Identifying and targeting evolutionary trajectories in cancer
识别和瞄准癌症的进化轨迹
基本信息
- 批准号:10670750
- 负责人:
- 金额:$ 33.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-14 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:ABL1 geneAcuteAdmixtureAffectAftercareB-Cell Acute Lymphoblastic LeukemiaB-Cell LeukemiaBiochemicalBypassCancer PatientCancer RemissionCellsChemicalsChronic Myeloid LeukemiaClinicClinicalCombined Modality TherapyComplexComputer ModelsDataDevelopmentDiseaseDisease ManagementDisease ResistanceDisease remissionDrug TargetingDrug resistanceEngineeringEpigenetic ProcessEvolutionGenerationsGeneticGleevecHematopoietic NeoplasmsHeterogeneityHumanHypersensitivityLeukemic CellMalignant NeoplasmsMalignant neoplasm of lungModelingModernizationMusMutationMyeloid LeukemiaNon-Small-Cell Lung CarcinomaOncogenesPathway interactionsPatientsPharmaceutical PreparationsPopulationRecurrent diseaseRefractoryRelapseResidual NeoplasmResistanceRetinoic Acid ReceptorRouteRunningSolidTherapeuticTherapeutic InterventionTimeTransplantationTreatment ProtocolsTretinoinValidationWorkarms racebcr-abl Fusion Proteinscancer therapycancer typecrizotinibdrug resistance developmenteffective therapyexperimental studygenetic profilinginhibitorleukemiamelanomamouse modelneoplastic cellnovel therapeutic interventionoptimal treatmentspatient derived xenograft modelpharmacologicpre-clinicalpreclinical studypreemptpressureresistance mechanismresponsesmall moleculesmall molecule inhibitortargeted agenttargeted cancer therapytargeted treatmenttreatment responsetumortumor heterogeneity
项目摘要
Project Summary/Abstract
Tumor evolution represents the fundamental obstacle to providing durable cures for cancer patients.
This problem has become increasingly apparent with the recent and clinical use of targeted
therapeutics. While small molecule inhibitors of cancer-promoting oncogenes have led to
unprecedented tumor regression in some leukemias, melanomas and non-small cell lung cancers,
these tumors inevitably relapse as chemorefractory (to the initial therapeutic) malignancies within a
year or two of initial treatment. In some cases, therapies exist to target drug resistant disease. Yet,
diverse mechanisms or “evolutionary trajectories” can lead to distinct forms of resistance to front-line
therapies, and each of these mechanisms may require a distinct second generation therapy. This
represents the current reality of targeted therapeutics, in which we treat relapsed tumors with agents
that target the drug resistant state, creating an unwinnable resistance arms race. Thus, modern
therapies have generally failed to yield prolongued cancer remission or disease management. In fact,
only BCR-ABL inhibitors in Chronic Myelogenous Leukemia have consistently achieved long-term
cancer remissions. We recently discovered a phenomenon of “temporal collateral sensitivity” in
leukemia, whereby distinct intermediate stages in the evolution of resistance to targeted therapeutics
present vulnerabilities for exploitation using small molecules from orthogonal drug classes. The
existence of these evolutionary vulnerabilities provides us with a means of blocking potential routes to
resistance and eradicating residual disease following front-line therapy. We believe this phenomenon
is relevant to many other cancer types. Here, we propose to characterize the mechanism of temporal
collateral sensitivity in BCR-ABL+ leukemia and ALK-driven lung cancer. We also plan to examine
how temporal collateral sensitivity can be exploited in preclinical settings to target evolutionary
trajectories towards drug resistance. We believe that this work will not only identify strategies for
preempt drug resistance, but also reveal ways to combine these strategies to promote durable
therapeutic responses.
项目摘要/摘要
肿瘤的演变代表了为癌症患者提供持久治疗方法的基本障碍。
随着目标的近期和临床使用,这个问题变得越来越明显
疗法。虽然促进癌症基因的小分子抑制剂已导致
某些白血病,黑色素瘤和非小细胞肺癌的空前肿瘤回归,
这些肿瘤不可避免地将其作为化学浪费(最初疗法)在
初始治疗的年或两年。在某些情况下,存在靶向抗药性疾病的疗法。然而,
各种机制或“进化轨迹”可以导致对前线的不同形式
疗法以及这些机制中的每一种都可能需要独特的第二代疗法。
代表了靶向疗法的当前现实,在该现实中,我们将其治疗带有药物的中继肿瘤
该针对耐药状态,创造了不可分割的抵抗力武器竞赛。那,现代
疗法通常无法产生长时间的癌症缓解或疾病治疗。实际上,
慢性粒细胞性白血病中只有BCR-ABL抑制剂始终达到长期
癌症减免。最近,我们发现了一种“暂时侧支灵敏度”现象
白血病,抗靶向治疗的耐药性演变中不同的中间阶段
目前使用正交药物类别的小分子进行剥削的漏洞。这
这些进化漏洞的存在为我们提供了阻止潜在路线的方法
前线治疗后的抵抗和消除残留疾病。我们相信这种现象
与许多其他癌症类型有关。在这里,我们建议表征临时机制
BCR-ABL+白血病和ALK驱动的肺癌中的侧支灵敏度。我们还计划检查
如何在临床前环境中探索临时侧支灵敏度以靶向进化
朝着耐药性的轨迹。我们认为,这项工作不仅会确定
先发制人的耐药性,但也揭示了结合这些策略以促进耐用的方法
治疗反应。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Integrated regulatory models for inference of subtype-specific susceptibilities in glioblastoma.
- DOI:10.15252/msb.20209506
- 发表时间:2020-09
- 期刊:
- 影响因子:9.9
- 作者:Liu Y;Shi N;Regev A;He S;Hemann MT
- 通讯作者:Hemann MT
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Michael Hemann其他文献
Michael Hemann的其他文献
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{{ truncateString('Michael Hemann', 18)}}的其他基金
Identifying and targeting evolutionary trajectories in cancer
识别和瞄准癌症的进化轨迹
- 批准号:
10224829 - 财政年份:2019
- 资助金额:
$ 33.57万 - 项目类别:
Identifying and targeting evolutionary trajectories in cancer
识别和瞄准癌症的进化轨迹
- 批准号:
10450872 - 财政年份:2019
- 资助金额:
$ 33.57万 - 项目类别:
Identifying and targeting evolutionary trajectories in cancer
识别和瞄准癌症的进化轨迹
- 批准号:
9816429 - 财政年份:2019
- 资助金额:
$ 33.57万 - 项目类别:
Identifying determinants of chemotherapeutic response in vivo
确定体内化疗反应的决定因素
- 批准号:
7296033 - 财政年份:2007
- 资助金额:
$ 33.57万 - 项目类别:
Identifying determinants of chemotherapeutic response in vivo
确定体内化疗反应的决定因素
- 批准号:
7899825 - 财政年份:2007
- 资助金额:
$ 33.57万 - 项目类别:
Identifying determinants of chemotherapeutic response in vivo
确定体内化疗反应的决定因素
- 批准号:
8111838 - 财政年份:2007
- 资助金额:
$ 33.57万 - 项目类别:
Identifying determinants of chemotherapeutic response in vivo
确定体内化疗反应的决定因素
- 批准号:
7500790 - 财政年份:2007
- 资助金额:
$ 33.57万 - 项目类别:
Identifying determinants of chemotherapeutic response in vivo
确定体内化疗反应的决定因素
- 批准号:
7647385 - 财政年份:2007
- 资助金额:
$ 33.57万 - 项目类别:
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