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 CDK4 靶向药物 (CDK4i)、Palbociclib、Abemaciclib 和 Ribociclib 已显示出临床前景 在转移性乳腺癌 (BC) 的治疗中，缺乏识别反应性的伴随诊断 患者仍然是一个问题。虽然 CDK4i 治疗可延长某些患者的无进展生存期 (PFS) 转移性 HR+ 患者，许多患者表现出对 CDK4/6 抑制的原发性耐药，并且不会衍生任何 从这些药物中获益，并在 6 个月内转为化疗。开发生物标志物来识别 活性 CDK4 靶标的存在以及因此 CDK4i 敏感的患者将能够做出反应 转移性乳腺癌患者在治疗开始时应进行精确定位。由于 CDK4/6 是所有 致癌信号通路，此类药物也可能至少在一部分中有效 其他肿瘤类型和 CDK4i 反应性生物标志物将加速这一领域的扩展 针对肿瘤类型的治疗类别，例如转移性 Her2+、三阴性乳腺癌或卵巢癌，其中 几乎没有治疗选择。预测 CDK4i 有效性的生物标志物意味着更快速地受益 正确的患者，节省成本和时间，并减少不会受益的患者的毒性， 在迫切需要新疗法的肿瘤类型中广泛使用这些疗法。在 本质：生物标志物将有助于为正确的患者提供正确的药物。该翻译项目将重点关注 使用新型诊断标记物 p27Kip1 pY88 来识别对当前治疗有反应的患者 使用CDK4i疗法。在已发表和提出的工作中，我们已经证明 pY88 可作为替代品 细胞系、原代外植体培养物中 CDK4 活性和 CDK4i 反应性的标记，现在在 来自临床接受 CDK4i 治疗的患者的活检。该 RO1 项目的目标是展示 p27 pY 是一种诊断生物标志物，可识别 CDK4/6i 反应性患者，然后也可用于识别 CDK4/6i 反应性患者 协调为什么 pY 可能通过将其与耐药机制相关联来划分耐药性， 认为这将进一步告知 CDK4/6i 药物的潜在用途。在目标 1 和 2（转化目标）中，我们 计划测试基于 IHC 的测定，以确定 pY88 是否可以作为预测显着 PFS 的生物标志物 使用 CDK4/6i 治疗的 HR+/HER2- BC 患者的改善。在目标3（机制目标）中，我们将 确定 pY 状态与 CDK4/6i 敏感性和耐药性的关系。目标1：测试pY的能力 通过比较 HR+ 患者活检材料中的 pY88 状态来预测显着 PFS 的生物标志物 BC 使用 CDK4/6i 进行临床治疗并提供患者结果数据。目标 2. 测试经过验证的 pY 测试 临床相关队列，来自两项已完成和正在进行的临床试验。目标 3：确定 pY 如何 状态与 CDK4/6i 敏感性和耐药性相关，通过使用生化研究来检查 pY 状态 CDK4/6i 耐药性的体外和体内模型。