Development of novel protein-based therapeutics for lung cancer
开发基于蛋白质的新型肺癌疗法
基本信息
- 批准号:10373026
- 负责人:
- 金额:$ 55.26万
- 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:2018-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAnimal ModelBindingBiochemicalBiologicalBiological AssayBiomedical EngineeringBiophysicsCRISPR screenCRISPR/Cas technologyCancer EtiologyCancer ModelCancer cell lineCell Surface ReceptorsCellsCessation of lifeCharacteristicsCiliary Neurotrophic FactorCiliary Neurotrophic Factor ReceptorClinicalCombined Modality TherapyComplementComplexCritical PathwaysDataDevelopmentDrug KineticsEffectivenessEngineeringEtanerceptFDA approvedFamilyFibroblastsGenetic EngineeringGenetically Engineered MouseGoalsGrowthHuman Cell LineIL6 geneIL6ST geneIn VitroLIFR geneLaboratoriesLibrariesLigandsMAP Kinase GeneMalignant NeoplasmsMalignant neoplasm of lungMeasuresMediatingModelingNon-Small-Cell Lung CarcinomaOncogenicOutcomePatientsPharmaceutical PreparationsPharmacologyPhosphorylationPre-Clinical ModelPropertyProtein EngineeringProteinsProteomicsPublishingReceptor SignalingRoleSignal PathwaySignal TransductionSurfaceTestingTherapeuticTherapeutic InterventionTimeToxic effectTreatment EfficacyValidationWorkXenograft Modeladvanced diseaseanti-cancer therapeuticbasecancer therapyclinical developmentcombinatorialcytokinecytokine-like factor-1designdrug candidatedrug developmentfunctional genomicsgenetic approachimmunogenicityimmunoregulationin vivoinnovationknock-downlung cancer cellmanufacturabilitymouse modelneoplastic cellneutralizing antibodynew therapeutic targetnoveloverexpressionpatient derived xenograft modelpre-clinicalpreclinical studyreceptorsmall hairpin RNAtargeted treatmenttherapeutic candidatetherapeutic developmenttherapeutic evaluationtherapeutically effectivetranslational potentialtreatment strategytumortumor growthtumor progression
项目摘要
Lung cancer is the leading cause of cancer deaths worldwide. The most prevalent type of lung cancer is Non-
Small Cell Lung Cancer (NSCLC). The goal of this application is to implement a collaborative effort involving
preclinical models, bioengineering and functional genomics to further characterize and validate a novel “first in
class” therapeutic strategy for the treatment of lung cancer. Our prior published work and extensive
preliminary data indicates that blockade of CLCF1-CNTFR signaling represents a unique and previously
unexplored approach for lung cancer therapy. The Sweet-Cordero and Cochran laboratories have
collaborated extensively over the past several years to validate this signaling axis, first with shRNA genetic
approaches, and now through the development of an engineered CNTFR receptor decoy (eCNTFR). In Aim 1,
we will further develop eCNTFR as a therapeutic candidate by measuring its thermal and proteolytic stability,
potential for immunogenicity and toxicity, manufacturability, and pharmacokinetics, and will optimize these
properties as needed. We will also perform structural analysis of eCNTFR in complex with CLCF1 to define
high affinity binding characteristics. Lastly, we will test eCNTFR for therapeutic efficacy across a wide array of
preclinical models of NSCLC including human cell lines and patient-derived xenografts. In Aim 2, we will
perform in vitro biochemical assays to fully define the cell-autonomous mechanism of action of eCNTFR
blockade. To further understand the mechanism of action of eCNTFR in vivo, we will complement xenograft
models with a well-characterized genetically engineered mouse model of lung cancer. Importantly, this model
will allow us to study the effects of eCNTFR not only on tumor cells but also on the microenvironment, and to
assess whether eCNTFR has immunomodulatory effects. In Aim 3, we will identify the most effective
combination approaches to enhance eCNTFR therapy. These efforts will be carried out in a rational and
unbiased manner by leveraging CRISPR/CAS9 using a library directed specifically at the targets of FDA
approved drugs. Candidate combination therapies will then be tested in animal models. Our studies will
elucidate critical biological underpinnings of this ligand/receptor signaling axis, and will provide preclinical
validation of an innovative strategy for targeting lung cancer to warrant its further clinical development.
肺癌是全球癌症死亡的主要原因。肺癌的早期症状有哪些?
