Abstract A9: Preclinical modeling of responses and resistance of residual metastatic disease to adjuvant chemotherapy

The questionable predictive power of available preclinical models is explained in part by their failure to adequately replicate the clinical setting. Prevailing human xenograft models do not consider advanced disease, require the use of immunocompromised mice that reconstitute aberrant tumor-host interactions, and employ delayed tumor growth as an endpoint, which has limited clinical relevance. To overcome these deficiencies, we have developed a rapid preclinical model of spontaneous metastasis that more accurately recapitulates clinical procedures for advanced non-small cell lung cancer patients. Lewis Lung Carcinoma tumor tissue that was never adapted to cell culture was stably labeled using lentivirus-encoding bioimaging markers, inoculated into syngeneic C57BL/6 mice, and resected upon reaching a predetermined size. Mice were then treated in a setting akin to post-surgical, first-line adjuvant chemotherapy using cisplatin, paclitaxel and/or antiangiogenic agents. As in the clinic, these drugs were most effective against progression in combination. However, the response of metastases to agents could not be predicted from, and often opposed, their effects on subcutaneous tumors. Time to macrometastatic onset, instead of growth, correlated with mouse survival. Moreover, the most effective adjuvant chemotherapy did not inhibit growth, but rather extended the equivalent of clinical dormancy. These results indicate that metastatic disease is driven by micrometastatic to macrometastatic transition, and resistance to therapies is caused by the failure to maintain clinical dormancy. Identification of the mechanisms involved in these processes will provide new targets of anti-cancer therapies and biomarkers for monitoring therapeutic efficacy. We demonstrate the inadequacies of current preclinical models, and introduce a paradigm for a more clinically relevant model that may more accurately predict therapeutic response in late-stage cancer patients. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A9