Multi-Omic Biomarkers for Neuropathic Pain Secondary to Chemotherapy
化疗继发神经病理性疼痛的多组学生物标志物
基本信息
- 批准号:10056337
- 负责人:
- 金额:$ 477.54万
- 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:2020-09-30 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlgorithmsAnxietyAreaBehaviorBiochemicalBiological MarkersBlood specimenBreast Cancer PatientCessation of lifeChemotherapy-induced peripheral neuropathyClinicalComplexDNA MethylationDevelopmentDiagnosticDoseDose-LimitingEarly treatmentGenerationsGenesGenomeGenotypeGoalsHealthIndividualKnowledgeLifeMachine LearningMeasurementMeasuresMental DepressionMessenger RNAMetastatic breast cancerMissionModelingMolecularMonitorMotorNatureNumeric Rating ScaleOrganismPainPain intensityPain interferencePain-FreePathway interactionsPatient Outcomes AssessmentsPatientsPeripheralPhasePhenotypePhysical FunctionPublic HealthQuality of lifeQuestionnairesROC CurveRecurrence ScoreResearchRiskSamplingSecondary toSensoryStandardizationSymptomsSystemTestingTimeToxic effectUnited States National Institutes of Healthbiomarker panelblood-based biomarkercandidate markerchemokinechemotherapeutic agentchemotherapyclinical practicecytokinedisabilityepigenomeexperiencegenome-widehigh riskimprovedinnovationinstrumentmalignant breast neoplasmmetabolomemolecular markermultiple omicsnovelnovel markernovel strategiesoncotypepain catastrophizingpain scorepainful neuropathypersonalized chemotherapypersonalized medicinepredictive markerpredictive signaturepreventresponseside effecttaxanetherapy outcometooltraittransmission process
项目摘要
PROJECT SUMMARY
Taxanes are among the most efficacious chemotherapeutic agents and are frequently used in the treatment of
early stage and metastatic breast cancer, but are known to produce a pain condition known as chemotherapy-
induced peripheral neuropathic pain (CIPNP). CIPNP is one of the primary dose-limiting toxicities of taxane
administration. No diagnostic tool exists to identify patients that will develop CIPNP in response to taxane
therapy. To address this unmet clinical need, this proposal seeks to develop biomarker signatures associated
with taxane-induced neuropathic pain to 1) identify patients at risk for developing debilitating taxane neuropathic
pain before chemotherapy is initiated and 2) to identify patients on treatment that are at risk of developing
neuropathic pain and need dose adjustments to prevent the onset of symptoms. Our long-term goal is to identify
biomarker signatures that can identify patients at high risk of developing taxane-induced CIPNP to enable
personalized dose adjustments to minimize CIPNP and optimize therapeutic outcomes. During the R61 phase,
we will perform genome-wide, epigenome-wide, miRNome-wide, and untargeted metabolome-wide associations
of the 11-point pain-intensity Numerical Rating Scale (NRS), Chemotherapy-induced peripheral neuropathy 20-
item (CIPN20), the Pain Catastrophizing Scale (PCS), and Patient Reported Outcome Measurement System
(PROMIS) scores for physical function, anxiety, depression, and pain interference to identify novel biomarkers
associated with identifiable phenotypes (Aim 1A). Next, we will test panels of candidate mRNA and cytokine
biomarkers for their association with NRS, CIPN20, PCS, and PROMIS scores (Aim 1B). An added strength of
this study is that by collecting samples before, during, and after taxane treatment we will be able to compare
those patients who develop CIPNP to those that remain pain free, providing a better understanding of the
molecular mechanism predisposing a patient to developing neuropathic pain. R61 milestones include developing
biomarker signatures that identify patients at risk of developing neuropathic pain that compromise quality of life
(i) before taxane therapy is started and (ii) over the time course of taxane therapy. One rationale is that some
patients will have a detectable biomarker profile suggesting a high likelihood of long term (i.e., greater than 1
year) neuropathic pain and a need to either avoid or reduce taxane doses. A second rationale is that some
patients may not have a biomarker signature indicating an adverse response to taxane therapy at baseline, but
develop one through the course of taxane therapy. This biomarker signature will be used to detect these
susceptible patients early and personalize their taxane therapy to minimize CIPNP. In the R33 phase (Aim 2),
we will use machine learning to develop and validate algorithms using biomarker signatures from associations
with phenotypic changes from Aim 1 (A and B) to predict individuals at risk of developing CIPNP and to identify
patients who are at risk of developing an adverse profile as taxane therapy is administered.
