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

• 批准号: 10016097
• 负责人: ANDREW KOFF
• 金额: $ 31.5万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016097
• 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; 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; Progression-Free Survivals; Proteins; RAS genes; Radiation; Recurrence; Regulation; Resistance; Sampling; Soft tissue sarcoma; Testing; Therapeutic; Tissues; Translating; Work; Xenograft procedure; base; biomarker identification; candidate marker; chemotherapy; design; differential expression; drug efficacy; experimental study; genetic approach; immune clearance; improved; inhibitor/antagonist; insight; liposarcoma; malignant breast neoplasm; neoplastic cell; outcome forecast; patient response; predictive marker; prevent; primary endpoint; programs; prospective; response; response biomarker; sarcoma; senescence; transcriptome sequencing; tumor; tumor growth; tumor progression

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抑制剂疗法：脂肪肉瘤的生物标志物和联合疗法的鉴定 项目摘要/摘要 CDK4抑制剂（CDK4IS）的临床试验在治疗良好方面已有望 分化和去分化的脂肪肉瘤（WD/DDLS）。 CDK4I PALBOCICLIB相关 无进展生存期显着延长，有67％的患者患有进展 自由生存12周或更长时间。 16％的患者有非凡的反应， 无进展生存率> 36周，包括一项持久的缓解（> 2年）。 Palbociclib收到了 2013年FDA的突破疗法状况，现在与LeTrozole结合 开处方用于乳腺癌。但是，对于WD/DDLS的患者，没有明确的迹象表明谁 会受益，谁不会，也没有迹象表明其他代理商可能是什么 结合起来，以改善具有非凡益处的患者数量。 我们发现MDM2的加速降解可以区分CDK4抑制剂是否 在WD/DDLS细胞中引起静止或衰老。 CDK4I诱导的MDM2损失是正面的 在七名患者的试点研究中，与患者反应相关。我们还表明Atrx是 CDK4I诱导的MDM2降解所需。因此，我们相信生物标志物可以预测 通过更好地了解机制，将获得治疗前的患者反应 在CDK4抑制后诱导退出细胞周期的细胞中的MDM2调节。 因此，我们在特定目标中提出了一套生化，分子和遗传的套件 确定调节MDM2降解的途径的方法。在特定目标2中，我们将确定 治疗引起的衰老所需的其他关键基因。在特定目标3中，我们将探测 患者结局与两个候选生物标志物之间的关系：ATRX的磷酸化和 CDH18的表达是一种负调节器，可隔离PDLIM7，从而允许MDM2 降解。该分析将使用先前临床试验中获得的档案患者材料。我们将 还可以预期验证ATRX和CDH18，以及通过 在我们与CDK4I Abemaciclib进行的新临床试验中，AIMS 1和2的研究。 我们还发现，ATRX与HRAS基因座的表达结合并抑制。 细胞，减少HRA的细胞促进了从静止到衰老的过渡。因此，在 特定目标4，我们将与RAS途径抑制剂结合使用CDK4抑制剂。