Dissecting and overcoming cross-resistance to DNA damaging agents in SCLC
剖析和克服 SCLC 中 DNA 损伤剂的交叉耐药性
基本信息
- 批准号:10224137
- 负责人:
- 金额:$ 24.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressArchivesBiological AssayBiological MarkersBiological ModelsBiopsyBiopsy SpecimenCancer PatientClinicalClinical SensitivityClinical TrialsCollectionDNA DamageDiagnosisDiseaseEtoposideFormalinGene ExpressionGene Expression ProfileGenesGeneticGuidelinesHeterogeneityImmune responseImmune systemImmunocompromised HostIn Situ HybridizationInter-tumoral heterogeneityInterferonsInvestigationInvestigational TherapiesKnock-outLearningMalignant NeoplasmsMediatingModelingMolecularMusMutationNOR MouseNational Comprehensive Cancer NetworkNatureNeoplasm Circulating CellsOutcomeParaffin EmbeddingPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhasePhase I/II TrialPlatinumPopulationPrognosisPropertyRNARecording of previous eventsRegimenRelapseResistanceRoleSamplingSignal TransductionSolid NeoplasmSpecimenStimulator of Interferon GenesTestingTimeTissue SampleTopotecanTranslational ResearchValidationVariantXenograft procedurearmbiomarker-drivenchemotherapyco-clinical trialcomparativecytokinedrug sensitivityeffusionepigenetic silencingestablished cell lineexperienceexperimental studygenetic signatureindividual patientlung small cell carcinomamouse modelnovelpathogenpatient derived xenograft modelpatient populationpatient responseresistance mechanismresponsetargeted treatmenttemozolomidetrial designtumor
项目摘要
Project Summary
Small cell lung cancer (SCLC) afflicts more than 30,000 patients per year and is rapidly fatal in 95% of cases,
with median survival is less than one year. Belying this grim prognosis, treatment-naive SCLC is highly
sensitive to chemotherapy. However, relapse is nearly inevitable, and relapsed SCLC presents two obstacles
that have been insurmountable for at least 30 years: cross-resistance to chemotherapy, and absence of
biomarker-driven targeted therapy.
Following relapse, resistance often extends beyond etoposide/platinum (EP) to other DNA damaging agents.
Although topotecan is the only approved second-line therapy for SCLC, the NCCN guidelines list 10 agents of
roughly equivalent efficacy. None are particularly effective in unselected patients, and a disease that was once
highly chemosensitive becomes inexorably progressive. However, the molecular determinants of cross-
resistance in SCLC remain unclear. Although critically important, cross-resistance is difficult to study
experimentally, as it requires a model system that faithfully reproduces clinical outcomes, and is adequately
powered to capture inter-tumoral molecular heterogeneity across a population of patients.
We have generated a panel of 44 SCLC patient-derived xenograft models (PDXs) from biopsy specimens and
circulating tumor cells (CTCs). Our panel includes successive models from individual patients at time points
before and after specific lines of therapy, with detailed information about the corresponding clinical response.
For both standard chemotherapy and experimental agents in clinical trial, these models faithfully mirror patient
responses. However, unlike the patient experience, multiple strategies can be compared for identical tumors.
We propose to use these models to directly compare three clinical strategies that depend on induction of DNA
damage: standard first line EP, second line topotecan, anad a promising experimental regimen, olaparib plus
temozolomide (OT), currently in a phase I/II trial at MGH. Individually, these PDX population trials are designed
to reveal biomarkers of sensitivity and mechanisms of resistance for promising experimental therapies.
Collectively, through comparative analysis with reference to the clinical histories of each model, they present a
novel opportunity to model cross-resistance, a problem that has beleaguered management of SCLC for over
three decades.
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)
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 }}
Benjamin J Drapkin其他文献
Benjamin J Drapkin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('Benjamin J Drapkin', 18)}}的其他基金
Dissecting and overcoming cross-resistance to DNA damaging agents in SCLC
剖析和克服 SCLC 中 DNA 损伤剂的交叉耐药性
- 批准号:
9977639 - 财政年份:2020
- 资助金额:
$ 24.69万 - 项目类别:
Dissecting and overcoming cross-resistance to DNA damaging agents in SCLC
剖析和克服 SCLC 中 DNA 损伤剂的交叉耐药性
- 批准号:
10448427 - 财政年份:2020
- 资助金额:
$ 24.69万 - 项目类别:
Dissecting and overcoming cross-resistance to DNA damaging agents in SCLC
剖析和克服 SCLC 中 DNA 损伤剂的交叉耐药性
- 批准号:
10686224 - 财政年份:2020
- 资助金额:
$ 24.69万 - 项目类别:
相似海外基金
Sediment Drilling Facility for environmental and genetic archives
环境和遗传档案沉积物钻探设施
- 批准号:
LE240100064 - 财政年份:2024
- 资助金额:
$ 24.69万 - 项目类别:
Linkage Infrastructure, Equipment and Facilities
Aerial Archives of Race and American-Occupied Japan
种族和美国占领的日本的航空档案
- 批准号:
24K03721 - 财政年份:2024
- 资助金额:
$ 24.69万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
CAREER: Understanding biosphere-geosphere coevolution through carbonate-associated phosphate, community archives, and open-access education in rural schools
职业:通过碳酸盐相关磷酸盐、社区档案和农村学校的开放教育了解生物圈-地圈协同进化
- 批准号:
2338055 - 财政年份:2024
- 资助金额:
$ 24.69万 - 项目类别:
Continuing Grant
Designing a Bridging Model Using Learning Content Information LOD to Link School Education and Digital Archives
使用学习内容信息 LOD 设计桥接模型来链接学校教育和数字档案
- 批准号:
23H03695 - 财政年份:2023
- 资助金额:
$ 24.69万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Doris Lessing's Archives: Communism, Decolonisation and Literary Practice
多丽丝·莱辛档案:共产主义、非殖民化和文学实践
- 批准号:
2888789 - 财政年份:2023
- 资助金额:
$ 24.69万 - 项目类别:
Studentship
Integrated High-Definition Visualization of Digital Archives for Borobudur Temple
婆罗浮屠寺数字档案集成高清可视化
- 批准号:
22KJ3026 - 财政年份:2023
- 资助金额:
$ 24.69万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Research on multilingual data integration for digital archives of Japanese culture
日本文化数字档案多语言数据集成研究
- 批准号:
23K11780 - 财政年份:2023
- 资助金额:
$ 24.69万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Building a sustainable future for anthropology's archives: Researching primary source data lifecycles, infrastructures, and reuse
为人类学档案构建可持续的未来:研究主要源数据生命周期、基础设施和重用
- 批准号:
2314762 - 财政年份:2023
- 资助金额:
$ 24.69万 - 项目类别:
Standard Grant
A Preliminary Study for Constructing International Network of Image Archives on Afghan Cultural Heritages
构建阿富汗文化遗产国际图像档案网络的初步研究
- 批准号:
23K00915 - 财政年份:2023
- 资助金额:
$ 24.69万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Reading Writing Lives: Publishing & Preserving Australian Literary Archives
阅读写作生活:出版
- 批准号:
DP230101797 - 财政年份:2023
- 资助金额:
$ 24.69万 - 项目类别:
Discovery Projects