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Circulating Genomic Determinants of Treatment Failure in Hodgkin Lymphoma

霍奇金淋巴瘤治疗失败的循环基因组决定因素

基本信息

批准号：
10588252
负责人：
Ash Arash Alizadeh
金额：
$ 64.09万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-04 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588252
关键词：
Antibody-drug conjugates Biological Assay Biological Markers Biotechnology Blood Cancer Patient Cells Clinical Cytotoxic Chemotherapy DNA Sequence Alteration Dependence Development Diagnosis Disease Disease remission Doctor of Medicine Doctor of Philosophy Event Failure Frequencies Genetic Genomics Genotype Goals Heterogeneity Hodgkin Disease Human Human Herpesvirus 4 IL4 gene Image Individual Interleukin 4 Receptor Malignant Neoplasms Measurable Measurement Measures Metabolic Methods Modeling Molecular Monitor Mutation Nature Outcome Pathologic Pathway interactions Patients Phenotype Plasma Positron-Emission Tomography Precision therapeutics Prediction of Response to Therapy Property Public Health Recurrence Regimen Risk Risk Factors STAT6 gene Signal Transduction Somatic Mutation Stereotyping Techniques Testing Therapeutic Therapeutically Targetable Toxic effect Toxicity due to chemotherapy Treatment Efficacy Treatment Failure Treatment outcome Tumor Tissue Tumor Volume Variant Viral Genome Work biological heterogeneity cancer cell cancer imaging clinical biomarkers clinical heterogeneity cohort cytokine disorder risk exome experimental study gain of function genetic variant high risk imaging modality imaging study immune checkpoint blockade improved indexing induced pluripotent stem cell innovation insight integration site liquid biopsy molecular marker neoplastic cell novel novel therapeutic intervention outcome prediction personalized medicine personalized risk prediction pre-clinical precision medicine prognostication response response biomarker risk prediction risk prediction model targeted treatment therapeutic target therapy outcome tumor tumor DNA

项目摘要

PROJECT SUMMARY/ABSTRACT PIs: Ash Alizadeh, M.D./Ph.D. & Maximilian Diehn, M.D./Ph.D. Classical Hodgkin lymphoma (HL) is among the most curable human malignancies. However, strategies to personalize HL therapies and to minimize long-term attendant toxicities of chemotherapy are currently limited to baseline risk factors and imaging. This is due to our incomplete understanding of targetable pathways and lack of good biomarkers. Because of the low fraction of malignant cells in tumor tissue and consecutive technical challenges, the landscape of HL is not well-defined. Our long-term goal is to study the ability of baseline and dynamic risk factors, including genetic mutations, circulating tumor DNA (ctDNA) and imaging studies (PET), to accurately predict treatment outcomes in HL patients, and to provide a basis for individualized precision medicine. Our central hypothesis is that clinical and biological heterogeneity in HL reflects distinct genomic features that are noninvasively measurable using ultrasensitive ctDNA techniques, and that refining early response assessment integrating interim PET and blood based methods improves prognostication. We will test our hypotheses via three specific aims: (1) To noninvasively define the genomic landscape of somatic variations in HL, and to determine the relationship of genomic variants with biological heterogeneity at initial disease presentation, (2) To associate molecular features at baseline and molecular response with ultimate therapeutic outcome, and to integrate clinical and molecular biomarkers in a personalized dynamic risk model for predicting HL outcomes, and (3) To functionally characterize novel mutations in Interleukin-4 receptor (IL4R) resulting in gain-of-function IL4/STAT6 signaling, and to test the utility of precision therapeutic targeting of these mutations. If successful, our project will lead to novel ways to select better therapies for patients at highest risk of failure, and to minimize toxicity for the majority of patients responding well to standard therapy. Our innovative approach, in which we will combine blood-based methods for genotyping and disease monitoring with imaging studies, will provide the basis for a personalized treatment approach in HL.

项目总结/文摘