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
基本信息
- 批准号:10377535
- 负责人:
- 金额:$ 42.76万
- 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:2018-04-17 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAdoptedBRAF geneBindingBiologicalCancer ModelCecumCellsClinicalClinical TreatmentClinical TrialsColorectalColorectal CancerDataDevelopmentDiagnosisDiseaseDoseDrug KineticsEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorExhibitsFamily memberFutureGene Expression ProfilingGoalsGrowthHumanImplantIn VitroKRAS2 geneLeadLongevityMEKsMalignant NeoplasmsMediatingMitogen-Activated Protein KinasesModelingMolecularMolecular ProfilingMolecular TargetMusMutationNeoplasm MetastasisOncogenicPTEN genePathway interactionsPatientsPatternPharmacodynamicsPharmacologic SubstancePhosphatidylinositide 3-Kinase InhibitorPhosphotransferasesPreclinical TestingPrognosisPrognostic MarkerRefractoryRegimenReportingScheduleSignal TransductionSignaling MoleculeSpecimenSurvival RateTestingTherapeutic IndexToxic effectTumor Suppressor ProteinsValinebiomarker developmentbiomarker signaturecancer cellcandidate markerclinical developmentcolon cancer patientscolorectal cancer treatmentcomparativecomparative efficacydesigndrug candidateeffective therapyefficacy studyexome sequencingimplantationimprovedimproved outcomein vivoin vivo evaluationinhibitormetastatic colorectalmutantnovelpatient derived xenograft modelpatient prognosispatient subsetsphosphoproteomicspre-clinicalrational designresponders and non-respondersresponsesmall moleculesmall molecule inhibitorsuccesstargeted agenttherapy outcometreatment durationtreatment strategytumortumor progression
项目摘要
Despite the emergence of an increased number of molecular targeted agents, the prognosis for patients with
metastatic colorectal cancer (CRC) remains poor with 5 year survival rates of <10%. Agents targeting epidermal
growth factor receptor (EGFR) have met with limited success in the clinical treatment of CRC and are limited to
treatment of those patients whose tumors do not harbor mutations in KRAS or BRAF. Approximately 10% of
colorectal malignancies are known to possess a BRAF valine 600 (BRAFV⁶⁰⁰) mutation, conferring an extremely
poor prognosis. Reactivation of the MAP kinase pathway by EGFR and the co-occurrence of PIK3A mutations
or loss of expression of the tumor suppressor PTEN serve to render BRAFmt tumors refractory to MEK or BRAF
inhibitor monotherapies. Our central hypothesis is that a dual small molecule inhibitor that potently and
selectively targets only EGFR and PI3KA in combination with an inhibitor of MAP kinase signaling represents a
viable strategy for the treatment of BRAF mutant colorectal cancers. To test this hypothesis, we have designed
small molecules that exhibit potent and selective dual inhibition of EGFR and PIK3A family members. To the
best of our knowledge, the lead compound MTX-211 represents a first in class selective inhibitor of these two
critical oncogenic kinases. We have generated crystallographic evidence confirming that MTX-211 binds to
these two kinases in the manner predicted from its computational design, adopting a flipped binding mode to
selectively and potently inhibit both EGFR and PI3K. Preliminary data have shown a striking increase in lifespan
of mice implanted with patient-derived BRAFmt CRC when treated with the combination of MTX-211 and the MEK
inhibitor trametinib. We now propose to carry out more extensive preclinical testing of MTX-211 in patient derived
xenograft models established from patients diagnosed with BRAFmt CRC to bolster the case for this clinical
development path. 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. Additionally, we propose to
maximize durability of response by carrying out comparative efficacy studies of MTX-211 combined with clinically
approved MEK versus RAF inhibitors to inform the design of future clinical trials of this promising drug candidate
for treatment of this recalcitrant disease.
尽管出现了越来越多的分子靶向药物,但患者的预后
转移性结直肠癌(CRC)仍然很差,5年生存率为10%。以表皮为靶点的药物
生长因子受体(EGFR)在结直肠癌的临床治疗中取得了有限的成功,且仅限于
治疗那些肿瘤中没有KRAS或BRAF突变的患者。约10%的
已知的结直肠癌具有BRAF valin600(BRAFV⁶⁰⁰)突变,赋予极端
预后不良。表皮生长因子受体激活MAPK通路与PIK3A突变共存
抑癌基因PTEN的表达缺失导致BRAFmt肿瘤对MEK或BRAF不耐药
抑制剂单一疗法。我们的中心假设是,一种双重的小分子抑制剂可以有效地
选择性地仅以EGFR和PI3KA为靶点,与MAP激酶信号转导抑制剂联合使用代表
治疗BRAF突变的结直肠癌的可行策略。为了验证这一假设,我们设计了
对EGFR和PIK3A家族成员表现出有效和选择性双重抑制作用的小分子。发送到
据我们所知,先导化合物MTX-211是这两种物质的一种一流的选择性抑制剂
关键的致癌蛋白。我们已经产生了结晶学证据,证实MTX-211与
这两个激酶以其计算设计预测的方式,采用翻转结合模式来
选择性和有效地抑制EGFR和PI3K。初步数据显示,人们的寿命显著延长
用MTX-211和MEK联合治疗时,移植患者来源的BRAFmt CRC的小鼠
曲美替尼抑制剂。我们现在建议对患者来源的MTX-211进行更广泛的临床前测试
从诊断为BRAFmt CRC的患者建立异种移植模型以支持这一临床病例
发展路径。将进行分子图谱分析以阐明与固有基因相关的标记
敏感性以及导致进展的适应性信号变化。此外,我们建议
结合临床开展MTX-211疗效对比研究,最大限度提高疗效耐受性
批准的MEK和RAF抑制剂,为这一有希望的候选药物的未来临床试验设计提供信息
用于治疗这种顽固不化的疾病。
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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Judith S Leopold其他文献
Judith S Leopold的其他文献
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{{ 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:
$ 42.76万 - 项目类别:
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:
10666698 - 财政年份:2022
- 资助金额:
$ 42.76万 - 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:
$ 42.76万 - 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:
$ 42.76万 - 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:
$ 42.76万 - 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:
$ 42.76万 - 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:
$ 42.76万 - 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:
$ 42.76万 - 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:
$ 42.76万 - 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:
$ 42.76万 - 项目类别:
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