项目总结
紫杉烷是最有效的化疗药物之一,经常用于治疗
早期和转移性乳腺癌,但已知会产生一种称为化疗的疼痛状况-
诱导周围神经病理性疼痛(CIPNP)。CIPNP是紫杉烷的主要剂量限制毒性之一。
行政管理。目前还没有诊断工具来识别紫杉烷引起CIPNP的患者
心理治疗。为了解决这一未得到满足的临床需求,这项提议寻求开发与
通过紫杉烷诱导的神经病理性疼痛1)确定有可能发展为衰弱的紫杉烷神经病理性疼痛的患者
化疗开始前的疼痛和2)识别治疗中有发展风险的患者
神经病理性疼痛,需要调整剂量以防止症状的出现。我们的长期目标是确定
生物标志物签名,可以识别发生紫杉烷诱导CIPNP的高危患者,以使
个性化的剂量调整,以最大限度地减少CIPNP,优化治疗结果。在R61阶段期间,
我们将执行基因组范围、表观基因组范围、miRNome范围和非靶向代谢组范围的关联
在11点疼痛强度数字评定量表(NRS)中,化疗引起的周围神经病变20-
项目(CIPN20)、疼痛灾变量表(PCS)和患者报告结果测量系统
(PROMIS)身体功能、焦虑、抑郁和疼痛干扰的评分,以确定新的生物标记物
与可识别的表型相关(目标1A)。接下来,我们将测试候选信使核糖核酸和细胞因子的面板
生物标记物与NRS、CIPN20、PCS和PROMIS分数的关联(目标1B)。一个额外的力量
这项研究是通过在紫杉烷治疗之前、期间和之后收集样本,我们将能够比较
那些发展成CIPNP的患者到那些保持无痛状态的患者,提供了更好的理解
导致患者发生神经病理性疼痛的分子机制。R61的里程碑包括开发
识别有患神经病理性疼痛风险的患者的生物标记物特征
(I)在紫杉烷治疗开始之前,以及(Ii)在紫杉烷治疗的整个过程中。其中一个理由是,有些人
患者将有一个可检测的生物标志物档案,表明长期(即大于1)的可能性很高
年)神经性疼痛,以及需要避免或减少紫杉烷剂量。第二个理由是,有些人
患者可能没有生物标记物标记,表明基线时对紫杉烷治疗的不良反应,但
在紫杉烷治疗过程中发展出一种。这个生物标志物签名将被用来检测这些
易感患者及早进行个体化紫杉烷治疗,将CIPNP降至最低。在R33阶段(目标2),
我们将使用机器学习来开发和验证使用来自关联的生物标记物签名的算法
根据目标1(A和B)的表型变化来预测患CIPNP的风险个体并识别
接受紫杉烷治疗时有出现不良症状的风险的患者。
项目成果
期刊论文数量(0)
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JOSEPH F FOSS其他文献
JOSEPH F FOSS的其他文献
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{{ truncateString('JOSEPH F FOSS', 18)}}的其他基金
Multi-Omic Biomarkers for Neuropathic Pain Secondary to Chemotherapy
化疗继发神经病理性疼痛的多组学生物标志物
- 批准号:
10709410 - 财政年份:2020
- 资助金额:
$ 477.54万 - 项目类别:
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