奇金淋巴瘤的治疗靶点。然而，严重的毒性限制了硼替佐米的剂量强度，其临床疗效也因耐药性的出现而受到阻碍。有很大的需要的方法靶向递送新的，有效的细胞毒性药物，特别是骨，骨髓瘤细胞驻留。本提案的长期目标是开发新的创新策略，旨在选择性地将治疗剂输送到骨微环境中，以有效地管理MM。我们最近对双磷酸盐-蛋白酶体抑制剂（BP-PI）偶联物的研究表明，酰胺键的稳定性不允许有效释放药物，并且高电荷的双磷酸盐部分的存在阻止了细胞对偶联物的摄取。导致细胞毒性降低。在这个应用中，我们的目标是合成和评估一系列新的肿瘤激活骨靶向蛋白酶体抑制剂的功效，使用双靶向策略，靶向骨髓瘤细胞在骨微环境中产生的基质金属蛋白酶（MMPs），以切割一个独特的二磷酸盐-七肽连接体。这将使我们能够研究利用MMP-9激活合理设计的靶向MM细胞的前药作为一种新的肿瘤特异性治疗方法的潜力。我们的假设是，通过mmp可切割的七肽将双膦酸盐与蛋白酶体抑制剂连接起来，1)我们可以将这些化合物靶向于骨微环境中骨髓瘤细胞的沉积物，2)肿瘤细胞产生的MMPs将有效地切割双膦酸盐以释放“弹头”，并在局部获得更有效的蛋白酶体抑制剂浓度。3)肿瘤活化前药可选择性杀伤肿瘤细胞，防止或降低药物的剂量限制性全身毒性。本课题的具体目的是：1)设计和合成新的MMP-9可切割bp - heptapep肽- pi偶联物，作为在骨微环境中选择性递送PS-341到MM细胞的手段；2)对所提出的化合物进行体外和体内研究。总之，这些筛选将为骨靶向肿瘤激活前药作为治疗MM和其他骨转移性癌症的有效治疗方式提供验证。