Integrative subtyping to improve therapeutic options for metastatic hormone receptor-positive breast cancer

综合亚型分型可改善转移性激素受体阳性乳腺癌的治疗选择

• 批准号: 10676801
• 负责人: Jennifer Caswell-Jin
• 金额: $ 22.55万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-03 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676801
• 关键词: Affect; Applications Grants; Area; Automobile Driving; Award; Bioinformatics; Biological Assay; Biology; Biopsy; Breast; CCND1 gene; CDK4 gene; Cancer Etiology; Categories; Cessation of life; Characteristics; Classification; Clinical; Clinical Trials; DNA Sequence Alteration; Data; Data Set; Development; Diagnosis; Disease; Distant Metastasis; ERBB2 gene; Exhibits; FGF19 gene; Fibroblast Growth Factor Receptors; Fluorescent in Situ Hybridization; Frequencies; Genes; Genome; Genomic approach; Genomics; Goals; Health; In Situ; Institution; Intelligence; Knowledge; Learning; Length; Life; Ligands; Malignant Neoplasms; Mammary Neoplasms; Mentorship; Metastatic breast cancer; Metastatic/Recurrent; Methods; Molecular; Multiomic Data; Neoplasm Metastasis; Oncologist; Participant; Pathway interactions; Patients; Phase Ib Clinical Trial; Plasma; Proteomics; Public Health; Receptor Inhibition; Recurrence; Research; Resistance; Role; Safety; Sampling; Signal Pathway; Specimen; System; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tissue Sample; Training; Tumor Tissue; Tumor stage; United States; Universities; Woman; biomarker development; breast cancer genomics; cancer subtypes; career; career development; cohort; design; effective therapy; genetic variant; genome sequencing; genome-wide; high risk; hormone receptor-positive; hormone therapy; improved; improved outcome; inhibitor; insight; instructor; machine learning algorithm; machine learning method; malignant breast neoplasm; novel; novel strategies; novel therapeutic intervention; overexpression; patient subsets; personalized approach; personalized therapeutic; precision oncology; resistance mechanism; response; targeted treatment; transcriptome sequencing; translational scientist; treatment response; tumor; tumor-immune system interactions; whole genome

Project Summary/Abstract This is an application for a K08 Award to Dr Jennifer Caswell-Jin, an Instructor and breast oncologist at Stanford University establishing a career in translational breast cancer genomic research. The Award will support her career development by providing training in clinical trials, biomarker development, and bioinformatic analysis of multi-omic data under the expert mentorship of Dr Christina Curtis, computational and cancer systems biologist, and Dr George Sledge, breast cancer clinical trialist and translational researcher. The proposed research focuses on the major public health problem of metastatic breast cancer, estimated to affect over 150,000 women and to cause over 40,000 deaths each year in the United States. Hormone receptor-positive (HR+) breast cancer is the most common subtype. Eight “integrative” subtypes of HR+ breast cancer have been identified based on the integration of genome-wide copy number and expression information in early-stage breast tumors. Four integrative subtypes, together comprising one-quarter of all HR+ early-stage breast cancers, exhibit a very high risk of distant metastasis; each of these subtypes is characterized by a distinct area of the genome that exhibits concomitant copy number gain and overexpression. The studies in this proposal will examine for the first time how integrative subtypes behave after metastasis, with the driving hypothesis that they may derive benefit from personalized therapeutic approaches. Aim 1 is to investigate the biology and impact of integrative subtypes in metastatic HR+ breast cancer. We will develop novel approaches to assess integrative subtypes and will learn whether they change across metastasis, whether they are associated with timing of metastasis, and whether they have differential lengths of response to standard therapies. Aim 2 is to evaluate the effects of a novel combination of targeted therapy in two integrative subtypes of metastatic breast cancer. We will perform a clinical trial that tests a targeted therapeutic approach in tumors classifying as one of two of the four high-risk integrative subtypes. Because these two subtypes are defined by focal areas of genomic alteration involving either the fibroblast growth factor receptor ligand (FGF3; integrative subtype 2) or the fibroblast growth factor receptor (FGFR1; integrative subtype 6), we hypothesize that these tumors may benefit from FGFR inhibition. Participants in this trial will receive standard endocrine therapy in combination with CDK4/6 inhibition, as well as an investigational agent that inhibits the fibroblast growth factor receptor pathway. We will also perform tumor biopsies before and during treatment to evaluate for changes that occur with this combination targeted therapy approach. Successful completion of the proposed studies will lay the groundwork for continued efforts to develop a precision oncology approach for metastatic HR+ breast cancer, with next steps to be proposed in an R01 grant application before the end of the K08 Award.

项目总结/文摘