Evaluating prostate cancer phenotype and genotype classification from circulating tumor DNA as biomarkers for predicting treatment outcomes
根据循环肿瘤 DNA 评估前列腺癌表型和基因型分类作为预测治疗结果的生物标志物
基本信息
- 批准号:10804464
- 负责人:
- 金额:$ 59.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-19 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdenocarcinomaAdoptionAndrogen ReceptorAutopsyBRCA2 geneBiological MarkersBiopsyBloodBlood specimenBreast CarcinomaCancer EtiologyCancer PatientCategoriesCell CycleCessation of lifeCharacteristicsClassificationClinicalDNA Sequence AlterationDNA analysisDNA sequencingDetectionEngineeringEvolutionExhibitsFDA approvedFOLH1 geneFrequenciesGene ExpressionGene Expression RegulationGenerationsGenesGenetic TranscriptionGenomicsGenotypeHeterogeneityHistologyIndividualInter-tumoral heterogeneityMalignant NeoplasmsMalignant neoplasm of prostateMethodsMolecularMonitorMorbidity - disease rateMusNeoplasm MetastasisNeuroendocrine CellNeuroendocrine Prostate CancerNucleosomesOncogenesOutcomePatient-Focused OutcomesPatientsPatternPerformancePhenotypePlasmaPositron-Emission TomographyPrediction of Response to TherapyProceduresPrognosisPrognostic MarkerProliferatingProspective cohortProstate AdenocarcinomaProstate Cancer therapyRB1 geneReceptor SignalingResearchResearch PersonnelResistanceResistance developmentSamplingSelection for TreatmentsSignal TransductionSiteSmall Cell CarcinomaTP53 geneTestingTherapeuticTimeTissuesTranscriptional RegulationTreatment outcomeTumor SubtypeTumor Suppressor ProteinsVariantandrogen deprivation therapyblood treatmentcancer classificationcancer heterogeneitycancer subtypescastration resistant prostate cancercell free DNAclinically relevantcost effectivecurative treatmentsfluorodeoxyglucose positron emission tomographyimprovedimproved outcomein vivoinhibitorinhibitor therapyinnovationliquid biopsylung Carcinomamedicine manmenmolecular diagnosticsmolecular subtypesmortalityneoplastic cellneuroendocrine differentiationpatient derived xenograft modelpatient screeningpatient subsetspotential biomarkerpre-clinicalprecision medicinepredicting responsepredictive markerpressureradiation resistanceradioligandresponsestandard of caretargeted treatmenttherapy outcometherapy resistanttooltransdifferentiationtreatment responsetreatment strategytumortumor DNAtumor diagnosistumor heterogeneity
项目摘要
PROJECT SUMMARY/ABSTRACT
Prostate cancer is the second most common cause of cancer mortality among men. The majority of these deaths
are due to resistance to androgen deprivation therapy and progression to lethal castration-resistant prostate
cancer (CRPC). New generation androgen receptor signaling inhibitors (ARSI) that target the AR signaling axis
have been used in the CRPC setting; however, the majority of patients still develop resistance. Recently,
prostate-specific membrane antigen (PSMA) has become a promising target for positron-emission tomography
imaging (PSMA-PET) and targeted therapies, such as the recently FDA-approved radioligand (PSMA-RL) for
CRPC patients who progressed on ARSI treatment. Despite a survival benefit for PSMA-RL therapy, the
improved outcome is modest and only half the patients show favorable responses. The emergence of resistance
to ARSI and PSMA-RL may arise through changes in tumor phenotype, such as trans-differentiation from
prostate adenocarcinoma (ARPC) into treatment-related small-cell neuroendocrine prostate cancer (NEPC) and
other phenotypes with loss of AR activity. Current methods require a biopsy to diagnose tumor histology, which
can be challenging due to invasive procedures accompanied by morbidity and some tumors are not accessible
or have poor sample quality. Furthermore, tumor heterogeneity is a major contributor to therapy resistance and
is particularly challenging to identify using a biopsy of a single metastatic site. These challenges exemplify major
limitations of current treatment strategies and precision medicine for men with CRPC.
Circulating tumor DNA (ctDNA) released from tumor cells into the blood as cell-free DNA (cfDNA) is a non-
invasive “liquid biopsy” solution for addressing challenges in tissue accessibility. Current research and clinical
efforts have focused on the detection of genetic mutations from ctDNA sequencing as potential biomarkers;
however, these do not fully explain why treatments fail. The objective of this proposal is to develop and evaluate
innovative methods for classifying aggressive CRPC genotypes and phenotypes from ctDNA, overcoming
challenges of tumor heterogeneity. The investigators hypothesize that ctDNA can be used to classify tumor
subtypes in CRPC and that this can be used to predict treatment outcomes. In Aim 1, they will study tumor
heterogeneity in men who have undergone rapid autopsy to evaluate the ctDNA classifiers for predicting
heterogeneous phenotypes from post-mortem plasma. In Aim 2, they will determine the utility of ctDNA for
predicting prostate cancer treatment outcomes in a prospective cohort of patients treated with ARSI and a subset
of patients screened by PSMA-PET and treated with PSMA-RL therapy. They will evaluate the ctDNA classifiers
as biomarker tools to aid in the initial allocation of PSMA-RL therapy and inform early indications of treatment
resistance. In Aim 3, they will develop extensions to ctDNA methods that infer gene expression and tumor
aggressiveness in prostate cancer phenotypes using preclinical mouse PDX models, including in vivo
engineering of phenotype mixtures.
