Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates
使用刷状结构的聚(乙二醇)-DNA 缀合物靶向致癌 KRAS
基本信息
- 批准号:10430047
- 负责人:
- 金额:$ 36.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-06 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAnimal Cancer ModelAnimal ModelAntisense OligonucleotidesArchitectureArea Under CurveAutomobile DrivingBindingBiodistributionBiological ProductsBlood Coagulation DisordersCancer ModelCancer cell lineCell ProliferationCellsCellular biologyCharacteristicsChemicalsChemistryClinicClinicalClinical ResearchColorectal CancerDNADataDeoxyribonucleasesDevelopmentDrug KineticsEffectivenessExhibitsGene Expression RegulationGenesGenetically Engineered MouseGoalsHalf-LifeHumanImmune systemImmunizationInflammationIntracellular TransportIntravenousInvestigationKidneyLiverLung AdenocarcinomaMEKsMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of pancreasMediatingMessenger RNAMethodsModalityModelingMusMutateMutationNon-Small-Cell Lung CarcinomaNucleic AcidsOligonucleotidesOncogenesOncogenicOncoproteinsOutcomePatientsPharmaceutical PreparationsPharmacologic SubstancePharmacologyPlasmaPolyethylene GlycolsPolymersPre-Clinical ModelPropertyProteinsRAS Family GeneRattusRefractoryResearchRibonuclease HSafetySideSignal PathwaySignal TransductionStructureTherapeutic AgentsTherapeutic InterventionToll-like receptorsToxic effectTranslatingTranslationsTumor SuppressionTumor-DerivedValidationViral OncogeneWorkXenograft ModelXenograft procedureacute toxicityalternative treatmentbiological systemscancer celldosageethylene glycolimprovedin vivoinhibitorinsightknock-downlung cancer cellmouse modelmutantnanoparticleneoplastic cellnovelnucleic acid-based therapeuticspatient derived xenograft modelpharmacokinetics and pharmacodynamicspre-clinicalpreventsarcomaside effectsingle moleculesmall moleculesmall molecule inhibitorstemsubcutaneoustherapeutic DNAthree dimensional cell culturethree-dimensional modelingtraffickingtreatment strategytumortumor microenvironmentuptake
项目摘要
Project Summary/Abstract
Mutant forms of KRAS are a key driver in human tumors but remains refractory to therapeutic intervention
despite over three decades of research. Clinical attempts to directly or indirectly inhibit KRAS function have
both yielded unsatisfactory results. The difficulty for developing small molecule KRAS inhibitors has heightened
the importance of alternative methods targeting the oncogene. One such strategy involves therapeutic nucleic
acids, which make it possible to deplete target proteins that are intractable to conventional drug modalities. We
have developed a novel form of nucleic acid therapeutics, termed pacDNA, that substantially enhances the
antitumor activity of nucleic acid drugs by elevating in vivo stability, accelerating cellular uptake, and improving
plasma pharmacokinetics and tumor accumulation, allowing a much lower dosage to be used compared to
conventional methods. The pacDNA also suppresses nearly all side effects associated with traditional nucleic
acid drugs by reducing unwanted nucleic acid-protein interactions. In this proposal, we aim to build upon our
promising preliminary results, and gain deeper insights into the cell biology of the pacDNA with respect to cell
uptake mechanism, intracellular trafficking, KRAS depletion and subsequent cell signaling, and demonstrate
efficacy in KRAS-dependent non-small cell lung cancer cell lines and 3D models. In addition, we will study the
primary pharmacology and antitumor activity of pacDNA in advanced preclinical lung cancer models including
an orthotopic tumor model, a patient derived tumor model, and a syngeneic genetically engineered mouse
model (GEMM), and perform initial in vivo safety and tolerability studies. The outcome of this project will be a
safe and potent anti-KRAS agent that can be readily translated into clinical studies for non-small cell lung
cancer and potentially additional cancer classes.
