Abstract 4933: In vivo visualization of heterogeneous cancer cell populations by fluorescence molecular tomography

Abstract

Abstract Glioblastoma is the most common and aggressive tumor type that affects the central nervous system in adults. Despite advances in treatment strategies, its prognosis remains poor. EGFR and its mutant form EGFRvIII are amplified in a subset of clinical cases and interaction between cell populations expressing each receptor has been shown to enhance overall tumor growth. For instance, EGFRvIII induces expression of several secreted oncogenic factors, such as IL6 and LIF, which in turn stimulate the growth of EGFR expressing cells through an IL6 receptor (gp130)/EGFR cross-talk interaction. Therapy directed towards EGFR or EGFRvIII inhibition has been ineffective because of mechanisms that inhibit cell death. We hypothesize that these factors secreted by EGFRvIII expressing cells, in addition to promoting tumor growth, play a role in the failure of EGFR-directed therapies reported for glioblastoma. Preliminary data indicate that EGFRvIII-expressing cells prompt an IL6/LIF-mediated paracrine and autocrine antiapoptotic signaling cascade, leading to upregulation of the pro-survival protein, Survivin. RNAi-mediated downregulation of Survivin reverts this phenotype. To determine the effect of identified signaling effectors and cytokines in promoting EGFR tyrosine kinase inhibitor resistance, an in vivo model system of heterogeneous tumor growth was established and imaged using fluorescence molecular tomography (FMT) technology. Survivin, upstream pathways and cytokines were ablated in EGFR or EGFRvIII-expressing glioma cell lines tagged with different near infrared fluorescent proteins (turboFP635 or iRFP713). Orthotopically engrafted tumors of mixed EGFR/EGFRvIII populations were then evaluated for their tumor growth and cellular composition when challenged with EGFR tyrosine kinase inhibitors. In conclusion, this system allows for the validation of molecular mechanisms that promote cancer cell survival and establishes the basis for alternative treatment strategies. Citation Format: Ciro Zanca, Maria del Mar Inda, Rudy Bonavia, Jill Wykosky, Vladislav Verkhusha, Webster Cavenee, Frank Furnari. In vivo visualization of heterogeneous cancer cell populations by fluorescence molecular tomography. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4933. doi:10.1158/1538-7445.AM2014-4933