Ligand-Directed KRAS G12V Mutant-Specific Therapeutics
配体导向的 KRAS G12V 突变特异性治疗
基本信息
- 批准号:10757070
- 负责人:
- 金额:$ 27.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-05 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAccelerationAddressAffinityBiodistributionBiologicalCancer EtiologyCancer ModelCancer cell lineCell ProliferationCessation of lifeCharacteristicsChemicalsChemistryCirculationColonDataDevelopmentDrug KineticsDrug TargetingEndosomesEpidermal Growth Factor ReceptorExhibitsGenesGenetic EngineeringGrowthHalf-LifeHepatocyteHourHumanImmuneIn VitroInvestigational DrugsInvestigational New Drug ApplicationKRAS oncogenesisKRAS2 geneKidneyLeadLibrariesLigandsLiquid substanceLiverLungLung AdenocarcinomaLung NeoplasmsMAP Kinase GeneMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of pancreasModelingModificationMolecularMolecular AbnormalityMusMutationNon-MalignantNucleic AcidsNucleotidesOligonucleotidesOncogenicOperative Surgical ProceduresOrganPIK3CG genePancreasPathway interactionsPharmacodynamicsPhasePhosphorylationProteinsProto-OncogenesRNA InterferenceReadinessSafetySerumSignal TransductionSmall Business Innovation Research GrantSmall Interfering RNATechnologyTestingTherapeuticThermodynamicsTissuesToxic effectTranscriptTumor BurdenUnited StatesVertebral columnXenograft Modelcancer cellcancer therapyfeasibility testingimprovedin vivokinase inhibitorknock-downlipid nanoparticlelocked nucleic acidlung cancer cellmortalitymouse modelmutantneoplastic cellnovelnovel therapeutic interventionpatient derived xenograft modelpharmacokinetics and pharmacodynamicsphase 2 studyphase 2 testingphosphorothioatepreservationprogramssafety assessmentsafety studyscale upsmall moleculesubcutaneoussuccesstargeted treatmenttumor
项目摘要
Project Summary
The proto-oncogene KRAS is one of the most critical genes in cancer, yet, as a drug target, it has proven
to be among the most elusive. A remarkable 30% of lung adenocarcinomas, 45% of colon, and 98% of pancreatic
cancers are driven by KRAS mutations. These cancers account for the top 3 causes of cancer-related
deaths in the United States. Most cancer associated KRAS mutations result in a constitutively active protein,
which drives aberrantly high downstream signaling of pro-proliferative and pro-survival effectors including the
MAPK and PI3K pathways. Kinase inhibitors have revolutionized treatment of many cancers driven by other
molecular aberrations, yet, unfortunately a lack of such success in KRAS-driven cancers has led to KRAS
itself to be widely regarded as “undruggable”. EnFuego Therapeutics, Inc. (EFTX) was founded to address
the growing number of “undruggable” targets in cancer using RNA interference (RNAi)-based therapeutics. RNAi
is particularly attractive for KRAS targeting because it can be optimized to enable selective silencing of mutant
transcripts while sparing wild type transcripts, which is important for maintaining normal function in nonmalignant
tissue. Mutation-specific therapeutics against KRAS are under development by several companies such as
Amgen and Mirati, and rely on small molecules (specific only to G12C mutations). Unlike prior RNAi strategies
in cancer, the EFTX approach employs nucleotide modification and ligand conjugation chemistries to promote
in vivo stability and affinity-based targeting in cancer cells. In particular, ligand conjugation represents a
significant advantage over legacy delivery technologies such as lipid nanoparticles. We have shown that
EnFuego siRNAs targeting mutant KRAS transcripts result in: 1) reduced oncogenic MAPK signaling, 2) reduced
cancer cell proliferation, and 3) reduced tumor burden in murine cancer models. Based on these preliminary
data, this Fast Track program will further develop EFTX siRNA technologies for targeting mutant KRAS in
humans. During Phase I, we will focus on optimization of fully chemically modified (FM) siRNA compounds that
potently and specifically silence mutant G12V transcripts, exhibit serum stability and immune stealth, and inhibit
downstream cancer cell signaling. Two to three FM siRNAs will be selected as lead compound candidates for
progression to Phase II studies. Phase II Specific Aims will focus on optimization of pharmacokinetics, tissue
targeting, and efficacy in murine models of metastatic lung cancer. These data will inform the selection of a single
candidate for scale up and a 4-week GLP safety assessment study. As such, this Fast Track program will
accelerate progression of this novel therapeutic strategy toward filing an Investigational New Drug application
for metastatic lung cancer therapy.
项目总结
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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Chad V Pecot其他文献
Chad V Pecot的其他文献
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{{ truncateString('Chad V Pecot', 18)}}的其他基金
Circle RNA Regulation of Lung Cancer Metastasis
Circle RNA对肺癌转移的调控
- 批准号:
10637900 - 财政年份:2023
- 资助金额:
$ 27.56万 - 项目类别:
Development of EFTX-001 to target KRAS mutations in cancer
开发 EFTX-001 以靶向癌症中的 KRAS 突变
- 批准号:
9906510 - 财政年份:2020
- 资助金额:
$ 27.56万 - 项目类别:
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