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

RP2：CDK4抑制剂治疗：脂肪肉瘤生物标志物的鉴定和联合治疗 项目摘要/摘要 CDK4抑制剂(CDK4)的临床试验在治疗肺癌方面前景看好。 分化和去分化脂肪肉瘤(WD/DDLS)。CDK4i Palbociclib与 显著延长了无进展生存期，67%的患者有进展- 免费存活12周或更长时间。16%的患者有不寻常的反应， 无进展生存期&36周，包括一次持久缓解(&gt；2年)。已收到Palbociclib 2013年获得FDA突破性治疗地位，现在与来曲唑联合使用， 为乳腺癌开具的处方。然而，对于WD/DDLS患者，没有明确的迹象表明是谁 谁会受益，谁不会受益，也没有迹象表明CDK4i可能是其他药物 与之相结合，对提高患者数量具有非同寻常的好处。 我们发现，MDM2的加速降解可以区分CDK4抑制剂 导致WD/DDLS细胞静止或衰老。CDK4I诱导的MDM2丢失呈正相关 在一项对7名患者进行的先导性研究中，与患者反应相关。我们还展示了ATRX是 CDK4i诱导的MDM2降解所需。因此，我们有信心预测生物标志物 患者在治疗前的反应将通过更好地了解其机制而获得。 CDK4抑制后被诱导退出细胞周期的MDM2的调节。 因此，我们在特定的目标1中提出了一套生化、分子和遗传学的 确定调节MDM2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 两种候选生物标志物与患者预后的关系：ATRX和ATRX的磷酸化 CDH18的表达，它是一种负调控因子，可以隔离PDLIM7，从而允许MDM2 退化。这项分析将使用在以前的临床试验中获得的患者档案资料。我们会 还前瞻性地验证ATRX和CDH18以及通过以下途径获得的其他预测标记物 在我们使用CDK4i abemaciclib进行新的临床试验期间，进行了目标1和目标2的研究。 我们还发现ATRX结合并抑制衰老过程中HRAS基因的表达 细胞，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途径抑制剂的联合应用。

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.