Abstract 4361: Target and drug discovery for recalcitrant, rare and neglected cancers.
Authors: Anne Monks, Annamaria Rapisarda, Kazimierz O. Wrzeszczynski, E. Michael August, Eric C. Polley, Sudhir B. Kondapaka, Gurmeet Kaur, Dianne Newton, Beverley A. Teicher
Journal: Cancer Research (2013)

Abstract Efforts are underway to improve the treatment of recalcitrant, rare and neglected cancers through the discovery of potential therapeutic targets, the identification of possible therapeutic combinations, and the identification of genomic vulnerabilities, using state-of-the-art drug discovery, molecular characterization, and mechanism-of-action techniques. Our current focus is on sarcoma and small cell lung cancer. Sarcoma comprises approximately 1% of cancers inclusive of 50 subtypes and occurs in patients of all ages with a frequency spread evenly over the human age range. Small cell lung cancer (SCLC) constitutes approximately 15% of lung cancers, is extremely aggressive, has a high mortality rate and frequently recurs after conventional cytotoxic chemotherapy. We have established comprehensive panels of human sarcoma and small cell lung cancer cell lines (approximately 80 per tumor type). Cell lines are being screened for response to all of the FDA approved anticancer agents and to a library of investigational agents with a goal of identifying existing agents that may be suitable for novel clinical trials, plus identifying potential points of vulnerability for drug discovery. Analysis of selected somatic mutations showed that ATM is frequently mutated in both soft tissue and bone sarcoma. In addition, gene expression profiles were measured in sarcoma cell lines using Affymetrix Exon 1.0 ST arrays in an effort to facilitate identification of splice variants and fusion genes. The gene-level data from the Exon ST1 array compares well with published U133plus 2 expression profiles. Principal components analysis of genes in 48 sarcoma lines indicates that expression varies primarily by disease subtype. For instance, Ewing's Sarcoma overexpressed genes including PRKCB, NPY5R and NPY1R, ITM2A plus adrenergic receptors B1, B3 and A1D, while ACTC1, IGF2 and CHRNA1 were dysregulated in rhabdomyosarcoma. Predicted associations between gene and miRNA expression included CSF1 with miR-128, thioredoxin reductase with miR-324-5p, MDM4 with miR-152, and PODXL with miR-199a-5p, suggesting potential regulatory relationships that might be exploited as cancer targets. In these lines, exome expression was found to be altered more than 10% in 232 genes, including known splice variant genes such as KLK11, UBE2C and sarcoma related fusion genes EWSR1 and ETV. Calculated fusion scores based on EWSR1-FLI1 expression profiles successfully segregated Ewing's sarcoma from all other sarcoma cell lines. Association analysis between gene and microRNA expression and sensitivity to specific anticancer agents is ongoing. Our mission is to improve the treatment of these neglected cancers by providing a comprehensive public database of molecular signatures and sensitivities that can be leveraged by the scientific community at large. Funded by NCI Contract no. HHSN261200800001E. Citation Format: Anne Monks, Annamaria Rapisarda, Kazimierz O. Wrzeszczynski, E. Michael August, Eric C. Polley, Sudhir B. Kondapaka, Gurmeet Kaur, Dianne Newton, Beverley A. Teicher. Target and drug discovery for recalcitrant, rare and neglected cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4361. doi:10.1158/1538-7445.AM2013-4361