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.

项目总结/文摘