Companion Diagnostics and Cancer Biomarkers Utilization of the El-Myc Mouse to Model Heterogeneity of Therapeutic Response

Human aggressive B-cell non-Hodgkin lymphomas (NHL) encompass the continuum between Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL), and display considerable clinical and biologic heterogeneity, most notably related to therapy response. We previously showed that lymphomas arising in the Em-Myc transgenic mouse are heterogeneous, mirroring genomic differences between Burkitt lymphoma and DLBCL. Given clinical heterogeneity in NHL and the need to develop strategies to match therapeutics with discrete forms of disease, we investigated the extent to which genomic variation in the Em-Myc model predicts response to therapy. We used genomic analyses to classify Em-Myc lymphomas, link Em-Myc lymphomas with NHL subtypes, and identify lymphomas with predicted resistance to conventional and NF-kB–targeted therapies. Experimental evaluation of these predictions links genomic profiles with distinct outcomes to conventional and targeted therapies in the Em-Myc model, and establishes a framework to test novel targeted therapies or combination therapies in specific genomically defined lymphoma subgroups. In turn, this will rationally inform the design of new treatment options for aggressive human NHL. Mol Cancer Ther; 13(12); 1–11. 2014 AACR.