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节途径至关重要确定对内分泌疗法的反应以及经常使用的靶向疗法在治疗ER+转移性乳腺癌中。在这里，我们将重点关注RB肿瘤抑制途径与ER+乳房治疗相关的多种途径下游控制增殖的中央节点癌症（例如内分泌治疗和CDK4/6抑制剂）。虽然有效的细胞固化需要RB 对ER+乳腺癌采用的一系列靶向疗法的反应，多种途径可以有助于 “细胞周期塑性”，因此代表了产生治疗抗性的不同手段。我们会在这里描述这种抗性形式的基础的过程，用于引起持久的细胞周期停滞，并如临床上观察到的靶向抗性方法（AIM 1）。我们的数据和新发表的研究表明 RB丧失发生在ER+乳腺癌中，是逃避细胞抑制疗法的一种手段。 RB分析 ER+乳腺癌中的基因座表明，在ER+乳房的很大一部分中出现了一份13Q的副本癌症表明，这种肿瘤是为了引发RB损失。如何随后治疗肿瘤 RB的异质性或仅是RB缺乏代表了一个重大挑战。使用药物筛查和器官方法我们定义了几种针对RB阴性特别有效的方案肿瘤，可以代表靶向CDK4/6抑制剂上进展的ER+肿瘤的一般手段（AIM 2）。这些目标共同审问手段，以进一步利用RB肿瘤抑制剂以精确治疗ER+乳腺癌的方法。