Abstract 4836: In vitro drug sensitivity testing along with full genome and transcriptome sequencing and phosphoproteomics: Comprehensive “next-generation” molecular oncology portrait of a sarcoma for facilitating treatment decisions
Authors: Caroline Heckman, Kari Alitalo, Leif Andersson, Peter Campbell, Henrik Edgren, Andy Futreal, Tanja Holopainen, Paul Huang, Heikki Joensuu, Olli Kallioniemi, Sara Kangaspeska, Sami Kilpinen, Jami Mandelin, Outi Monni, Astrid Murumägi, Daniel Nicorici, Arto Orpana, Merja Perälä, Maarit Sarlomo-Rikala, Mike Stratton, Forest White
Journal: Cancer Research (2011)

Abstract We describe here comprehensive multi-layered genomic, molecular, functional and drug-sensitivity profiles of cancer specimens for clinical diagnostic and therapeutic use. A clinically and histologically atypical metastatic bone tumor was studied with the intent to inform clinicians in real time, should actionable findings emerge. This represents a pilot for future individualized molecular oncology. Methods: We describe integration of the following profiling data: 1) Full genomic sequencing and bioinformatic analysis with 31x coverage of the tumor and 36x of germline DNA 2) aCGH analysis of the tumor and comparison with tumor derived primary cell line 3) Full transcriptome sequencing and microarray analysis 4) Bioinformatic analysis linking gene expression profiles from the patient's tumor with published data on 47 normal and 57 cancer types 5) Phosphoprotein analysis with antibody microarrays and MS covering most therapeutically relevant pathways 6) IHC profiles with multiple antibodies 7) Establishment and molecular representativity of an in vitro cell culture model and mouse xenograft 8) development of personalized plasma-DNA based monitoring of tumor load 9) High-throughput drug sensitivity testing of the patient-derived cell line against a panel of 1500 compounds, including most clinically actionable cancerdrugs and their combinations. Selected key results: The tumor resembled malignant fibrocytic histiocytoma, was pleiomorphic with high mitotic counts. Clinical presentation was atypical with multiple metastatic bone lesions but no primary tumor. Genome sequencing revealed 12 genomic rerrangements and 34 putative missense mutations, including an oncogenic p53 mutation. Array-CGH revealed p16 deletion, and amplification of PDGFRA, KIT and VEGFR2 at 4q, but no clear overexpression. In vitro drug sensitivity testing revealed little impact of targeted drugs and kinase inhibitors like sunitinib, but strong inhibition by eg. bortezomib, daunorubicin, taxanes and zolendronic acid, which helped clinicial treatment decisions. The bone cancer initially responded to the treatment, but later progressed in soft tissues. Conclusions: This deep individualized molecular oncology study highlights the advantages and challenges of translating molecular oncology data on individual patients. Transcriptome and protein expression of the primary tumors and drug sensitivity testing with representative in vitro cell lines may be informative even when diagnostic or therapeutically “actionable” gene mutations are not found. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4836. doi:10.1158/1538-7445.AM2011-4836