Enhanced Antitumoral Activity of Sorafenib or Cetuximab In Comparison to Etoposide In a Disseminated Human AML Model In Vivo

Abstract 2141

Acute myeloid leukemia (AML), one of the most common leukemia in adults, is characterized by the accumulation of abnormal white blood cells in the bone marrow. Even with modern advances in therapeutics and molecular diagnostics, the majority of AML patients die from their disease. Angiogenesis contributes to the development of hematologic malignancies, although its role has not been as clearly defined in hematologic malignancies as in solid tumors. In the present study we have determined antitumoral activity of two well-known inhibitors of angiogenesis. Sorafenib, a small molecule inhibitor affecting inter alia the VEGF pathway (100mg/kg/day (d); applied 12 consecutive days) and Cetuximab, a chimeric antibody against human EGFR (30 mg/kg/d; applied once weekly for 3 weeks) were evaluated in comparison to Etoposide, a topoisomerase II inhibitor (24mg/kg/day; applied 3 consecutive days) as a well established compound in AML treatment regimens in comparison with a control group. Equal parts of HL-60 cells were injected intravenously and into the peritoneal cavity of NOD/SCID mice and respective therapies were started 14 days after implantation. Tumor growth was monitored by a) daily monitoring of AML symptoms, and b) weekly fluorescence-based in vivo imaging (FI) using a Alexa750-labeled anti-human CD45 antibody and c) verification of the FI data by histological examination of bone marrow and spleen at the end of the study. Tumor inhibition was calculated as the proportional reduction of mean AML cell infiltration at the respective compartment of the test- compared to the control-group (in %). HL-60 cells engrafted predominantly in bone marrow (BM; take rate = 100%), but were as well detectable in the spleen (30%). At the respective doses and schedules the examined compounds were well tolerated in tumor-bearing mice. No acute toxicity could be observed and maximal body weight loss was below 15%. Tumor development was clearly reduced by Cetuximab (reduction of 53% vs control), albeit to a lesser extend then Sorafenib (reduction of 99% vs control), which induced a complete remission within the treatment period. Treatment of Etoposide induced no markable tumor growth inhibition (reduction of 10% vs control). Thus, HL-60 cells engrafted in NOD/SCID mice representing a valuable in vivo model for AML which exhibits high reproducibility and take-rates in relevant compartments closely mimicking the clinical situation. Collection of whole-body FI data proved to be a time- and animal-saving analysis that allows to closely monitor AML growth. With regard to the demographic development, AML will be more and more a disease of the elderly. Thus, development of new therapeutic options compared to high-dose chemotherapy will be highly required. As the VEGF and EGFR pathways are closely related, further investigations will include the evaluation of potentially synergistic effects in combination of Sorafenib with Cetuximab in human disseminated AML xenograft models.