Novel targeted therapeutics for multiple myeloma

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质破坏。 尽管多发性骨髓瘤的一线治疗最近取得了进展，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。 Bortezomib 的临床研究已验证蛋白酶体作为治疗多发性骨髓瘤和非霍奇金淋巴瘤的治疗靶点。然而，显着的毒性限制了硼替佐米的给药强度，并且其临床疗效因耐药性的出现而受到阻碍。非常需要将新型、有效的细胞毒剂靶向递送至骨髓瘤细胞所在的骨骼的方法。该提案的长期目标是开发新颖和创新的策略，旨在选择性地将治疗药物递送至骨微环境，以有效管理多发性骨髓瘤。我们最近对双膦酸盐-蛋白酶体抑制剂（BP-PI）缀合物的研究表明，酰胺键的稳定性不允许药物有效释放，并且高电荷双膦酸盐部分的存在阻止了细胞对缀合物的摄取，从而导致细胞毒性减弱。在此应用中，我们的目标是合成并评估一系列新的肿瘤激活骨靶向蛋白酶体抑制剂的功效，该抑制剂使用双重靶向策略，靶向骨微环境中骨髓瘤细胞产生的基质金属蛋白酶（MMP），以裂解独特的二磷酸盐-七肽接头。它将使我们能够研究利用 MMP-9 激活合理设计的前药以靶向 MM 细胞作为新的肿瘤特异性疗法的潜力。我们的假设是，通过 MMP 可裂解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骨微环境中骨髓瘤细胞的沉积物，2）肿瘤细胞产生的 MMP 将有效裂解双膦酸盐以释放“弹头”并在局部达到更有效浓度的蛋白酶体抑制剂，3）肿瘤激活的前药将选择性杀死肿瘤细胞并预防或减少肿瘤细胞的生长。药物的剂量限制性全身毒性。该提案的具体目标是 i) 设计和合成新型 MMP-9 可裂解 BP-七肽-PI 缀合物，作为将 PS-341 选择性递送至骨微环境中 MM 细胞的手段，以及 ii) 在体外和体内研究所提出的化合物。总之，这些筛选将验证骨靶向肿瘤激活前药作为治疗多发性骨髓瘤和其他骨转移癌的有效治疗方式。 公共卫生相关性：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质破坏。标准化疗药物并不能有效地显着延长多发性骨髓瘤患者的生存期，而且这些药物通常会带来严重的剂量限制性副作用。非常需要将新型、有效的细胞毒剂靶向递送至骨髓瘤细胞所在的骨骼的方法。

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.