H epatocellular carcinoma (HCC) is the fifth most common human cancer and third most frequent cause of cancer death worldwide. 1 Although over 80% of new HCC cases will occur in Eastern Asia and subSaharan Africa, 2 the startling increase in HCC incidence in the United States over the past 20-25 years and the typically high mortality from this disease have established HCC as an important health concern in this country. [2][3][4][5][6] The clinical management of HCC is complicated by typically late-stage disease at presentation and prevalent underlying liver dysfunction that can render patients ineligible for potentially curative surgical therapies, which are generally suitable for only 20%-30% of HCC patients. 3,5,7 Although regional therapies, such as transarterial embolization and percutaneous treatments, are used in patients with nonresectable disease, their success is curtailed by recurrence as locally advanced or metastatic disease. For these patients, systemic therapy is indicated but has been largely unsuccessful. 3,4,[8][9][10] Thus, a clear need exists to develop effective, life-prolonging therapeutic strategies for the large number of HCC patients with advanced disease.A major challenge in the systemic treatment of HCC is cellular resistance to conventional cytotoxic agents, which, at