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

• 批准号: 10804464
• 负责人: Gavin Ha
• 金额: $ 59.65万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10804464
• 关键词: Address; Adenocarcinoma; Adoption; Androgen Receptor; Autopsy; BRCA2 gene; Biological Markers; Biopsy; Blood; Blood specimen; Breast Carcinoma; Cancer Etiology; Cancer Patient; Categories; Cell Cycle; Cessation of life; Characteristics; Classification; Clinical; DNA Sequence Alteration; DNA analysis; DNA sequencing; Detection; Engineering; Evolution; Exhibits; FDA approved; FOLH1 gene; Frequencies; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Genomics; Genotype; Heterogeneity; Histology; Individual; Inter-tumoral heterogeneity; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Molecular; Monitor; Morbidity - disease rate; Mus; Neoplasm Metastasis; Neuroendocrine Cell; Neuroendocrine Prostate Cancer; Nucleosomes; Oncogenes; Outcome; Patient-Focused Outcomes; Patients; Pattern; Performance; Phenotype; Plasma; Positron-Emission Tomography; Prediction of Response to Therapy; Procedures; Prognosis; Prognostic Marker; Proliferating; Prospective cohort; Prostate Adenocarcinoma; Prostate Cancer therapy; RB1 gene; Receptor Signaling; Research; Research Personnel; Resistance; Resistance development; Sampling; Selection for Treatments; Signal Transduction; Site; Small Cell Carcinoma; TP53 gene; Testing; Therapeutic; Time; Tissues; Transcriptional Regulation; Treatment outcome; Tumor Subtype; Tumor Suppressor Proteins; Variant; androgen deprivation therapy; blood treatment; cancer classification; cancer heterogeneity; cancer subtypes; castration resistant prostate cancer; cell free DNA; clinically relevant; cost effective; curative treatments; fluorodeoxyglucose positron emission tomography; improved; improved outcome; in vivo; inhibitor; inhibitor therapy; innovation; liquid biopsy; lung Carcinoma; medicine man; men; molecular diagnostics; molecular subtypes; mortality; neoplastic cell; neuroendocrine differentiation; patient derived xenograft model; patient screening; patient subsets; potential biomarker; pre-clinical; precision medicine; predicting response; predictive marker; pressure; radiation resistance; radioligand; response; standard of care; targeted treatment; therapy outcome; therapy resistant; tool; transdifferentiation; treatment response; treatment strategy; tumor; tumor DNA; tumor diagnosis; tumor heterogeneity

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.

项目摘要/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治疗的抵抗和进展为致命的去势抵抗的前列腺 癌症(CRPC)。针对AR信号轴的新一代雄激素受体信号抑制物(ARSI) 已经在CRPC环境中使用；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重要靶点。 成像(PSMA-PET)和靶向治疗，例如最近FDA批准的放射配基(PSMA-RL) ARSI治疗进展的CRPC患者。尽管PSMA-RL疗法对生存有好处，但 改善的结果是温和的，只有一半的患者表现出良好的反应。抵抗的出现 对ARSI和PSMA-RL的影响可能是通过肿瘤表型的改变而发生的，例如从 前列腺癌(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，这是 由于侵入性手术伴随着并发症和一些肿瘤无法触及，因此可能是具有挑战性的 或样品质量较差。此外，肿瘤的异质性是治疗耐药性的一个主要因素， 使用单个转移部位的活检来确定是特别具有挑战性的。这些挑战体现了重大的 男性慢性前列腺癌现有治疗策略和精确医学的局限性。 循环中的肿瘤DNA(CtDNA)从肿瘤细胞释放到血液中作为无细胞DNA(CfDNA)是一种非 侵入性“液体活组织检查”解决方案，以解决组织可及性方面的挑战。当前的研究和临床 努力的重点是从ctDNA测序中检测潜在的生物标志物的基因突变； 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中分类侵袭性CRPC基因和表型的创新方法，克服了 肿瘤异质性的挑战。研究人员假设ctdna可以用于肿瘤的分类。 CRPC中的亚型，这可以用于预测治疗结果。在目标1中，他们将研究肿瘤 接受快速尸检以评估ctDNA分类器用于预测的男性的异质性 来自死后血浆的异质性表型。在目标2中，他们将确定ctDNA对 预测接受ARSI和一个子集治疗的前列腺癌患者的前瞻性队列结果 接受PSMA-PET筛查并接受PSMA-RL治疗的患者比例。他们将评估ctDNA分类器 作为生物标志物工具，帮助PSMA-RL治疗的初始分配并告知治疗的早期适应症 抵抗。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 包括体内在内的临床前小鼠PDX模型对前列腺癌表型侵袭性的影响 表型混合物的工程学。