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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

基本信息

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
项目类别：
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

项目摘要

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.

总结