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：
10579888
负责人：
Erik Knudsen
金额：
$ 42.09万
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/10579888
关键词：
13q Adjuvant Chemotherapy Affect Aromatase Inhibitors Biological Breast Cancer Model Breast Cancer Patient 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 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 Proliferating Publishing Recurrent disease Regimen Regulatory Pathway Relapse Resistance Retinoblastoma Genes Risk Sampling Seminal Signal Pathway Therapeutic Therapeutic Intervention Tumor Suppressor Proteins United States Woman Work antagonist de novo mutation drug use screening genetic evolution genetic selection hormone therapy improved in vivo inhibitor 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 tumor progression

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：我们过去几年的工作表明细胞周期调控途径至关重要对内分泌治疗以及经常采用的靶向治疗的反应的决定因素在此我们将重点关注 RB 肿瘤抑制通路。控制与 ER+ 乳腺治疗相关的多种途径下游增殖的中央节点癌症（例如内分泌治疗和 CDK4/6 抑制剂），而 RB 是有效的细胞抑制剂所必需的。对 ER+ 乳腺癌采用的一系列靶向治疗的反应，多种途径可以促进 “细胞周期可塑性”因此代表了产生治疗耐药性的不同方式。描述这种形式的抵抗的潜在过程，引发持久细胞周期停滞的方法，以及临床观察到的目标耐药性的方法（目标 1）。 ER+ 乳腺癌中发生 RB 丢失，作为逃避细胞抑制疗法的一种手段。 ER+ 乳腺癌中的位点表明 ER+ 乳腺癌的很大一部分发生了 13q 拷贝的丢失癌症，表明此类肿瘤已经为 RB 损失做好了准备。 RB 异质性或仅 RB 缺乏是使用药物筛选和治疗的重大挑战。类器官方法我们已经定义了几种对 RB 阴性特别有效的方案肿瘤，并可能代表一种针对使用 CDK4/6 抑制剂进展的 ER+ 肿瘤的通用方法（目标 2）。这些目标共同探讨进一步利用 RB 肿瘤抑制因子实现精确治疗的方法 ER+乳腺癌的治疗方法。