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

摘要： 雌激素受体阳性(ER+)疾病占新发乳腺癌病例的70%以上， 在转移的环境下接受内分泌治疗和CDK4/6抑制剂治疗。虽然这些方法有 临床影响，所有患者最终在治疗上都取得了进展。通常情况下，CDK4/6抑制剂 通过抑制细胞周期的G1/S期进展来抑制细胞增殖。 然而，越来越多的数据收集表明，CDK4/6抑制剂的全身给药已经 对肿瘤的广泛影响(例如，适应性信号和代谢)和相关的微环境 (例如，免疫环境)。这种复杂的作用机制可能与对 治疗和获得抵抗力和疾病进展。其推论是，完全 了解耐药性的功能驱动因素可以开发新的干预措施来加强 反应或治疗进展性疾病的持久性。 研究ER+乳腺癌的挑战之一是缺乏健壮的小鼠模型。如图所示 在初步数据中，使用导管内注射建立了ER+腔内乳腺癌的健壮小鼠模型 已经被开发出来了。我们将使用这个模型来询问CDK4/6抑制对多焦点的影响 在这个模型中出现的肿瘤，强调了对细胞周期的典型影响以及对细胞周期的影响。 在肿瘤微环境中进行编程。对于这项工作，我们将使用多光谱成像和单光谱 我们最近发表的用于肿瘤特征和免疫学的细胞测序方法 疾病的特征。这些模型服从于体细胞基因操作，这也使司机能够 体内治疗耐药(目标1)。由于许多患者正在接受CDK4/6抑制剂的治疗，因此 越来越多的患者的肿瘤在治疗中进展。认识到…… 了解真实世界的体验很重要，我们启动了一项临床研究，进行纵向跟踪 正在接受治疗或肿瘤已经进展的患者接受基于CDK4/6抑制剂的治疗。在……里面 转移性乳腺癌活检是常见的进展性疾病，以评估常规的临床生物标志物； 因此，对于许多患者，我们正在收集多个组织标本。这里，我们将使用以下集合 组织来定义肿瘤的生物学特征，重点关注肿瘤的蛋白质和空间特征 在典型的分子分析中丢失(目标2)。来自这两个目标的数据将严格整合到 阐明ER+乳腺癌对CDK4/6抑制耐药的机制。

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.