Tyrosine phosphorylation of p27Kip1 as a biomarker to identify Cdk4/6 inhibitor response

p27Kip1 的酪氨酸磷酸化作为识别 Cdk4/6 抑制剂反应的生物标志物

• 批准号: 10426292
• 负责人: JANICE L BRISSETTE
• 金额: $ 62.08万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-10 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426292
• 关键词: Address; Back; Benign; Biochemical; Biochemistry; Biological Assay; Biological Markers; Biopsy; Breast Cancer Patient; CDK2 gene; CDK4 gene; Cell Line; Clinical; Clinical Trials; Complex; Cyclin D1; Data; Development; Drug Targeting; Drug resistance; ERBB2 gene; Effectiveness; Estrogens; Exhibits; Feedback; Flow Cytometry; Fulvestrant; Goals; Hormones; Immunohistochemistry; In Vitro; Letrozole; Malignant neoplasm of ovary; Mediating; Metastatic breast cancer; Methods; Oncogenic; Pathologic; Patient Rights; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phosphorylation; Prediction of Response to Therapy; Progression-Free Survivals; Publishing; Refractory; Resistance; Resistance development; Savings; Signal Pathway; Stains; Stratification; Subgroup; Surrogate Endpoint; Surrogate Markers; Testing; Therapeutic; Time; Toxic effect; Tyrosine; Tyrosine Phosphorylation; Work; base; chemotherapy; clinically relevant; clinically significant; cohort; companion diagnostics; cost; diagnostic biomarker; differential expression; dimer; improved; in vivo; in vivo Model; inhibitor; malignant breast neoplasm; mammary epithelium; monomer; novel; novel diagnostics; novel therapeutics; patient derived xenograft model; patient response; precision medicine; predicting response; predictive marker; resistance mechanism; response; targeted treatment; tissue culture; triple-negative invasive breast carcinoma; tumor

SUMMARY While the CDK4 targeting drugs (CDK4i), Palbociclib, Abemaciclib, and Ribociclib, have shown clinical promise in the treatment of metastatic breast cancer (BC), lack of a companion diagnostic to identify responsive patients remains a problem. While CDK4i therapy increases progression-free survival (PFS) in some metastatic HR+ patients, many patients exhibit primary resistance to CDK4/6 inhibition and do not derive any benefit from these agents, switching to chemotherapy within 6 months. Development of a biomarker to identify the presence of the active CDK4 target, and therefore CDK4i sensitive patients, would enable responsive metastatic breast cancer patients to be pinpointed at the onset of therapy. As CDK4/6 is downstream of all oncogenic signaling pathways, it is also likely that this class of drugs will have efficacy in at least a subset of additional tumor types, and a biomarker for CDK4i responsiveness would accelerate the expansion of this class of therapy into tumor types, such as metastatic Her2+, Triple negative breast or ovarian cancer, which have few therapeutic options. A biomarker to predict effectiveness of CDK4i would mean more rapid benefit to the correct patients, a cost and time savings and reduced toxicity for patients who would not be benefited and extended use of these therapies across tumor types where novel therapies are desperately needed. In essence: a biomarker would help get the right drug to the right patients. This translational project will focus on the utility of a novel diagnostic marker, p27Kip1 pY88, to identify patients who would respond to the currently used CDK4i therapy. In published and presented work, we have shown that pY88 serves as a surrogate marker for CDK4 activity and in turn CDK4i responsiveness, in cell lines, primary explant culture, and now in biopsies from patients treated clinically with CDK4i therapy. The goal of this RO1 project is to demonstrate that p27 pY is a diagnostic biomarker to identify CDK4/6i-responsive patients and then also to reconcile why pY might demarcate resistance by associating it to mechanisms of resistance, with the idea that this will further inform potential uses of the CDK4/6i drugs. In Aims 1 and 2 (translational aims) we plan to test an IHC based assay to determine if pY88 can serve as a biomarker to predict significant PFS improvement in patients with HR+/HER2- BC treated with CDK4/6i. In Aim 3 (mechanism aim), we will determine how pY status relates to CDK4/6i sensitivity and resistance. Aim 1: To test the ability of the pY biomarker to predict significant PFS, by comparing pY88 status in biopsy material from patients with HR+ BC treated clinically with CDK4/6i with patient outcome data. Aim 2. To test the validated pY test in clinically relevant cohorts, from two completed and ongoing clinical trials. Aim 3: To determine how pY status relates to CDK4/6i sensitivity and resistance, by using biochemical studies to examine pY status in in vitro and in vivo models of CDK4/6i resistance.

概括 而CDK4靶向药物（CDK4I），palbociclib，abemaciclib和ribociclib已显示出临床承诺 在治疗转移性乳腺癌（BC）中，缺乏伴侣诊断来识别反应迅速 患者仍然是一个问题。而CDK4I疗法在某些人中增加了无进展生存率（PFS） 转移性HR+患者，许多患者表现出对CDK4/6抑制的主要抵抗力，并且不会得出任何 受益于这些药物，在6个月内改用化学疗法。开发生物标志物以识别 活性CDK4靶标，因此CDK4I敏感患者的存在将使响应能力 转移性乳腺癌患者将在治疗发作时精确定位。因为CDK4/6在所有人的下游 致癌信号通路，这类药物也很可能在至少一部分中具有功效 其他肿瘤类型，以及CDK4I响应能力的生物标志物将加速这种扩展 肿瘤类型的治疗类别，例如转移性HER2+，三重阴性乳腺癌或卵巢癌，它们 几乎没有治疗选择。预测CDK4I有效性的生物标志物将意味着更快的好处 正确的患者，成本和时间节省的时间以及对不会受益的患者的毒性降低，并且 这些疗法在迫切需要新型疗法的肿瘤类型中的扩展使用。在 本质：生物标志物将有助于将正确的药物送给正确的患者。这个翻译项目将重点放在 新型诊断标记物P27KIP1 PY88的实用性，以识别会对当前反应的患者 用过的CDK4I治疗。在出版和介绍的工作中，我们证明PY88用作代理 CDK4活性和CDK4I响应性的标记，在细胞系，主要外植体培养物中，现在 接受CDK4I治疗治疗的患者的活检。这个RO1项目的目标是证明 该P27 PY是一种诊断CDK4/6-i-6-i-emersigative患者的诊断生物标志物，然后 调和为什么PY通过将抵抗与抗药机制相关联，将其与抗药性相关联 这将进一步为CDK4/6i药物的潜在用途提供信息。在目标1和2中（转化目的）我们 计划测试基于IHC的测定法，以确定PY88是否可以用作生物标志物来预测重要的PFS 用CDK4/6i治疗的HR+/HER2- BC患者的改善。在AIM 3（机制AIM）中，我们将 确定PY状态与CDK4/6i的敏感性和抗性的关系。目标1：测试PY的能力 通过比较HR+患者的活检材料中的PY88状态，可以预测重要的PFS。 卑诗省用CDK4/6i在临床上使用患者结果数据进行处理。目标2。测试已验证的PY测试 临床相关的队列，来自两个完整且正在进行的临床试验。目标3：确定如何PY 状态与CDK4/6i的敏感性和抗性有关，通过使用生化研究来检查PY状态 CDK4/6i抗性的体外和体内模型。