Exploiting myeloma proteome remodeling to extend proteasome inhibitor efficacy
利用骨髓瘤蛋白质组重塑来延长蛋白酶体抑制剂的功效
基本信息
- 批准号:10341162
- 负责人:
- 金额:$ 27.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-03-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAddressAlternative SplicingApoptosisApoptoticArchitectureBiochemicalBiological AssayBortezomibCRISPR interferenceCell DeathCell LineCellsCellular biologyClinicalClinical TrialsComplexDataDiagnosisDiseaseEventExonsExposure toFDA approvedFamilyGeneticGenetic TranscriptionGoalsHeat shock proteinsHeat-Shock Proteins 70Hematologic NeoplasmsHematopoietic NeoplasmsImmunoglobulinsIntronsInvestigationKineticsLeadLongevityMalignant - descriptorMalignant NeoplasmsMass Spectrum AnalysisMediatingMethodsModificationMolecular ChaperonesMonitorMultiple MyelomaMutationOutcomePathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhosphorylationPhysiologic pulsePlasma CellsPost-Translational Protein ProcessingProteasome InhibitionProteasome InhibitorProtein BiosynthesisProteinsProteomeProteomicsRNA SplicingRefractoryRelapseResistanceRoleSamplingSignal TransductionSpliceosomesSystemTherapeuticTimeTranscriptTreatment EfficacyUbiquitinbasecell typeclinically relevantcombatfollow-upfunctional genomicsgenomic dataimprovedin vivo Modelinhibitorinsightknock-downmRNA Precursormouse modelmulticatalytic endopeptidase complexneoplastic cellnovelnovel therapeutic interventionnovel therapeuticsphosphoproteomicspre-clinicalprotein degradationprotein foldingproteostasisresponsesmall molecule inhibitorsynergismtherapy resistanttooltranscriptome sequencingtreatment strategyvalosin-containing protein
项目摘要
PROJECT SUMMARY/ABSTRACT
Multiple myeloma is an aggressive hematologic malignancy that remains incurable despite recent progress.
This disease of malignant plasma cells is fundamentally associated with aberrant protein homeostasis, defined
by an extremely high burden of immunoglobulin synthesis. Proteasome inhibitors (PIs), a widely-used first-line
therapy in myeloma, are thought to directly take advantage of this aberrancy by increasing unfolded protein
stress leading to cell death. However, this mechanism is not fully proven, and further insight into PI-induced
cell death may lead to more effective combination strategies. In addition, PI resistance is a major clinical
problem in myeloma, and new strategies are needed to overcome this condition. Here, we hypothesize that
the remodeling of the plasma cell proteome after therapy is central to both PI response and resistance. We
specifically propose that proteome remodeling is mediated through rewiring of proteostasis pathways involving
chaperones, the VCP/p97 complex, and the ubiquitin-proteasome system, as well as through changes to the
alternative splicing landscape, as mediated by post-translational modification of the splicing machinery. To
explore this hypothesis we will take advantage of novel pharmacologic and genetic perturbation tools, cellular
and biochemical assays, in vivo models, clinical trial genomic data, primary sample analysis, RNA sequencing,
and mass spectrometry approaches. The overall goals of this proposal are 1) develop new therapy strategies
either in combination with PIs or in the PI-refractory setting, and 2) describe a new, systematic approach to
probe the architecture of proteostasis networks. Importantly, our preliminary results challenge existing
paradigms related to PI efficacy. In Aim 1, we address paradoxical findings relating the unfolded protein
response, the interaction between the p97 degradation machinery and PIs, and the relevance of inducible
HSP-family chaperones. We will take advantage of novel pharmacology available to us, including active site
and allosteric inhibitors of p97 and allosteric inhibitors of HSP70, in combination with functional genetics by
CRISPR interference, to define the role of central protein homeostasis nodes defining PI response and
resistance. Furthermore, we will use our unique expertise in pulsed-SILAC proteomics to determine specific
substrates of the p97 machinery and the proteasome in the presence of clinically-relevant resistance
modifications. Toward Aim 2, our preliminary studies using unbiased mass spectrometry have revealed
significant phosphorylation of the spliceosome after PI treatment. We first aim to characterize the relationship
between specific alternative splicing events and proteome remodeling after PIs. We then aim to extend our
promising preliminary data demonstrating the efficacy of splicing inhibitors as a new anti-myeloma therapy.
Overall, the studies here will have a direct impact on delineating the surprisingly broad range of PI-mediated
effects in plasma cells, validate the novel therapeutic strategy of splicing inhibition, and reveal new mechanistic
approaches to dissect proteostasis networks and alternative splicing that could extend far beyond myeloma.
