Abstract 351: Tumor kinome profiling of early systemic disease dissemination in rectal cancer

Abstract

Abstract Tumor hypoxia as common determinant of resistance to cytotoxic therapies and metastatic behavior is an emerging hypothesis. In baseline tumor biopsy specimens from rectal cancer patients receiving preoperative chemoradiotherapy, using peptide arrays with 144 tyrosine kinase substrates, we have recently shown [Folkvord et al., Int J Radiat Oncol Biol Phys 2010] that phosphopeptide levels generated by tumors with poor response to the chemoradiotherapy were significantly higher than substrate phosphorylation resulting from tumors with good treatment response. The elevated kinase activity in poor-responding tumors was suppressed by the ex vivo addition of the tyrosine kinase inhibitor sunitinib and proved to represent signaling mediated by VEGFR, EGFR, and PI3K/AKT, which is known to be implicated in experimental radiation resistance. Given that these signaling pathways might be involved in adaptive responses to tumor hypoxia, this follow-up study aimed to determine whether the tumor kinase activity signatures might also correlate to systemic disease dissemination. Immunomagnetic detection of tumor cells in bone marrow aspirates was undertaken at the time of diagnosis, and bone marrow micrometastases (BMM) were observed in 33 of 55 (60%) of the patients from whom tumor kinase activity signatures had been obtained. In this new analysis, association between ex vivo sunitinib inhibition of the kinase activity and BMM status was studied, and phosphorylation of 31 tyrosine kinase substrates was significantly more strongly inhibited by sunitinib in the BMM negative patients than in the BMM positive individuals. Interestingly, discriminating phosphopeptides represented proteins derived from signaling pathways implicated in angiogenesis; e.g., signaling mediated by PDGFR, VEGFR, and EPOR, which is a central response to tumor hypoxia and fundamental for metastasis formation. At present, this patient cohort has a median follow-up of 41 months (range 13-58) and has demonstrated significantly poorer metastasis-free survival for the BMM-positive group than for the BMM-negative group (p = 0.008). In conclusion, in this cohort of rectal cancer patients, a tumor phenotype defined by a subset of tyrosine kinase activities insusceptible to the ex vivo inhibitory effect of sunitinib was associated with early systemic dissemination. This project was supported by the EU FP7 grant number 222741 (METOXIA). 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 351. doi:10.1158/1538-7445.AM2011-351