Targeting Multiple Myeloma with Smac-mimetics and HDAC Inhibitors

使用 Smac 模拟物和 HDAC 抑制剂靶向多发性骨髓瘤

• 批准号: 9252428
• 负责人: Steven Grant
• 金额: $ 31.4万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252428
• 关键词: Acetylation; Antineoplastic Agents; Apoptosis; Apoptosis Inhibitor; Apoptotic; Attention; BCL2 gene; BIRC4 gene; Biological Markers; Bone Marrow; Bortezomib; Bypass; CASP8 gene; CD19 gene; CD34 gene; Caspase; Cell Survival; Cells; Cessation of life; Clinical Research; Clinical Trials; Complex; Critical Pathways; Development; Disease; Disease Progression; Down-Regulation; Drug Interactions; Drug resistance; Epigenetic Process; Family; Foundations; Future; Gene Expression; Genetic; Goals; Hematopoietic; Histone Deacetylase Inhibitor; Human; Immunocompetent; Immunocompromised Host; In Vitro; Inhibition of Apoptosis; Interruption; Lead; MAP3K7 gene; MS4A1 gene; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Molecular Abnormality; Multiple Myeloma; Mus; Mutation; Normal Cell; Oral; Pathway interactions; Pharmacodynamics; Play; Proteasome Inhibitor; Protein Family; RIPK1 gene; Refractory; Regimen; Regulation; Relapse; Reporting; Resistance; Revlimid; Role; Signal Transduction; Solid Neoplasm; Specimen; TNF receptor-associated factor 3; TNFRSF5 gene; TRADD gene; TRAF2 gene; Testing; Therapeutic; Toxic effect; Ubiquitination; base; cell transformation; cell type; clinical development; clinically relevant; effective therapy; experience; in vivo; individualized medicine; inhibitor-of-apoptosis protein; inhibitor/antagonist; insight; killings; mimetics; mouse model; neoplastic cell; novel; novel therapeutics; outcome forecast; personalized medicine; personalized strategies; pre-clinical; prevent; public health relevance; small molecule inhibitor; stem-like cell; treatment strategy; tumor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Despite therapeutic advances, multiple myeloma (MM) is generally incurable, and new and more effective treatment options are urgently needed. Inhibitor of apoptosis (IAP) antagonists/Smac-mimetics (SMs) such as LCL161 or birinopant, initially developed to prevent IAPs from inhibiting activated caspases and apoptosis, have shown pre-clinical potential as anti-cancer agents, including in MM. Recent attention has focused on the ability of SMs to down-regulate the core E3 ubiquitin ligases cIAP1/2, thereby inhibiting both the canonical and non-canonical NF-κB pathways, critical for MM cell survival, while activating the extrinsic apoptotic pathway through the ripoptosome. Histone deacetylase inhibitors (HDACIs) modulate gene expression and acetylation of numerous non-histone substrates. Notably, the HDACI panobinostat (PB) has very recently been approved (with proteasome inhibitors; PIs) in MM. Recently, we and others have demonstrated that HDACIs play important roles in regulation of the NF-κB and extrinsic apoptotic pathways. Here, we propose a novel mechanism-driven strategy combining SMs with HDACIs in MM based on multiple complementary rationales i.e., a) SMs and HDACIs target common signaling cascades, and in combination simultaneously inhibit both the canonical and non-canonical NF-κB pathways while activating the intrinsic and extrinsic apoptotic pathways; b) NF-κB is constitutively activated in MM cells due to frequent genetic aberrations and bone marrow microenvironmental factors; c) NF-κB inhibition (e.g., by PIs) significantly increases HDACI activity in MM. Indeed, preliminary evidence suggests highly synergistic interactions between SMs and HDACIs in various MM cell types. To advance this novel concept, three Aims are proposed. In Specific Aim #1, we will define MOAs by which SMs potentiate HDACI anti-MM activity, highlighting disruption of the canonical or non- canonical NF-κB pathways, and engagement of the extrinsic pathway via the ripoptosome; establish regimen efficacy in MM cells resistant to conventional or novel agents, particularly by bypassing acquired resistance due to aberrant Bcl-2 family expression through MOAs involving activation of the extrinsic apoptotic pathway; determine whether this strategy circumvents microenvironmental forms of drug-resistance by interrupting the non-canonical NF-κB pathway. In Specific Aim #2, we will determine whether the regimen selectively kills primary MM cells while sparing normal cells; test the hypothesis that this strategy also targets MM stem cell- like cells; determine whether certain primary MM cell subtypes with genetic aberrations involving NF-κB or apoptotic pathways are particularly sensitive to this regimen, and if so, which mechanisms are operative. In Specific Aim #3, we will test whether the regimen is effective and tolerated in immunocompromised or immunocompetent MM mouse models, and determine if MOAs identified in vitro are operative in vivo. If successful, these studies will provide the necessary foundation for clinical development of a new and potentially more effective individualized treatment strategy for relapsed/refractory MM.

