Retroperitoneal liposarcomas are rare, but can progress with high mortality, where current medical therapies are ineffective. All carry amplification of the CDK4 cell-cycle promoter, and CDK4 inhibitors can induce cell senescence, but not all liposarcomas respond. Our broad objective is to discover drugs or druggable targets that in combination with CDK4 inhibition might drive liposarcoma cell senescence or death. Specific aims include a small-molecule screen of bioactive compounds, and a CRISPR genetic screen of druggable protein targets. During the reporting period, we have encountered some challenges, including a sarcoma research community reluctant to share cell lines, and an inability to reproduce certain previously published findings in the field. Nevertheless, we have made substantial progress, including validating 4 liposarcoma lines with CDK4 amplification, characterizing CDK4 inhibitor responses (senescence phenotype assays), piloting drug combination assays with candidate synergizing compounds, and generating stable Cas9-expressing cell subclones. We are on target to complete our studies during the no-cost extension period, where completion will identify new treatment avenues for this rare but deadly cancer.