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

• 批准号: 10436675
• 负责人: Erik Knudsen
• 金额: $ 35.13万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 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/10436675
• 关键词: Biological; Biological Markers; Biology; Biopsy; CDK4 gene; Cancer Etiology; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Cessation of life; Clinical; Clinical Research; Complement; Data; Data Collection; Disease; Disease Progression; Estrogen Receptors; Estrogen receptor positive; Evolution; FDA approved; G1 Phase; Gene Expression; Genetic; Goals; Immunologics; Injections; Intervention; Measures; Metabolism; Metastatic breast cancer; Modeling; Molecular Analysis; Mus; Mutation; PIK3CA gene; Patients; Progressive Disease; Prospective Studies; Protein Analysis; Proteins; Publishing; Regimen; Resistance; Resistance development; Signal Transduction; Specimen; Tissue Banks; Tissues; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; United States; Woman; Work; base; clinical biomarkers; clinically relevant; experience; genetic manipulation; hormone therapy; in vivo; inhibitor; interest; malignant breast neoplasm; mouse model; novel; predictive marker; resistance mechanism; response; single cell sequencing; spectrograph; therapeutic target; therapy resistant; tool; treatment response; tumor; tumor heterogeneity; tumor microenvironment; tumorigenesis

ABSTRACT: Estrogen receptor-positive (ER+) disease represents greater than 70% of new breast cancer cases and is treated with endocrine-therapy and CDK4/6 inhibitors in the metastatic setting. While these approaches have clinical impact, veritably all patients ultimately progress on treatment. Conventionally, CDK4/6 inhibitors function by inhibiting cellular proliferation by inhibiting progression through G1/S phase of the cell cycle. However, an ever-increasing collection of data indicate that the systemic delivery of CDK4/6 inhibitors has broad effects on both the tumor (e.g. adaptive signaling and metabolism) and the associated microenvironment (e.g. immunological milieu). This complexity in mechanism of action is likely relevant for the response to therapy and acquisition of resistance and disease progression. The corollary of which, is that by fully understanding the functional drivers of resistance new interventions could be developed to enhance the durability of response or treat progressed disease. One of the challenges in studying ER+ breast cancer is the lack of robust mouse models. As shown in the preliminary data, using intraductal injection a robust mouse model for ER+ luminal breast cancer has been developed. We will use this model to interrogate the impact of CDK4/6 inhibition on the multi-focal tumors that arise in this model with an emphasis on both the canonical effects on cell cycle as well as re- programming within the tumor microenvironment. For this work we will use multi-spectral imaging and single cell sequencing approaches as we have recently published for tumor characterization and immunological features of the disease. These models are amenable to somatic genetic manipulation that also enable drivers of therapeutic resistance in vivo (Aim 1). Since many patients are being treated with CDK4/6 inhibitors, there are progressively more patients whose tumors have progressed on therapy. In recognition that understanding the real world experience is important, we initiated a clinical study to longitudinally follow patients who are being treated or whose tumors have progressed on CDK4/6 inhibitor based therapy. In metastatic breast cancer it is common to biopsy progressive disease to evaluate routine clinical biomarkers; therefore, for many patients we are collecting multiple tissue specimens. Here we will use this collection of tissues to define biological features of the tumors with a focus on proteins and spatial features of the tumor that are lost with typical molecular analyses (Aim 2). The data from these two Aims will be integrated to rigorously delineate the mechanisms of resistance to CDK4/6 inhibition in ER+ breast cancer.

抽象的： 雌激素受体阳性（ER+）疾病占新乳腺癌病例的70％，IS 在转移性环境中用内分泌疗法和CDK4/6抑制剂治疗。尽管这些方法有 临床影响，有效所有患者最终都会在治疗上进展。通常，CDK4/6抑制剂 通过抑制细胞周期的G1/S相抑制细胞增殖来抑制细胞增殖。 但是，越来越多的数据集合表明，CDK4/6抑制剂的全身传递具有 对肿瘤（例如自适应信号传导和代谢）和相关微环境的广泛影响 （例如免疫环境）。作用机理的这种复杂性可能与对的反应有关 抗药性和疾病进展的治疗和获取。推论的是完全 了解阻力的功能驱动因素可以开发出新干预措施以增强 反应的耐用性或治疗进展的疾病。 研究ER+乳腺癌的挑战之一是缺乏强大的小鼠模型。如图所示 在初步数据中，使用导管内注射一个可ER+腔内乳腺癌的鲁棒小鼠模型具有 已开发。我们将使用此模型来询问CDK4/6抑制对多焦点的影响 在该模型中出现的肿瘤，重点介绍了对细胞周期的规范作用以及重新的影响 肿瘤微环境中的编程。对于这项工作，我们将使用多光谱成像和单个成像 我们最近发表的有关肿瘤表征和免疫学的细胞测序方法 疾病的特征。这些模型适合躯体遗传操作，这也使驱动器能够 体内治疗性抗性（AIM 1）。由于许多患者接受了CDK4/6抑制剂的治疗，因此 逐渐增加了肿瘤在治疗方面的患者。认识到这一点 了解现实世界的体验很重要，我们开始了一项临床研究，以纵向遵循 正在接受治疗或其肿瘤在基于CDK4/6抑制剂治疗上的患者。在 转移性乳腺癌是活检进行性疾病通常评估常规临床生物标志物的常见。 因此，对于许多患者，我们正在收集多个组织标本。在这里，我们将使用此集合 定义肿瘤生物学特征的组织，重点是蛋白质和肿瘤的空间特征 由于典型的分子分析而丢失（AIM 2）。这两个目标的数据将被整合到严格的 描述ER+乳腺癌中对CDK4/6抑制的抗性机制。