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
• 负责人: Gavin Ha
• 金额: $ 16.82万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10487475
• 关键词: Address; Adenocarcinoma; Adoption; Adult; Advanced Malignant Neoplasm; Area; Benchmarking; Biological Assay; Biopsy; Blood; Cessation of life; Chromatin; Classification; Clinical; Clinical Data; Clinical Treatment; Collaborations; Communities; Computer Analysis; Computing Methodologies; DNA Sequence Alteration; DNA sequencing; Data; Detection; Disease; Disease Progression; Disseminated Malignant Neoplasm; Environment; Evolution; Gene Expression Profile; Gene Expression Profiling; Gene Expression Regulation; Genome; Genomics; Hormone Receptor; Life; Location; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Metastatic/Recurrent; Methods; Molecular; Mutation; Neuroendocrine Carcinoma; Nucleosomes; Oncogenes; Patients; Pattern; Performance; Phenotype; Plasma; Precision therapeutics; Primary Neoplasm; Research; Resistance; Sampling; Site; Surveys; Testing; Time; Tissues; Transcriptional Regulation; Tumor Subtype; Tumor Tissue; anticancer research; base; cancer diagnosis; cancer therapy; cancer type; cell free DNA; clinical care; clinical diagnostics; computerized tools; genome sequencing; innovation; liquid biopsy; malignant breast neoplasm; molecular phenotype; molecular subtypes; multiple omics; neoplastic cell; novel therapeutics; open source; patient derived xenograft model; patient subsets; precision medicine; precision oncology; predictive modeling; resistance mechanism; standard of care; targeted treatment; therapy resistant; tool; transcriptome; transdifferentiation; treatment strategy; tumor; tumor DNA; whole genome

Project Summary/Abstract Tumor phenotype changes, such as trans-differentiation in lethal prostate cancers and hormone receptor conversions in breast cancer, are increasingly frequent observations as resistance mechanisms to targeted therapies. Therefore, characterizing the transcriptional regulation that drives treatment-induced tumor phenotype changes during therapy in “real-time” has critical implications for studying mechanisms of resistance to therapies and informing clinical treatment decisions. Surveillance of molecular changes in tumors is especially challenging because the location and number of metastatic sites make it intractable to perform repeated biopsies. As a result, it is difficult to characterize tumor evolution and cellular plasticity during therapy, exemplifying a major limitation of current treatment strategies and precision medicine for patients with metastatic cancer. Circulating tumor DNA (ctDNA) released from tumor cells into the blood is a non-invasive “liquid biopsy” solution for addressing challenges in tissue accessibility. Current research and clinical efforts have focused on detecting genomic alterations in ctDNA. However, studying the tumor phenotype from ctDNA remains challenging and is still a nascent area of research. The objective of this proposal is to develop an innovative computational method to profile and integrate genomic alterations, chromatin accessibility, and transcriptional regulation directly from standard ctDNA sequencing data. Recent advances and our preliminary studies now demonstrate the intriguing possibility to profile these “multi- omic” patterns solely from computational analysis of standard ctDNA whole genome sequencing data. However, there is still a lack of tools to predict transcriptional profiles from ctDNA. In Aim 1, we will develop a generalized framework to predict transcriptional regulation from ctDNA. We will optimize ctDNA data normalization and develop an unsupervised probabilistic generative model for predicting chromatin accessibility and transcriptional regulation in ctDNA. To evaluate the method, we will perform benchmarking using plasma ctDNA from patient- derived xenograft models. In Aim 2, we will test the hypothesis that the multi-omic signatures profiled from ctDNA will provide a non-invasive approach to classify tumor subtypes and to survey molecular phenotype changes during therapy. We will develop classifiers for predicting tumor subtypes and phenotype changes in adult and pediatric cancers. To test the utility for characterizing multi-omic signature and predicting treatment-induced phenotype changes, we will analyze serial ctDNA samples from patients receiving targeted therapies. The method will be implemented as an open-source R package, and a workflow that can be deployed on local and cloud environments, facilitating its adoption in the cancer research community. This proposal addresses the urgent unmet clinical need for better analytical approaches to study cancer treatment resistance in “real-time” and to advance cancer precision medicine.

项目总结/文摘