描述（由申请人提供）：尽管治疗取得了进展，但多发性骨髓瘤（MM）通常无法治愈，迫切需要新的、更有效的治疗选择。细胞凋亡抑制剂 (IAP) 拮抗剂/Smac 模拟物 (SM)，例如 LCL161 或 birinopant，最初是为了防止 IAP 抑制活化的半胱天冬酶和细胞凋亡而开发的，现已显示出作为抗癌药物（包括多发性骨髓瘤）的临床前潜力。最近的注意力集中在 SM 下调核心 E3 泛素连接酶 cIAP1/2 的能力，从而抑制对 MM 细胞存活至关重要的经典和非经典 NF-κB 通路，同时通过核糖体激活外源性凋亡通路。组蛋白脱乙酰酶抑制剂 (HDACIs) 调节多种非组蛋白底物的基因表达和乙酰化。值得注意的是，HDACI 帕比司他 (PB) 最近已被批准（与蛋白酶体抑制剂；PI）用于 MM。最近，我们和其他人证明 HDACIs 在 NF-κB 和外源性细胞凋亡途径的调节中发挥重要作用。在这里，我们提出了一种新的机制驱动策略，将 SM 与 HDACIs 结合在 MM 中，基于多个互补的原理，即：a) SM 和 HDACIs 靶向共同的信号级联，并结合起来同时抑制经典和非经典 NF-κB 通路，同时激活内在和外在凋亡通路； b) 由于频繁的遗传畸变和骨髓微环境因素，NF-κB在MM细胞中被组成型激活； c) NF-κB 抑制（例如通过 PI）显着增加 MM 中的 HDACI 活性。事实上，初步证据表明 SM 和 HDACIs 在各种 MM 细胞类型中存在高度协同相互作用。为了推进这一新颖的概念，提出了三个目标。在具体目标#1中，我们将定义 MOA，通过 SM 增强 HDACI 抗 MM 活性，强调对经典或非经典 NF-κB 通路的破坏，以及通过核糖体参与外在通路；确定对传统或新型药物耐药的 MM 细胞的治疗方案疗效，特别是通过涉及外源性细胞凋亡途径激活的 MOA，绕过由于异常 Bcl-2 家族表达而产生的获得性耐药；确定该策略是否通过中断非经典 NF-κB 通路来规避微环境形式的耐药性。在具体目标 #2 中，我们将确定该方案是否选择性杀死原代 MM 细胞，同时不伤害正常细胞；检验该策略也针对 MM 干细胞样细胞的假设；确定具有涉及 NF-κB 或凋亡途径的遗传畸变的某些原代 MM 细胞亚型是否对该方案特别敏感，如果是，则哪些机制起作用。在具体目标 #3 中，我们将测试该方案在免疫功能低下或免疫功能正常的 MM 小鼠模型中是否有效和耐受，并确定体外鉴定的 MOA 是否在体内有效。如果成功，这些研究将为临床开发针对复发/难治性多发性骨髓瘤的新的且可能更有效的个体化治疗策略提供必要的基础。