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

RP 2：CDK 4抑制剂治疗：脂肪肉瘤的生物标志物鉴定和联合治疗 项目摘要/摘要 CDK 4抑制剂（CDK 4 is）的临床试验在治疗良好的 分化型和去分化型脂肪肉瘤（WD/DDLS）。CDK 4 i palbociclib与 无进展生存期显著延长，67%的患者出现进展- 12周或更长时间的自由生存。百分之十六的病人有一个非凡的反应， 无进展生存期>36周，包括一次持久缓解（>2年）。接受Palbociclib治疗 2013年获得FDA的突破性治疗地位，现在与来曲唑联合使用， 开给乳腺癌的药然而，对于WD/DDLS患者，没有明确的迹象表明 将受益和谁不会受益，也没有迹象表明其他药物CDK 4 i可能是 与提高患者数量相结合，具有非凡的益处。 我们发现MDM 2的加速降解可以区分CDK 4抑制剂是否 引起WD/DDLS细胞的静止或衰老。CDK 4 i诱导的MDM 2丢失呈阳性。 与7名患者的初步研究中的患者反应相关。我们还表明，ATRX是 CDK 4 i诱导的MDM 2降解所必需的。因此，我们有信心，生物标志物来预测 通过更好地了解机制，将获得治疗前的患者反应 在CDK 4抑制后诱导退出细胞周期的细胞中的MDM 2调节。 因此，我们在具体目标1中提出了一套生物化学、分子和遗传学的方法， 确定调节MDM 2降解的途径的方法。在具体目标2中，我们将确定 治疗诱导衰老所需的其他关键基因。在具体目标3中，我们将探讨 患者结局与两种候选生物标志物之间的关系：ATRX的磷酸化和 CDH 18的表达，CDH 18是一种螯合PDLIM 7并由此允许MDM 2的负调节因子， 降解该分析将使用既往临床试验中获得的存档患者材料。我们将 还前瞻性验证了ATRX和CDH 18，以及通过以下方法获得的其他预测标志物： 目标1和2中的研究，在我们使用CDK 4 i abemaciclib的新临床试验期间。 我们还发现，ATRX结合并抑制HRAS基因座的表达，在衰老细胞中， 细胞，减少HRAS促进从静止到衰老的过渡。因此在 具体目标4，我们将评估CDK 4抑制剂与Ras通路抑制剂的组合。

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.