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

基本信息

批准号：
9892981
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
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892981
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 MCL1 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 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

项目摘要

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（由适用提供）：尽管有治疗性进步，但多发性骨髓瘤（MM）通常无法治愈，并且迫切需要新的，更有效的治疗选择。凋亡（IAP）拮抗剂/SMAC-MIMETICS（SMS）的抑制剂，例如LCL161或Birinopant，最初是为防止IAP抑制活化的caspase和凋亡而开发的，已显示出临床前的潜力，作为抗癌药物，包括MMM。最近的注意力集中在SMS下调核心E3泛素连接酶CIAP1/2的能力上，从而抑制了MM细胞存活至关重要的规范和非典型的NF-κB途径，同时激活通过Ripopopoptosom体激活额外的蛋白质途径。组蛋白脱乙酰基酶抑制剂（HDACIS）调节许多非固定底物的基因表达和乙酰化。值得注意的是，HDACI Panobinostat（PB）最近有了我们在MM中获得了批准（蛋白酶体抑制剂； PIS）。最近，我们和其他人表明，HDACIS在调节NF-κB和外部凋亡途径中起着重要作用。在这里，我们提出了一种新型机制驱动的策略，该策略将SMS与MM中的HDACI相结合，基于多种互补的理由，即a）SMS和HDACIS目标共同信号级联，并组合仅抑制规范和非官方的NF-κB途径，同时激活固有和外源和外源性的Apoptopic pathocation pation途径； b）由于经常遗传像差和骨髓微环境因素，在MM细胞中始终激活NF-κB； C）NF-κB抑制（例如，PIS）显着增加了MM的HDACI活性。确实，初步证据表明，在各种MM细胞类型中，SMS和HDACIS之间的高度协同相互作用。为了推进这一新颖的概念，提出了三个目标。在特定的目标＃1中，我们将定义MOAS SMS潜在的HDACI抗MM活性，强调了规范或非规范的NF-κB途径的破坏，并通过Ripopopoptoptoptoptosmos对外部途径的参与。在对传统或新型药物的抗MM细胞中建立方案效率，尤其是通过通过MOAS激活外部凋亡途径激活的异常Bcl-2家族表达而绕过获得的耐药性；确定该策略是否通过中断非典型的NF-κB途径来规避微环境形式的抗药性。在特定的目标＃2中，我们将确定该方案在保留正常细胞时是否有选择地杀死原代MM细胞。检验该策略还靶向MM干细胞样细胞的假设。确定涉及NF-κB或凋亡途径的遗传像差的某些原发性MM细胞亚型是否对该方案特别敏感，如果是，哪些机制正在运行。在特定的目标＃3中，我们将测试该方案在免疫功能低下或免疫功能的MM小鼠模型中是否有效和耐受性，并确定在体内鉴定的MOAS是否在体内工作。如果成功，这些研究将为新的且可能更有效的临床发展提供必要的基础。继电器/难治性MM的个性化治疗策略。