Sarcoma Cell Line Screen of Oncology Drugs and Investigational Agents Identifies Patterns Associated with Gene and microRNA Expression

Abstract

The diversity in sarcoma phenotype and genotype make treatment of this family of diseases exceptionally challenging. Sixty-three human adult and pediatric sarcoma lines were screened with 100 FDA approved oncology agents and 345 investigational agents. The investigational agents library enabled comparison of several compounds targeting the same molecular entity allowing comparison of target specificity and heterogeneity of cell line response. Gene expression was derived from exon array data and microRNA expression was derived from direct digital detection assays. The compounds were screened against each cell line at 9 concentrations in triplicate with an exposure time of 96 hrs using Alamar blue as the endpoint. Results are presented for inhibitors of the following targets: aurora kinase, IGF-1R, MEK, BET bromodomain, and PARP1. Chemical structures, IC50 heat maps, concentration response curves, gene expression and miR expression heat maps are presented for selected examples. In addition, two cases of exceptional responders are presented. The drug and compound response, gene expression and microRNA expression data are publicly available at http://sarcoma.cancer.gov. These data provide a unique resource to the cancer research community.

Pulmonary metastasectomy with therapeutic intent for soft-tissue sarcoma

“…34 The underlying mechanisms governing metastases in these mesenchymal cancers are not fully understood. 35 Cytotoxic agents remain first-line treatments for metastatic STS, and survival remains poor.…”

“…2 At least one targeted drug, the tyrosine kinase inhibitor pazopanib, is now approved as a second-line therapy for metastatic STS. 34 Additional therapies aimed at the insulin growth factor and mTOR pathways, as well as at mutations in ALK or MET, are undergoing clinical trials. 20 …”

Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target

“…KCNN1, on the other hand, is relatively highly expressed in the neuroblastoma lines and thus clearly not only in Ewing sarcomas. A microarray analysis studying expression in several Ewing sarcoma cell lines and other sarcoma types (including RMS) shows LINGO1 is consistently and significantly up-regulated only in Ewing sarcoma (21).…”

Englerins: A Comprehensive Review

“…63 A broader sarcoma cellular screen at NCI showed that 10/20 Ewing’s sarcoma cell lines were sensitive, while most other sarcomas were resistant, a result that paralleled the NCI 60 data (Table S1, Supporting Information). 69 The typology of Ewing’s sarcoma cell lines as distinguished by Khan et al 70 did not correlate with englerin A sensitivity, however.…”