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， 在转移性环境中用内分泌疗法和CDK 4/6抑制剂治疗。虽然这些方法 临床影响，实际上所有患者最终都在治疗中取得进展。通常，CDK 4/6抑制剂 通过抑制细胞周期的G1/S期来抑制细胞增殖。 然而，不断增加的数据收集表明，CDK 4/6抑制剂的全身递送具有显著的生物学效应。 对肿瘤（例如适应性信号传导和代谢）和相关微环境的广泛影响 (e.g.免疫学环境）。这种作用机制的复杂性可能与以下反应有关： 治疗和获得抗性和疾病进展。其必然结果是， 了解耐药性的功能驱动因素，可以制定新的干预措施，以加强 反应的持久性或治疗进展性疾病。 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，ER+管腔型乳腺癌的稳健小鼠模型， 开发了我们将使用该模型来询问CDK 4/6抑制对多灶性 在这个模型中出现的肿瘤，强调对细胞周期的典型影响以及对细胞周期的重新调节。 在肿瘤微环境中编程。对于这项工作，我们将使用多光谱成像和单 细胞测序方法，因为我们最近发表的肿瘤表征和免疫 疾病的特征。这些模型可以进行体细胞遗传操作， 体内治疗耐药性（目标1）。由于许多患者正在接受CDK 4/6抑制剂治疗， 越来越多的患者在治疗过程中肿瘤进展。因为认识到 了解真实的世界经验是重要的，我们启动了一项临床研究， 正在接受基于CDK 4/6抑制剂的治疗或肿瘤进展的患者。在 转移性乳腺癌通常对进展性疾病进行活检以评估常规临床生物标志物; 因此，对于很多病人，我们会收集多个组织样本。在这里，我们将使用这个集合， 组织来定义肿瘤的生物学特征，重点是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）。这两个目标的数据将被严格整合， 描述ER+乳腺癌中CDK 4/6抑制的抗性机制。

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.