Abstract

Cancer is a major health problem due to the failure of current therapies to effectively eradicate the disease. Extensive research over decades has led to the development of therapies that target cancer-specific signaling pathways. However, tumors escape such therapies by activating compensatory signaling pathways, a process referred to as ‘evasive resistance’. The identities of the alternative signaling pathways and the functional interconnections that underlie evasive resistance remain widely unknown. We integrate clinical, molecular, and computational sciences to understand the signaling defects that enable tumors to evade therapy. Within the framework of rigorously designed clinical studies, hepatocellular carcinoma (HCC) tissue is isolated before therapy, during treatment, or at the time of tumor progression. The tumor tissue is obtained by needle biopsy and immediately snap frozen to preserve in vivo tumor properties. High- and low-throughput experimental and computational methods are then applied to determine the underlying signaling defects. This endeavor will elucidate mechanisms of evasive resistance and may ultimately improve cancer diagnosis, treatment and clinical outcome. Recent progress in this ambitious project and a related study with an mTOR-driven mouse model for HCC will be described.