小细胞肺癌(NSCLC)。这个应用程序的目标是实现一个协作工作,
临床前模型,生物工程和功能基因组学,以进一步表征和验证一种新的“首次在
肺癌的治疗策略。我们先前发表的工作和广泛的
初步数据表明,CLCF 1-CNTFR信号传导的阻断代表了一种独特的,
肺癌的治疗方法。Sweet-Cordero和Cochran实验室
在过去的几年里,他们进行了广泛的合作,以验证这一信号轴,首先是用shRNA遗传学。
方法,现在通过开发工程CNTFR受体诱饵(eCNTFR)。在目标1中,
我们将通过测量其热稳定性和蛋白水解稳定性来进一步开发eCNTFR作为治疗候选物,
潜在的免疫原性和毒性、可制造性和药代动力学,并将优化这些
所需的属性。我们还将对eCNTFR与CLCF 1的复合物进行结构分析,以确定
高亲和力结合特性。最后,我们将测试eCNTFR在各种各样的治疗效果。
NSCLC的临床前模型,包括人细胞系和患者来源的异种移植物。在目标2中,我们将
进行体外生化试验,以充分确定eCNTFR的细胞自主作用机制
封锁为了进一步了解eCNTFR在体内的作用机制,我们将补充异种移植
用一个良好表征的肺癌基因工程小鼠模型。重要的是,这种模式
将使我们能够研究eCNTFR不仅对肿瘤细胞而且对微环境的影响,并
评估eCNTFR是否具有免疫调节作用。在目标3中,我们将确定最有效的
组合方法来增强eCNTFR治疗。这些努力将以合理和
通过利用CRISPR/CAS9使用专门针对FDA目标的库,
批准的药物。然后将在动物模型中测试候选组合疗法。我们的研究将
阐明这种配体/受体信号传导轴的关键生物学基础,并将提供临床前
验证靶向肺癌的创新策略,以保证其进一步的临床开发。
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)
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MICHAEL C BASSIK其他文献
MICHAEL C BASSIK的其他文献
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{{ truncateString('MICHAEL C BASSIK', 18)}}的其他基金
High-throughput development and characterization of compact tools for transcriptional and chromatin perturbations
用于转录和染色质扰动的紧凑工具的高通量开发和表征
- 批准号:
10632140 - 财政年份:2021
- 资助金额:
$ 55.26万 - 项目类别:
Project 3: Systematic characterization of factors controlling breast cancer progression and resistance
项目3:控制乳腺癌进展和耐药因素的系统表征
- 批准号:
10704691 - 财政年份:2021
- 资助金额:
$ 55.26万 - 项目类别:
Project 3: Systematic characterization of factors controlling breast cancer progression and resistance
项目3:控制乳腺癌进展和耐药因素的系统表征
- 批准号:
10272391 - 财政年份:2021
- 资助金额:
$ 55.26万 - 项目类别:
Project 3: Systematic characterization of factors controlling breast cancer progression and resistance
项目3:控制乳腺癌进展和耐药因素的系统表征
- 批准号:
10911510 - 财政年份:2021
- 资助金额:
$ 55.26万 - 项目类别:
High-throughput development and characterization of compact tools for transcriptional and chromatin perturbations
用于转录和染色质扰动的紧凑工具的高通量开发和表征
- 批准号:
10276866 - 财政年份:2021
- 资助金额:
$ 55.26万 - 项目类别:
High-throughput systematic characterization of regulatory element function
调控元件功能的高通量系统表征
- 批准号:
10238366 - 财政年份:2020
- 资助金额:
$ 55.26万 - 项目类别:
Development of novel protein-based therapeutics for lung cancer
开发基于蛋白质的新型肺癌疗法
- 批准号:
10133002 - 财政年份:2018
- 资助金额:
$ 55.26万 - 项目类别:
Development of novel protein-based therapeutics for lung cancer
开发基于蛋白质的新型肺癌疗法
- 批准号:
9894638 - 财政年份:2018
- 资助金额:
$ 55.26万 - 项目类别:
High-throughput systematic characterization of regulatory element function
调控元件功能的高通量系统表征
- 批准号:
9247643 - 财政年份:2017
- 资助金额:
$ 55.26万 - 项目类别:
Using Protein Interaction Networks and Combinatorial Screens to target KRAS driven cancer
使用蛋白质相互作用网络和组合筛选来靶向 KRAS 驱动的癌症
- 批准号:
9315124 - 财政年份:2015
- 资助金额:
$ 55.26万 - 项目类别:
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