Development of Novel Combination Strategies to Overcome Resistance to KRASG12C Inhibition in Colorectal Cancers
开发新的组合策略来克服结直肠癌对 KRASG12C 抑制的耐药性
基本信息
- 批准号:10666698
- 负责人:
- 金额:$ 17.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AntibodiesBiological AvailabilityBiopsyCancer ModelCetuximabClinicalClinical TrialsColorectalColorectal CancerColorectal NeoplasmsCombined Modality TherapyDevelopmentDiagnosisEGFR inhibitionEpidermal Growth Factor ReceptorEvaluationEventExhibitsFRAP1 geneFamily memberGrantHeadInterventionKRAS2 geneLeadLongevityMalignant NeoplasmsMeasuresMediatingMitogen-Activated Protein Kinase KinasesModelingMolecular ProfilingMolecular TargetMusMutateMutationNon-Small-Cell Lung CarcinomaOralPIK3CA genePIK3CG genePathway interactionsPatientsPharmacodynamicsPhasePhosphorylationPrognostic MarkerProtein MicrochipsPublic HealthResistanceRoleSignal TransductionSignaling ProteinSurvival RateTestingTherapeuticTimeXenograft Modelclinical candidatecolon cancer patientscomparative efficacycompare effectivenessdesigneffective therapyefficacy evaluationefficacy testinghead-to-head comparisonimprovedin vivo evaluationinhibitormutantnovelpatient derived xenograft modelpatient prognosisphosphoproteomicspre-clinicalprecision medicineresponsesmall moleculesmall molecule inhibitortargeted agenttherapy outcometreatment strategytumor
项目摘要
PROJECT SUMMARY/ABSTRACT
Patients diagnosed with advanced stage KRAS mutant colorectal cancer have an overall survival of roughly
one year. Despite the emergence of an increased number of molecular targeted agents, the prognosis for
patients with these cancers remains poor with 5-year survival rates of <10%. Recently, progress has been
made in the clinical advancement of therapeutics directed specifically against KRASG12C mutations, which are
present in roughly five percent of colorectal tumors. However, monotherapy trials conducted with KRASG12C
targeted agents, while encouraging, have met with disappointing lack of durable responses, dictating the need
for combination approaches. EGFR is known to reactivate MAPK kinase signaling in response to downstream
intervention, an event that is further complicated by the role of the PI3K/mTOR pathway in mediating
resistance. The central hypothesis of this proposal is that a dual small molecule inhibitor that potently and
selectively targets both EGFR and PI3 kinase represents a viable treatment strategy in combination with the
KRASG12C inhibitor clinical candidate AMG-510. To test this hypothesis, we have designed small molecules that
exhibit potent and selective dual inhibition of EGFR and PI3K family members. We propose to carry out a
mouse trial of our dual EGFR/PI3K lead molecule MTX-531 in combination with AMG-510 in xenograft models
established from patients diagnosed with KRASG12C mutant colorectal cancer. Molecular profiling will be
carried out to elucidate markers that correlate with inherent sensitivity as well as the adaptive signaling
changes that lead to progression. Responder models will be re-evaluated in confirmatory testing in head-to-
head comparison with the combination of cetuximab and AMG-510. The overall objective of this proposal is to
demonstrate preclinical proof of concept for pursuit of this development path to optimize the therapeutic
potential of MTX-531 as a precision medicine approach for the treatment of KRASG12C mutant colorectal
cancer.
项目总结/摘要
诊断为晚期KRAS突变结直肠癌的患者的总生存期约为
一年尽管出现了越来越多的分子靶向药物,
患有这些癌症的患者仍然很差,5年生存率<10%。最近,
在针对KRASG 12 C突变的特异性治疗的临床进展中,
在大约百分之五的结直肠肿瘤中存在。然而,使用KRASG 12 C进行的单药治疗试验
有针对性的代理人,虽然令人鼓舞,但令人失望的是缺乏持久的反应,这表明需要
对于组合方法。已知EGFR响应于下游信号转导而重新激活MAPK激酶信号传导。
干预,这是一个事件,进一步复杂化的作用PI 3 K/mTOR途径介导的
阻力这一提议的中心假设是,一种双重小分子抑制剂,
选择性靶向EGFR和PI 3激酶代表了一种可行的治疗策略,
KRASG 12 C抑制剂临床候选药物AMG-510。为了验证这一假设,我们设计了一些小分子,
