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

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.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(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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