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，例如 LCL161 或 birinopant 等凋亡抑制剂（IAP）拮抗剂/Smac 模拟物（SM）。最初开发的目的是防止 IAP 抑制活化的半胱天冬酶和细胞凋亡，已显示出作为抗癌药物的临床前潜力，包括最近受到关注的多发性骨髓瘤 (MM) 治疗。研究重点是 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。 HDACI 帕比司他 (PB) 最近被批准（与蛋白酶体抑制剂；PI）用于 MM。最近，我们和其他人已经证明 HDACIs 在调节 NF-κB 和外源性细胞凋亡途径中发挥重要作用。基于多种互补原理，将 SM 与 HDACIs 在 MM 中结合的新颖机制驱动策略，即：a) SM 和 HDACIs 靶向共同的信号级联，以及联合使用，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；事实上，初步证据表明 κB 抑制（例如通过 PI）可显着增加 MM 中的 HDACI 活性。为了推进这一新概念，在具体目标 #1 中，我们将定义 SM 增强 HDACI 抗 MM 活性的 MOA，强调破坏经典或非经典 NF-κB。建立途径，通过核糖核酸酶体参与外在途径；对传统或新型药物耐药的 MM 细胞的治疗方案功效，特别是通过绕过异常 Bcl-2 家族导致的获得性耐药性通过 MOAs 激活外源性凋亡途径来表达；确定该策略是否通过中断非经典 NF-κB 途径来规避微环境形式的耐药性。在特定目标 #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；测试该策略也针对 MM 干细胞样细胞的假设，确定是否涉及具有遗传畸变的某些原代 MM 细胞亚型 NF-κB 或细胞凋亡途径对该方案特别敏感，如果是，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 是否有效。如果成功，这些研究将为临床开发一种新的、可能更有效的复发/难治性多发性骨髓瘤个体化治疗策略提供必要的基础。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Recruiting TP53 to target chronic myeloid leukemia stem cells.

招募 TP53 以靶向慢性粒细胞白血病干细胞。

DOI：
发表时间：
2020
期刊：
影响因子：
10.1
作者：
Grant; Steven
通讯作者：
Steven

Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models.

在急性髓系白血病模型中，Venetoclax 联合靶向 BCL2，cobimetinib 联合靶向 MAPK 信号。

DOI：
发表时间：
2020
期刊：
影响因子：
10.1
作者：
Han, Lina;Zhang, Qi;Dail, Monique;Shi, Ce;Cavazos, Antonio;Ruvolo, Vivian R;Zhao, Yang;Kim, Eugene;Rahmani, Mohamed;Mak, Duncan H;Jin, Sha S;Chen, Jun;Phillips, Darren C;Koller, Paul Bottecelli;Jacamo, Rodrigo;Burks, Jared K;DiNardo, Court
通讯作者：
DiNardo, Court

Targeting cereblon in AML.

AML 中的靶向 cereblon。