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CDK4 Inhibitor Therapy: Identification of Biomarkers and Combination Therapies for Liposarcoma

CDK4 抑制剂疗法：脂肪肉瘤生物标志物的鉴定和联合疗法

基本信息

批准号：
10468963
负责人：
ANDREW KOFF
金额：
$ 31.06万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468963
关键词：
12q13 ATRX gene Affect Archives Basic Science Binding Biochemical Biological Assay Biological Markers C-terminal CDK4 gene Cell Aging Cell Culture Techniques Cell Cycle Cell Line Cells Cessation of life Chromosomes Clinical Clinical Trials Collection Combined Modality Therapy Cyclin-Dependent Kinase Inhibitor 2A Dedifferentiated Liposarcomas Diffuse Disease Disease Progression Disease remission Down-Regulation Drug Combinations Effectiveness Engineering Enrollment Excision FDA approved Gene Expression Profile Genes Genetic Transcription Grant Immunization Incidence Letrozole Link MDM2 gene Mass Spectrum Analysis Messenger RNA Molecular Molecular Genetics Monoclonal Antibodies Mus Mutation Nature Operative Surgical Procedures Outcome Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase II Clinical Trials Phosphorylation Pilot Projects Post-Translational Protein Processing Prognosis Progression-Free Survivals Proteins RAS genes Radiation Recurrence Regulation Resistance Sampling Soft tissue sarcoma Testing Therapeutic Translating Work Xenograft procedure base biomarker identification candidate marker chemotherapy design differential expression drug efficacy experimental study genetic approach immune clearance improved inhibitor inhibitor therapy insight liposarcoma malignant breast neoplasm neoplastic cell patient response predictive marker prevent primary endpoint programs prospective response response biomarker sarcoma senescence tissue archive transcriptome sequencing tumor tumor growth tumor progression

项目摘要

RP2: CDK4 Inhibitor Therapy: Identification of Biomarkers and Combination Therapies for Liposarcoma Project Abstract/Summary Clinical trials for CDK4 inhibitors (CDK4is) have been promising in the treatment of well- differentiated and dedifferentiated liposarcoma (WD/DDLS). The CDK4i palbociclib was associated with significantly prolonged progression-free survival, with 67% of the patients having progression- free survival of 12 weeks or longer. Sixteen percent of the patients had an extraordinary response, with progression-free survival >36 weeks, including one durable remission (>2 years). Palbociclib received Breakthrough Therapy Status from the FDA in 2013 and is now, in combination with letrozole, prescribed for breast cancer. For patients with WD/DDLS, however, there is no clear indication of who would benefit and who would not, nor are there indications of what other agents CDK4i may be combined with to improve the number of patients with extraordinary benefit. We found that accelerated degradation of MDM2 can distinguish whether CDK4 inhibitors cause quiescence or senescence in WD/DDLS cells. CDK4i-induced loss of MDM2 was positively correlated with patient response in a pilot study of seven patients. We also showed that ATRX is required for CDK4i-induced MDM2 degradation. Thus, we are confident that biomarkers to predict patient response before treatment will be obtained by gaining a better understanding of the mechanism of MDM2 regulation in cells induced to exit the cell cycle following CDK4 inhibition. As such, we propose in Specific Aim 1 a suite of biochemical, molecular, and genetic approaches to identify the pathway regulating MDM2 degradation. In Specific Aim 2, we will identify other key genes required for therapy-induced senescence. In Specific Aim 3, we will probe the relationship between patient outcome and two candidate biomarkers: phosphorylation of ATRX and the expression of CDH18, a negative regulator that sequesters PDLIM7 and thereby allows for MDM2 degradation. This analysis will use archival patient material obtained in previous clinical trials. We will also prospectively validate ATRX and CDH18, as well as other predictive markers obtained through studies in aims 1 and 2, during our new clinical trials with the CDK4i abemaciclib. We also found that ATRX binds to and represses expression from the HRAS locus in senescent cells, and that reducing HRAS promotes the transition from quiescence to senescence. Therefore, in Specific Aim 4, we will evaluate CDK4 inhibitor in combination with Ras pathway inhibitors.

RP2: CDK4抑制剂治疗：脂肪肉瘤的生物标志物鉴定和联合治疗