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：脂肪肉瘤生物标志物的鉴定和联合疗法 项目摘要/总结 CDK4 抑制剂 (CDK4is) 的临床试验在治疗良好的 分化和去分化脂肪肉瘤（WD/DDLS）。 CDK4i palbociclib 关联 无进展生存期显着延长，67% 的患者出现进展- 自由生存期为 12 周或更长时间。百分之十六的患者有非凡的反应， 无进展生存期>36周，包括一次持久缓解（>2年）。哌柏西利收到 2013 年获得 FDA 突破性治疗地位，现在与来曲唑联合使用， 为乳腺癌开处方。然而，对于 WD/DDLS 患者，没有明确指出谁是 会受益，谁不会，也没有迹象表明其他药物 CDK4i 可能是什么 结合起来对提高患者数量具有非凡的益处。 我们发现MDM2的加速降解可以区分CDK4抑制剂是否 导致 WD/DDLS 细胞静止或衰老。 CDK4i 诱导的 MDM2 丢失呈阳性 在一项针对七名患者的试点研究中，该研究与患者反应相关。我们还表明 ATRX 是 CDK4i 诱导的 MDM2 降解所需。因此，我们有信心生物标志物能够预测 通过更好地了解该机制，可以获得治疗前的患者反应 CDK4 抑制后诱导细胞退出细胞周期的 MDM2 调节。 因此，我们在具体目标 1 中提出了一套生化、分子和遗传研究 确定调节 MDM2 降解途径的方法。在具体目标 2 中，我们将确定 治疗引起的衰老所需的其他关键基因。在具体目标 3 中，我们将探讨 患者结果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，CDH18 是一种负调节因子，可隔离 PDLIM7，从而允许 MDM2 降解。该分析将使用在之前的临床试验中获得的存档患者材料。我们将 还前瞻性验证 ATRX 和 CDH18，以及通过获得的其他预测标记 在我们使用 CDK4i abemaciclib 进行的新临床试验中，我们对目标 1 和 2 进行了研究。 我们还发现 ATRX 结合并抑制衰老中 HRAS 基因座的表达 细胞，并且减少 HRAS 促进从静止到衰老的转变。因此，在 具体目标4，我们将评估CDK4抑制剂与Ras途径抑制剂的组合。