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RB tumor suppressor as a therapeutic target in ER-positive breast cancer

RB 肿瘤抑制因子作为 ER 阳性乳腺癌的治疗靶点

基本信息

批准号：
10116343
负责人：
Erik Knudsen
金额：
$ 42.95万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10116343
关键词：
13q Adjuvant Chemotherapy Affect Aromatase Inhibitors Biological Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Bypass CDK2 gene CDK4 gene Cell Cycle Cell Cycle Arrest Cell Cycle Deregulation Cell Cycle Progression Cell Cycle Regulation Cell model Cessation of life Clinic Clinical Complex Critical Pathways Cytostatics Data Disease Disease Progression Drug Screening Drug usage Estrogen Antagonists Estrogen Receptor Status Estrogen Receptors Estrogen Therapy Estrogen receptor positive Estrogens Event Evolution Fulvestrant Gene Dosage Gene Expression Profile Gene Targeting Genetic Goals Hormonal Intervention Malignant Neoplasms Metastatic breast cancer Modeling Molecular Target Neoplasm Metastasis Organoids Pathway interactions Patients Pharmacologic Substance Pre-Clinical Model Process Publishing Recurrence Regimen Regulatory Pathway Relapse Resistance Risk Sampling Seminal Signal Pathway Therapeutic Therapeutic Intervention Tumor Suppressor Genes Tumor Suppressor Proteins United States Woman Work base de novo mutation genetic evolution genetic selection hormone therapy improved in vivo inhibitor/antagonist malignant breast neoplasm next generation patient derived xenograft model personalized approach pressure prognostic programs public health relevance receptor function response targeted agent targeted treatment therapeutic target therapy resistant treatment response tumor tumor heterogeneity

项目摘要

ABSTRACT: Our work over the last several years, indicates that cell cycle regulatory pathways are critical determinants of the response to endocrine therapy as well as targeted therapies that are frequently employed in the treatment of ER+ metastatic breast cancer. Here we will focus on the RB-tumor suppressor pathway as a central node controlling proliferation downstream of multiple pathways of relevance to therapy of ER+ breast cancer (e.g. endocrine therapy and CDK4/6 inhibitors). While RB is required for the effective cytostatic response to a range of targeted therapies employed in ER+ breast cancer, multiple pathways can contribute to “cell cycle plasticity” and therefore represent distinct means for generating therapeutic resistance. Here we will delineate the processes underlying this form of resistance, means to elicit durable cell cycle arrest, and approaches to target resistance as observed clinically (Aim 1). Our data and newly published studies indicate that RB loss occurs in ER+ breast cancer as a means to escape from cytostatic therapies. Analysis of the RB locus in ER+ breast cancer indicates loss of one copy of 13q occurs in a significant fraction of ER+ breast cancers, suggesting that such tumors are primed for RB loss. How to subsequently treat tumors that are heterogeneous for RB or are solely RB deficient represents a significant challenge. Using drug screening and organoid approaches we have defined several regimens that are particularly effective against RB-negative tumors and could represent a general means to target ER+ tumors that progress on CDK4/6 inhibitors (Aim 2). Together these aims will interrogate means to further leverage the RB tumor suppressor for a precision approach to the treatment of ER+ breast cancer.

摘要：在过去的几年里，我们的工作表明，细胞周期调控途径是至关重要的