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。