项目概要/摘要
前列腺癌是男性癌症死亡的第二大常见原因。这些死亡中的大多数
是由于对雄激素剥夺疗法的抵抗以及进展为致命的去势抵抗性前列腺所致
癌症(CRPC)。靶向 AR 信号轴的新一代雄激素受体信号抑制剂 (ARSI)
已在 CRPC 设置中使用;然而,大多数患者仍然产生耐药性。最近,
前列腺特异性膜抗原(PSMA)已成为正电子发射断层扫描的有希望的目标
成像 (PSMA-PET) 和靶向治疗,例如 FDA 最近批准的放射性配体 (PSMA-RL)
接受 ARSI 治疗后病情进展的 CRPC 患者。尽管 PSMA-RL 疗法具有生存获益,
改善的结果是有限的,只有一半的患者表现出良好的反应。抵抗的出现
ARSI 和 PSMA-RL 可能通过肿瘤表型的变化而产生,例如从
前列腺腺癌 (ARPC) 转化为治疗相关的小细胞神经内分泌前列腺癌 (NEPC) 和
AR 活性丧失的其他表型。目前的方法需要活检来诊断肿瘤组织学,这
由于伴随发病率的侵入性操作可能具有挑战性,并且某些肿瘤无法接近
或者样本质量较差。此外,肿瘤异质性是治疗耐药性和
使用单个转移部位的活检来识别是特别具有挑战性的。这些挑战体现了重大挑战
目前男性 CRPC 治疗策略和精准医疗的局限性。
循环肿瘤 DNA (ctDNA) 以游离 DNA (cfDNA) 的形式从肿瘤细胞释放到血液中,是一种非
侵入性“液体活检”解决方案,用于解决组织可及性方面的挑战。目前的研究和临床
工作重点是通过 ctDNA 测序检测基因突变作为潜在的生物标志物;
然而,这些并不能完全解释治疗失败的原因。该提案的目标是开发和评估
从 ctDNA 对侵袭性 CRPC 基因型和表型进行分类的创新方法,克服了
肿瘤异质性的挑战。研究人员假设 ctDNA 可用于对肿瘤进行分类
CRPC 的亚型,这可以用来预测治疗结果。在目标 1 中,他们将研究肿瘤
进行快速尸检以评估用于预测的 ctDNA 分类器的男性的异质性
死后血浆的异质表型。在目标 2 中,他们将确定 ctDNA 的效用
预测接受 ARSI 及其子集治疗的前瞻性患者队列中前列腺癌的治疗结果
通过 PSMA-PET 筛查并接受 PSMA-RL 治疗的患者。他们将评估 ctDNA 分类器
作为生物标志物工具,帮助初始分配 PSMA-RL 治疗并告知早期治疗适应症
反抗。在目标 3 中,他们将开发 ctDNA 方法的扩展,以推断基因表达和肿瘤
使用临床前小鼠 PDX 模型(包括体内)研究前列腺癌表型的侵袭性
表型混合物的工程。
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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Gavin Ha其他文献
Gavin Ha的其他文献
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{{ truncateString('Gavin Ha', 18)}}的其他基金
Translating the tumor regulome from cell-free DNA for precision oncology
将游离 DNA 转化为肿瘤调节组以实现精准肿瘤学
- 批准号:
10818290 - 财政年份:2022
- 资助金额:
$ 59.65万 - 项目类别:
Translating the tumor regulome from cell-free DNA for precision oncology
将游离 DNA 转化为肿瘤调节组以实现精准肿瘤学
- 批准号:
10473384 - 财政年份:2022
- 资助金额:
$ 59.65万 - 项目类别:
Predicting transcriptional signatures and tumor subtypes from circulating tumor DNA
从循环肿瘤 DNA 预测转录特征和肿瘤亚型
- 批准号:
10487475 - 财政年份:2021
- 资助金额:
$ 59.65万 - 项目类别:
Predicting transcriptional signatures and tumor subtypes from circulating tumor DNA
从循环肿瘤 DNA 预测转录特征和肿瘤亚型
- 批准号:
10305561 - 财政年份:2021
- 资助金额:
$ 59.65万 - 项目类别:
Predicting transcriptional signatures and tumor subtypes from circulating tumor DNA
从循环肿瘤 DNA 预测转录特征和肿瘤亚型
- 批准号:
10601439 - 财政年份:2021
- 资助金额:
$ 59.65万 - 项目类别:
Identifying driver non-coding alterations in metastatic prostate cancer from tumor and cell-free DNA
从肿瘤和游离 DNA 中识别转移性前列腺癌的驱动非编码改变
- 批准号:
10380659 - 财政年份:2020
- 资助金额:
$ 59.65万 - 项目类别:
Identifying driver non-coding alterations in metastatic prostate cancer from tumor and cell-free DNA
从肿瘤和游离 DNA 中识别转移性前列腺癌的驱动非编码改变
- 批准号:
9720173 - 财政年份:2020
- 资助金额:
$ 59.65万 - 项目类别:
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