项目总结/摘要
多发性骨髓瘤是一种侵袭性血液系统恶性肿瘤,尽管最近取得了进展,但仍然无法治愈。
这种恶性浆细胞疾病从根本上与异常的蛋白质稳态有关,
免疫球蛋白合成的高负荷。蛋白酶体抑制剂(PI),广泛使用的一线药物
骨髓瘤的治疗,被认为是直接利用这种异常,通过增加未折叠蛋白质
压力导致细胞死亡。然而,这一机制尚未得到充分证明,进一步了解PI诱导的
细胞死亡可能导致更有效的组合策略。此外,PI耐药是主要的临床
骨髓瘤的问题,需要新的策略来克服这种情况。在这里,我们假设,
治疗后浆细胞蛋白质组的重塑是PI应答和抵抗的中心。我们
特别提出蛋白质组重塑是通过蛋白质抑制途径的重新布线介导的,
分子伴侣,VCP/p97复合物和泛素-蛋白酶体系统,以及通过改变
选择性剪接景观,由剪接机制的翻译后修饰介导。到
探索这一假设,我们将利用新的药理学和遗传扰动工具,细胞
和生物化学测定,体内模型,临床试验基因组数据,原始样品分析,RNA测序,
和质谱分析方法。该提案的总体目标是:1)开发新的治疗策略
与PI联合使用或在PI难治性环境中使用,以及2)描述一种新的系统性方法,
探索蛋白质稳定网络的结构。重要的是,我们的初步结果挑战了现有的
与PI疗效相关的范例。在目标1中,我们解决了与未折叠蛋白质相关的矛盾发现,
反应,p97降解机制和PI之间的相互作用,以及诱导的
HSP-家族分子伴侣。我们将利用新的药理学提供给我们,包括活性位点,
以及p97的变构抑制剂和HSP 70的变构抑制剂,与功能遗传学结合,
CRISPR干扰,以定义定义PI反应的中心蛋白质稳态节点的作用,
阻力此外,我们将利用我们在脉冲SILAC蛋白质组学方面的独特专长,
p97机制和蛋白酶体的底物在临床相关耐药性的存在下
修改.为了实现目标2,我们使用无偏质谱法进行的初步研究表明,
PI处理后剪接体的显著磷酸化。我们首先要描述
特异性选择性剪接事件与PI后蛋白质组重塑之间的关系。我们的目标是扩大我们的
令人鼓舞的初步数据证明了剪接抑制剂作为一种新的抗骨髓瘤疗法的功效。
总的来说,这里的研究将对描绘PI介导的令人惊讶的广泛范围产生直接影响。
在浆细胞中的作用,验证了剪接抑制的新治疗策略,并揭示了新的机制,
研究蛋白质稳态网络和选择性剪接的方法可能远远超出骨髓瘤。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Arun P. Wiita其他文献
Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia
针对 CLL-1 的细胞免疫疗法用于幼年型粒单核细胞白血病
- DOI:
10.1038/s41467-025-59040-6 - 发表时间:
2025-04-23 - 期刊:
- 影响因子:15.700
- 作者:
Juwita Werner;Alex G. Lee;Chujing Zhang;Sydney Abelson;Sherin Xirenayi;Jose Rivera;Khadija Yousuf;Hanna Shin;Bonell Patiño-Escobar;Stefanie Bachl;Kamal Mandal;Abhilash Barpanda;Emilio Ramos;Adila Izgutdina;Sibapriya Chaudhuri;William C. Temple;Shubhmita Bhatnagar;Jackson K. Dardis;Julia Meyer;Carolina Morales;Soheil Meshinchi;Mignon L. Loh;Benjamin Braun;Sarah K. Tasian;Arun P. Wiita;Elliot Stieglitz - 通讯作者:
Elliot Stieglitz
Bladder cancer variants share aggressive features including a CA125+ cell state and targetable TM4SF1 expression
膀胱癌变异体具有侵袭性特征,包括 CA125+细胞状态和可靶向的 TM4SF1 表达
- DOI:
10.1038/s41467-025-59888-8 - 发表时间:
2025-06-17 - 期刊:
- 影响因子:15.700
- 作者:
Heiko Yang;Hanbing Song;Elizabeth Yip;Timothy Gilpatrick;Kevin Chang;Paul Allegakoen;Kevin L. Lu;Keliana Hui;Julia H. Pham;Corynn Kasap;Vipul Kumar;Janae Gayle;Bradley A. Stohr;Chien-Kuang Cornelia Ding;Arun P. Wiita;Maxwell V. Meng;Jonathan Chou;Sima P. Porten;Franklin W. Huang - 通讯作者:
Franklin W. Huang
Time-resolved proteomics vs. ribosome profiling reveals translation dynamics under stress
时间分辨蛋白质组学与核糖体分析揭示了压力下的翻译动态
- DOI:
10.1101/087486 - 发表时间:
2016 - 期刊:
- 影响因子:0
- 作者:
Tzu;Hector H. Huang;Diamond Wheeler;James A. Wells;Yun S. Song;Arun P. Wiita - 通讯作者:
Arun P. Wiita
Tumour-wide RNA splicing aberrations generate actionable public neoantigens
肿瘤范围的 RNA 剪接异常产生可操作的公共新抗原
- DOI:
