Overcoming Resistance Mechanisms to Anaplastic Lymphoma Kinase Inhibitors
Overcoming Resistance Mechanisms to Anaplastic Lymphoma Kinase Inhibitors
批准号:
10734260
负责人:
Aaron N Hata
金额:
$41.75万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
未结题
起止时间:
2012-02-20 至 2028-06-30
关键词:
ALK geneAccountingAddressAdoptive Cell TransfersAllelesAutomobile DrivingBiopsyBypassCancer EtiologyCancer PatientCell LineCessation of lifeChimeric ProteinsChromosomal RearrangementClinicClinicalClinical TrialsCollectionCombined Modality TherapyDataDevelopmentDiagnosisDiseaseDrug resistanceEP300 geneEngineeringEpigenetic ProcessEpitopesFoundationsFutureGene FusionGene RearrangementGenerationsGenetic TranscriptionGenomicsGoalsIL2-Inducible T-Cell KinaseImmuneImmune checkpoint inhibitorImmunotherapyIn VitroInstitutionInstitutional Review BoardsMHC Class I GenesMalignant neoplasm of lungMapsMediatingMethodsMutationNeuronsNew AgentsNon-Small-Cell Lung CarcinomaNormal tissue morphologyOncogenicOutcomePatientsPatternPhosphotransferasesPre-Clinical ModelProtocols documentationReceptor ActivationReceptor Protein-Tyrosine KinasesRecurrenceRecurrent diseaseResearchResearch PersonnelResistanceRoleSamplingSignal PathwaySignal TransductionSpecimenT-Cell ReceptorT-LymphocyteTherapeuticTissuesTranscription CoactivatorTumor Cell LineTyrosine Kinase InhibitorUnited Statesacquired drug resistanceanaplastic lymphoma kinasecohortcrizotinibimmunogenicimprovedin vivoinhibitorkinase inhibitormolecular subtypesmortalityneoantigensnext generationnon-genomicnovelnovel strategiesnovel therapeutic interventionpharmacologicprogramsrational designresistance mechanismresistance mutationstandard carestandard of caretherapeutic targettherapy developmenttumor
中文摘要
项目摘要
携带致癌间变性淋巴瘤激酶(ALK)基因的非小细胞肺癌(NSCLC)
重排(即,“ALK+”)包含对ALK具有显著敏感性的肺癌的不同分子亚组
酪氨酸激酶抑制剂(TKI)。虽然ALK TKI最初非常有效,但获得性耐药性仍然存在
这是一个根本性的挑战,限制了临床获益,并导致大多数患者的疾病复发。我们和其他人
已经表征了抗性机制,特别是所谓的“靶向”抗性,
继发性获得性ALK激酶结构域突变,可以通过更有效的下一代(第2代-
或第三代)抑制剂。近年来,标准治疗模式的患者诊断为
晚期ALK+肺癌已从使用第一代ALK TKI克唑替尼的序贯治疗转移
随后是下一代TKI,以使用下一代ALK TKI进行前期初始治疗。我们的初步数据
指示偏离目标(即,ALK非依赖性)耐药机制在下一代
ALK TKI。然而,脱靶耐药机制和克服这些耐药机制的策略仍然存在
对这些疾病的认识不足,阻碍了为这些患者开发治疗方案。的
拟议研究的总体目标是确定和发展互补的,机制知情的
以及克服下一代ALK TKI脱靶耐药的机制不可知方法。我们将
对患者肿瘤样本的扩展队列进行全面的基因组和非基因组评估
确定下一代ALK一线使用后脱靶耐药机制的临床谱
TKI,我们将开发新的方法来识别旁路介导的耐药患者,
从合理设计的联合疗法中获益。使用ALK TKI耐药肿瘤细胞系,
患者活检,我们将筛选表观遗传机制,驱动阻力独立于典型旁路
信号通路,最初的研究集中在定义转录辅激活因子p300/CBP的作用
作为ALK TKI脱靶耐药和治疗靶点的新型驱动因素。这些努力将使患者特异性,
机制知情的治疗策略。同时,我们将开发一种机制不可知的方法,
利用ALK作为肿瘤特异性“新抗原”,其表达在耐药肿瘤中得以维持。使用T
在基于细胞的功能筛选中,我们将鉴定ALK反应性T细胞受体(TCR),
识别耐药ALK+ NSCLC。这将为改造ALK TCR过继细胞提供基础。
作为TKI正交,免疫为基础的方法来克服耐药性的治疗。总体而言,拟议的
研究将全面了解下一代ALK TKI的耐药性,并为
开发新的治疗策略,可以有效地克服大多数脱靶耐药,
最终改善和延长晚期ALK+肺癌患者的生命。
英文摘要
Project Summary
Non-small cell lung cancers (NSCLC) harboring oncogenic anaplastic lymphoma kinase (ALK) gene
rearrangements (i.e., ‘ALK+’) comprise a distinct molecular subset of lung cancer with marked sensitivity to ALK
tyrosine kinase inhibitors (TKIs). While ALK TKIs are initially highly effective, acquired drug resistance remains
a fundamental challenge that limits clinical benefit and causes disease relapse in most patients. We and others
have characterized mechanisms of resistance, in particular so-called “on-target” resistance mediated by
secondary acquired ALK kinase domain mutations that can be overcome with more potent next-generation (2nd-
or 3rd-generation) inhibitors. In recent years, the standard treatment paradigm for patients diagnosed with
advanced ALK+ lung cancers has shifted from sequential therapy using the 1st-generation ALK TKI crizotinib
followed by next-generation TKIs, to initial therapy using a next-generation ALK TKI upfront. Our preliminary data