表现出对EGFR和PI 3 K家族成员的有效和选择性双重抑制。我们建议进行一项
我们的EGFR/PI 3 K双重先导分子MTX-531联合AMG-510在异种移植模型中的小鼠试验
从诊断为KRASG 12 C突变结直肠癌的患者建立。分子分析将是
进行阐明与固有敏感性以及适应性信号相关的标记物,
这些变化导致进步。应答者模型将在头对头验证性试验中重新评价,
与西妥昔单抗和AMG-510联合治疗的头部比较。本建议的总体目标是
证明了追求这一开发路径的临床前概念验证,以优化治疗
MTX-531作为治疗KRASG 12 C突变结直肠癌的精确药物方法的潜力
癌
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Judith S Leopold其他文献
Judith S Leopold的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Judith S Leopold', 18)}}的其他基金
Development of Novel Combination Strategies to Overcome Resistance to KRASG12C Inhibition in Colorectal Cancers
开发新的组合策略来克服结直肠癌对 KRASG12C 抑制的耐药性
- 批准号:
10512415 - 财政年份:2022
- 资助金额:
$ 17.87万 - 项目类别:
Development of Novel Therapeutic Molecules for Treatment of Squamous Head and Neck Cancers
开发治疗鳞状头颈癌的新型治疗分子
- 批准号:
10666868 - 财政年份:2022
- 资助金额:
$ 17.87万 - 项目类别:
Development of Novel Therapeutic Molecules for Treatment of Squamous Head and Neck Cancers
开发治疗鳞状头颈癌的新型治疗分子
- 批准号:
10325253 - 财政年份:2021
- 资助金额:
$ 17.87万 - 项目类别:
Combating Resistance of Pancreatic Cancer with a First-in-Class Dual Targeted PI3K/EGFR Inhibitor
使用一流的双靶向 PI3K/EGFR 抑制剂对抗胰腺癌耐药性
- 批准号:
10197037 - 财政年份:2019
- 资助金额:
$ 17.87万 - 项目类别:
Combating Resistance of Pancreatic Cancer with a First-in-Class Dual Targeted PI3K/EGFR Inhibitor
使用一流的双靶向 PI3K/EGFR 抑制剂对抗胰腺癌耐药性
- 批准号:
10652462 - 财政年份:2019
- 资助金额:
$ 17.87万 - 项目类别:
Combating Resistance of Pancreatic Cancer with a First-in-Class Dual Targeted PI3K/EGFR Inhibitor
使用一流的双靶向 PI3K/EGFR 抑制剂对抗胰腺癌耐药性
- 批准号:
10432048 - 财政年份:2019
- 资助金额:
$ 17.87万 - 项目类别:
Development of a Dual and Selective Small Molecule Inhibitor of EGFR and PI3 Kinase to Treat BRAF Mutant Colorectal Cancer
开发 EGFR 和 PI3 激酶双重选择性小分子抑制剂来治疗 BRAF 突变结直肠癌
- 批准号:
10377535 - 财政年份:2018
- 资助金额:
$ 17.87万 - 项目类别:
Development of a Dual and Selective Small Molecule Inhibitor of EGFR and PI3 Kinase to Treat BRAF Mutant Colorectal Cancer
开发 EGFR 和 PI3 激酶双重选择性小分子抑制剂来治疗 BRAF 突变结直肠癌
- 批准号:
9896781 - 财政年份:2018
- 资助金额:
$ 17.87万 - 项目类别:
Development of MTX-211 for the Treatment of KRAS Mutant Colorectal Cancer
开发用于治疗 KRAS 突变结直肠癌的 MTX-211
- 批准号:
9891971 - 财政年份:2017
- 资助金额:
$ 17.87万 - 项目类别:
Development of MTX-211 for the Treatment of KRAS Mutant Colorectal Cancer
开发用于治疗 KRAS 突变结直肠癌的 MTX-211
- 批准号:
9255740 - 财政年份:2017
- 资助金额:
$ 17.87万 - 项目类别:
相似海外基金
Nutrient bioavailability and metal toxicity with a focus on the influence of geochemical parameters on the biological availability of trace metals
营养物生物利用度和金属毒性,重点关注地球化学参数对微量金属生物利用度的影响
- 批准号:
346752-2007 - 财政年份:2007
- 资助金额:
$ 17.87万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's
SGER: Development of a Reporter System Regulated by the Biological Availability of Fe in Saltwater
SGER:开发由盐水中铁的生物有效性调节的报告系统
- 批准号:
0002968 - 财政年份:2000
- 资助金额:
$ 17.87万 - 项目类别:
Standard Grant
Pollutants in sediments and their environmental impact, esp speciation and biological availability of metals
沉积物中的污染物及其环境影响,特别是金属的形态和生物有效性
- 批准号:
5555510-1995 - 财政年份:1995
- 资助金额:
$ 17.87万 - 项目类别:
Bilateral Exchange Program (H)
Iron Speciation and Its Biological Availability in Seawater: A Workshop
海水中铁形态及其生物有效性:研讨会
- 批准号:
9314179 - 财政年份:1994
- 资助金额:
$ 17.87万 - 项目类别:
Standard Grant
Biological availability of amino acids from Canadian fish meals and fish silage in Atlantic salmo diets
大西洋鲑日粮中加拿大鱼粉和鱼青贮饲料中氨基酸的生物利用度
- 批准号:
45874-1989 - 财政年份:1991
- 资助金额:
$ 17.87万 - 项目类别:
Collaborative Research and Development Grants - Government (H)
Marine Humic Substances: Formation Via Vascular Plant Degradation and Biological Availability
海洋腐殖质:通过维管植物降解和生物利用度形成
- 批准号:
9116450 - 财政年份:1991
- 资助金额:
$ 17.87万 - 项目类别:
Continuing Grant
Special Foreign Currency Award (Including 3,900 Egyptian POunds) For Study of Some Factors Affecting Biological Availability of Drugs
影响药物生物利用度的部分因素研究特别外币奖(含3,900埃及镑)
- 批准号:
7310592 - 财政年份:1973
- 资助金额:
$ 17.87万 - 项目类别:
Standard Grant