10.1038/s41586-024-08552-0 - 发表时间:
2025-02-19 - 期刊:
- 影响因子:48.500
- 作者:
Darwin W. Kwok;Nicholas O. Stevers;Iñaki Etxeberria;Takahide Nejo;Maggie Colton Cove;Lee H. Chen;Jangham Jung;Kaori Okada;Senthilnath Lakshmanachetty;Marco Gallus;Abhilash Barpanda;Chibo Hong;Gary K. L. Chan;Jerry Liu;Samuel H. Wu;Emilio Ramos;Akane Yamamichi;Payal B. Watchmaker;Hirokazu Ogino;Atsuro Saijo;Aidan Du;Nadia R. Grishanina;James Woo;Aaron Diaz;Shawn L. Hervey-Jumper;Susan M. Chang;Joanna J. Phillips;Arun P. Wiita;Christopher A. Klebanoff;Joseph F. Costello;Hideho Okada - 通讯作者:
Hideho Okada
DNA methyltransferase inhibitors upregulate CD38 protein expression and enhance daratumumab efficacy in multiple myeloma
DNA 甲基转移酶抑制剂上调多发性骨髓瘤中 CD38 蛋白表达并增强达雷木单抗疗效
- DOI:
10.1038/s41375-019-0587-5 - 发表时间:
2019-10-08 - 期刊:
- 影响因子:13.400
- 作者:
Priya Choudhry;Margarette C. Mariano;Huimin Geng;Thomas G. Martin;Jeffrey L. Wolf;Sandy W. Wong;Nina Shah;Arun P. Wiita - 通讯作者:
Arun P. Wiita
Arun P. Wiita的其他文献
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{{ item.author }}
{{ truncateString('Arun P. Wiita', 18)}}的其他基金
Structural Surfaceomics: A Strategy for Immunotherapy Target Discovery
结构表面组学:免疫治疗靶点发现的策略
- 批准号:
10290239 - 财政年份:2021
- 资助金额:
$ 27.82万 - 项目类别:
ClinTAD: A Tool for Improving Clinical CNV Interpretation
ClinTAD:改善临床 CNV 解读的工具
- 批准号:
10461112 - 财政年份:2021
- 资助金额:
$ 27.82万 - 项目类别:
Exploiting myeloma proteome remodeling to extend proteasome inhibitor efficacy
利用骨髓瘤蛋白质组重塑来延长蛋白酶体抑制剂的功效
- 批准号:
10308238 - 财政年份:2021
- 资助金额:
$ 27.82万 - 项目类别:
Structural Surfaceomics: A Strategy for Immunotherapy Target Discovery
结构表面组学:免疫治疗靶点发现的策略
- 批准号:
10434121 - 财政年份:2021
- 资助金额:
$ 27.82万 - 项目类别:
ClinTAD: A Tool for Improving Clinical CNV Interpretation
ClinTAD:改善临床 CNV 解读的工具
- 批准号:
10286951 - 财政年份:2021
- 资助金额:
$ 27.82万 - 项目类别:
Exploiting myeloma proteome remodeling to extend proteasome inhibitor efficacy
利用骨髓瘤蛋白质组重塑来延长蛋白酶体抑制剂的功效
- 批准号:
10524110 - 财政年份:2018
- 资助金额:
$ 27.82万 - 项目类别:
In vivo monitoring of oxidative protein folding through time-resolved quantitative mass spectrometry
通过时间分辨定量质谱法体内监测氧化蛋白折叠
- 批准号:
9167306 - 财政年份:2016
- 资助金额:
$ 27.82万 - 项目类别:
Global Assessment of Myeloma Response to Chemotherapy
骨髓瘤化疗反应的整体评估
- 批准号:
8819976 - 财政年份:2014
- 资助金额:
$ 27.82万 - 项目类别:
Global Assessment of Myeloma Response to Chemotherapy
骨髓瘤化疗反应的整体评估
- 批准号:
8928081 - 财政年份:2014
- 资助金额:
$ 27.82万 - 项目类别:
Global Assessment of Myeloma Response to Chemotherapy
骨髓瘤化疗反应的整体评估
- 批准号:
9337420 - 财政年份:2014
- 资助金额:
$ 27.82万 - 项目类别:
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