Targeting Multiple Myeloma with Smac-mimetics and HDAC Inhibitors

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方案。细胞凋亡抑制剂（IAP）拮抗剂/Smac模拟物（SM），例如LCL 161或birinopant，最初开发用于防止IAP抑制活化的半胱天冬酶和细胞凋亡，已经显示出作为抗癌剂的临床前潜力，包括在MM中。最近的注意力集中在SM下调核心E3泛素连接酶cIAP 1/2的能力，从而抑制经典和非经典NF-κB途径，对于MM细胞存活至关重要，同时通过核糖体激活外源性凋亡途径。组蛋白去乙酰化酶抑制剂（HDACIs）调节基因表达和许多非组蛋白底物的乙酰化。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）在MM。最近，我们和其他人已经证明，HDACI在NF-κB和外源性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的战略相结合的SM与HDACI在MM的基础上，多个互补的理由，即，a）SM和HDACI靶向共同的信号传导级联，并且组合同时抑制经典和非经典NF-κB途径，同时激活内在和外在凋亡途径; B）NF-κB由于频繁的遗传畸变和骨髓微环境因素而在MM细胞中被组成性激活; c）NF-κB抑制（例如，确实，初步证据表明在各种MM细胞类型中SM和HDACI之间的高度协同相互作用。为了推进这一新概念，提出了三个目标。在具体目标#1中，我们将定义SM通过其增强HDACI抗MM活性的MOA，强调经典或非经典NF-κB途径的破坏，以及经由核糖体的外源性途径的参与;在对常规或新型药物具有抗性MM细胞中建立方案功效，特别是通过涉及激活外源性凋亡途径的MOA绕过由于异常Bcl-2家族表达引起的获得性抗性;确定该策略是否通过阻断非经典NF-κB途径来规避耐药的微环境形式。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，同时保留正常细胞;检验该策略也靶向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，哪些机制是有效的。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活性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，这些研究将为复发性/难治性MM的新的且可能更有效的个体化治疗策略的临床开发提供必要的基础。

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.