indicate that off-target (i.e., ALK-independent) resistance mechanisms are prevalent following next-generation
ALK TKIs. Yet, the spectrum of off-target resistance mechanisms and strategies to overcome these remain
poorly understood, presenting a barrier to the development of treatment options for these patients. The
overarching objective of the proposed research is to identify and develop complementary, mechanism-informed
and mechanism-agnostic approaches for overcoming off-target resistance to next-generation ALK TKIs. We will
use comprehensive genomic and non-genomic assessment of an expanded cohort of patient tumor specimens
to determine the clinical spectrum of off-target resistance mechanisms after first-line use of next-generation ALK
TKIs, and we will develop new methods for identifying patients with bypass-mediated resistance most likely to
benefit from rationally designed combination therapies. Using ALK TKI-resistant tumor cell lines derived from
patient biopsies, we will screen for epigenetic mechanisms that drive resistance independent of canonical bypass
signaling pathways, with initial studies focused on defining the role of the transcriptional co-activator p300/CBP
as a novel driver of off-target ALK TKI resistance and therapeutic target. These efforts will enable patient-specific,
mechanism-informed therapeutic strategies. In parallel, we will develop a mechanism-agnostic approach that
leverages ALK as a tumor-specific “neoantigen” whose expression is maintained in resistant tumors. Using T
cell-based functional screens, we will identify ALK-reactive T cell receptors (TCRs) that are capable of
recognizing resistant ALK+ NSCLCs. This will provide the foundation for engineering ALK TCR adoptive cellular
therapy as a TKI-orthogonal, immune-based approach for overcoming resistance. Collectively, the proposed
studies will provide a comprehensive understanding of resistance to next-generation ALK TKIs and pave the way
for the development of new therapeutic strategies that can effectively overcome most of off-target resistance in
the clinic, ultimately improving and prolonging the lives of patients with advanced ALK+ lung cancers.
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DOI:
10.1056/nejmoa1311107
发表时间:
2014-03-27
期刊:
The New England journal of medicine
影响因子:
--
作者:
[Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA]
通讯作者:
Engelman JA
DOI:
10.1016/j.jtho.2017.08.002
发表时间:
2017-11
期刊:
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子:
--
作者:
[Lin JJ, Shaw AT]
通讯作者:
Shaw AT
Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors through Longitudinal Analysis of Circulating Tumor DNA.
通过循环肿瘤DNA的纵向分析来跟踪对碱酪氨酸激酶抑制剂的耐药性的演变。
DOI:
10.1200/po.17.00160
发表时间:
2018
期刊:
JCO precision oncology
影响因子:
4.6
作者:
[Dagogo-Jack I, Brannon AR, Ferris LA, Campbell CD, Lin JJ, Schultz KR, Ackil J, Stevens S, Dardaei L, Yoda S, Hubbeling H, Digumarthy SR, Riester M, Hata AN, Sequist LV, Lennes IT, Iafrate AJ, Heist RS, Azzoli CG, Farago AF, Engelman JA, Lennerz JK, Benes CH, Leary RJ, Shaw AT, Gainor JF]
通讯作者:
Gainor JF
DOI:
10.1038/s41698-023-00464-y
发表时间:
2023-11-03
期刊:
NPJ precision oncology
影响因子:
7.9
作者:
[]
通讯作者:
DOI:
10.1016/j.jtocrr.2023.100534
发表时间:
2023-08
期刊:
JTO CLINICAL AND RESEARCH REPORTS
影响因子:
--
作者:
[Dagogo-Jack, Ibiayi, Kiedrowski, Lesli A., Heist, Rebecca S., Lin, Jessica J., Meador, Catherine B., Krueger, Elizabeth A., Do, Andrew, Peterson, Jennifer, V. Sequist, Lecia, Gainor, Justin F., Lennerz, Jochen K., Digumarthy, Subba R.]
通讯作者:
Digumarthy, Subba R.
共 23 条
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