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.
RP-2: CDK4 Inhibitor Therapy: Identification of Biomarkers and Combination Therapies for Liposarcoma Project Narrative (Public Relevance) Patients with well-differentiated and dedifferentiated liposarcoma have dismal prognosis, but we showed that palbociclib, a drug that received Breakthrough Therapy Designation from the FDA, is effective treating some patients. Based on our work in cell culture, and a pilot study in seven tumor samples from patients, we hypothesize that this was because the drug causes a loss of a protein called MDM2 and induces senescence in patients who did well. Thus we hope to develop pre-treatment markers of drug effectiveness by identifying molecules that predict whether CDK4 inhibitors such as palbociclib and abemaciclib will induce MDM2 downregulation and/or therapy-induced senescence, as these are likely to greatly improve the treatment of this disease.
