Potential targeted therapeutic approaches in liposarcoma

(LPS) is rare malignant tumor of fat cells in deep soft tissue that affects adults between the ages of 40 and 60 [1]. This tumor is extremely aggressive with high morbidity and mortality. World Health organization classifies LPS into five subtypes: well-differentiated (WDLPS)/Atypical lipomatous tumors (ALT); dedifferentiated (DDLPS); myxoid (MLPS); pleomorphic (PLPS); and mixed type LPS [2]. Most common modality of treatment is surgical removal of tumor followed by radiation and chemotherapy. The five year survival rate of LPS patients vary from 56%-100% based on different subtypes [3]. Previous genetic studies have focused either on a subset of target genes or one subtype of LPS. Till now no reports have provided a detailed genomic analysis of LPS which included all different subtypes of LPS. Therefore, recently we defined the genomic landscape of LPS using SNP array and whole exome sequencing and identified a spectrum of altered genes and pathways in different subtypes of LPS patients and cell lines [4]. WDLPS and DDLPS subtypes have a characteristic feature of amplified region of chromosome 12q13-15 containing several well-known oncogenes such as MDM2, CDK4 and HMGA2 [5]. SNP array analysis of LPS patients and cell lines identified recurrent amplification of Carboxypeptidase M (CPM) gene only in WDLPS and DDLPS subtypes. We studied in detail CPM gene in vitro and in vivo and showed its involvement in liposarcomagenesis. CPM is a membrane bound enzyme and we found it expressed on the cell surface of LPS cells suggesting it as a potential therapeutic target. Carboxypeptidase activity of CPM is known to regulate the processing of EGF [6]. We found downregulation of CPM expression leads to reduced EGFR signalling and induces apoptosis of LPS cells. Future studies are ongoing detailing further role of enzymatic activity of CPM in EGFR signaling and enhancement of tumor growth. Further, we are developing both a quantitative PCR assay and an ELISA to measure CPM activity in the serum to develop a biomarker to measure minimal residual disease which might aid in monitoring therapy. Specific and selective inhibitors of CPM are not available in the market; therefore, we are also aiming to do screening to find selective and specific small molecules to inhibit Editorial CPM enzymatic activity. We proposed CPM as potential therapeutic candidate which could be used as targeted approach to manage CPM amplified WDLPS or DDLPS patients. Next, whole exome sequencing and targeted exome sequencing identified various known cancer …