项目概要/摘要
KRAS 突变形式是人类肿瘤的关键驱动因素,但仍然难以治疗干预
尽管进行了三十多年的研究。直接或间接抑制 KRAS 功能的临床尝试
两者都取得了不令人满意的结果。小分子KRAS抑制剂开发难度加大
针对癌基因的替代方法的重要性。其中一种策略涉及治疗性核酸
酸,可以消除传统药物难以处理的靶蛋白。我们
开发了一种新型核酸疗法,称为 pacDNA,它大大增强了
通过提高体内稳定性、加速细胞摄取、改善核酸药物的抗肿瘤活性
血浆药代动力学和肿瘤蓄积,与相比允许使用低得多的剂量
常规方法。 pcDNA 还抑制了与传统核酸相关的几乎所有副作用
酸药物通过减少不需要的核酸-蛋白质相互作用。在本提案中,我们的目标是在我们的基础上
有希望的初步结果,并深入了解 pacDNA 的细胞生物学
摄取机制、细胞内运输、KRAS 消耗和随后的细胞信号传导,并证明
在 KRAS 依赖性非小细胞肺癌细胞系和 3D 模型中的功效。此外,我们还将研究
pacDNA 在晚期临床前肺癌模型中的主要药理学和抗肿瘤活性,包括
原位肿瘤模型、患者来源的肿瘤模型和同基因基因工程小鼠
模型(GEMM),并进行初步的体内安全性和耐受性研究。该项目的成果将是
安全有效的抗 KRAS 药物,可轻松转化为非小细胞肺的临床研究
癌症和潜在的其他癌症类别。
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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{{ truncateString('Ke Zhang', 18)}}的其他基金
Development of a highly sensitive and specific POCT testing asthma triggering allergic IgE
开发高度敏感和特异的 POCT 测试哮喘触发过敏性 IgE
- 批准号:
10600767 - 财政年份:2023
- 资助金额:
$ 36.72万 - 项目类别:
Development of a highly sensitive and specific POCT testing asthma triggering allergic IgE
开发高度敏感和特异的 POCT 测试哮喘触发过敏性 IgE
- 批准号:
10817658 - 财政年份:2023
- 资助金额:
$ 36.72万 - 项目类别:
Molecular brush-conjugated antisense oligonucleotide as a pan-KRAS depletion agent
分子刷偶联反义寡核苷酸作为泛 KRAS 耗竭剂
- 批准号:
10771051 - 财政年份:2022
- 资助金额:
$ 36.72万 - 项目类别:
Molecular brush-conjugated antisense oligonucleotide as a pan-KRAS depletion agent
分子刷偶联反义寡核苷酸作为泛 KRAS 耗竭剂
- 批准号:
10544115 - 财政年份:2022
- 资助金额:
$ 36.72万 - 项目类别:
Molecular brush-conjugated antisense oligonucleotide as a pan-KRAS depletion agent
分子刷偶联反义寡核苷酸作为泛 KRAS 耗竭剂
- 批准号:
10896563 - 财政年份:2022
- 资助金额:
$ 36.72万 - 项目类别:
Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates
使用刷状结构的聚(乙二醇)-DNA 缀合物靶向致癌 KRAS
- 批准号:
10653706 - 财政年份:2020
- 资助金额:
$ 36.72万 - 项目类别:
Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates
使用刷状结构的聚(乙二醇)-DNA 缀合物靶向致癌 KRAS
- 批准号:
10210369 - 财政年份:2020
- 资助金额:
$ 36.72万 - 项目类别:
Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates
使用刷状结构的聚(乙二醇)-DNA 缀合物靶向致癌 KRAS
- 批准号:
10035113 - 财政年份:2020
- 资助金额:
$ 36.72万 - 项目类别:
Making Oligonucleotides Better Biopharmaceuticals by Steric Protection
通过空间保护使寡核苷酸成为更好的生物制药
- 批准号:
10659672 - 财政年份:2017
- 资助金额:
$ 36.72万 - 项目类别:
Making Oligonucleotides Better Biopharmaceuticals by Steric Protection
通过空间保护使寡核苷酸成为更好的生物制药
- 批准号:
10259829 - 财政年份:2017
- 资助金额:
$ 36.72万 - 项目类别: