Abstract 1469: Radiosensitization of hepatocellular carcinoma using rationally combined molecular-targeted agents
Authors: Wild Aaron T. , Hacker-Prietz Amy , Daniel Hubert D. , Maitra Anirban , Torbenson Michael S. , Pawlik Timothy M. , Geschwind Jean-Francois H. , Herman Joseph M. 
Published: August 2012

Abstract
Background: Hepatocellular carcinoma (HCC) is the 5th most common cancer and 3rd-leading cause of cancer-related deaths worldwide and is generally recognized to be chemo- and radio-resistant. Aberrant RAS/RAF/MAPK and PI3K/AKT/mTOR signaling pathways have been reported in HCC, producing dysregulation of cell survival, growth, and proliferation that likely contributes to this resistant phenotype. Recently, several small-molecule inhibitors targeting these pathways have emerged, including sorafenib (S; a multi-kinase inhibitor with specific activity against the RAS/RAF/MAPK pathway). S has shown a survival benefit in global phase III randomized trials and has become standard 1st-line therapy for patients with advanced and metastatic HCC. However, disease stabilization with S lasts only a few months, possibly due to the development of resistance, and consequently the survival advantage has been modest (&lt;3 mos). A natural next step is to perform studies with the aim of enhancing the clinical performance of S. We seek to assess for radiosensitization of HCC by treating with S alone and in combination with 2 other molecular-targeted agents (BEZ235 [B], a PI3K/mTORC1/mTORC2 inhibitor; and nelfinavir [N], a dual PI3K/AKT inhibitor) with ionizing radiation (IR). Methods: We tested the efficacy of combining IR with S, B, and N using clonogenic survival assays. Drugs were administered both as single agents and in 2-drug combinations to assess for radiosensitization. Human HCC cell lines HuH7, HepG2, and Hep3B were treated with drug(s) for 24 hours prior to and following IR to 0-8 Gy with a 137Cs source. Plating efficiency and surviving fraction (SF) were calculated relative to those of unirradiated, untreated cells. Results: SF at 0, 4, and 8 Gy for several single- and dual-agent treatment cocktails was determined for the HuH7 cell line. While S (1 microM), N (10 microM), and B (50 nM) all effectively reduced clonogenic proliferation at 0 Gy (SF=0.63, 0.41, and 0.52, respectively), only B achieved substantial radiosensitization (enhancement ratio at 10% survival [ER] = 1.8, compared to an ER of 1.1 for both S and N; p&lt;0.05). Similar rates of radiosensitization were observed when S or N was given with B (ER = 1.6 and 1.8, respectively; p&gt;0.05), suggesting that no synergistic or additive effects are achieved through these 2-drug combinations compared to treatment with B alone. Conclusions: B alone achieves a substantially greater degree of radiosensitization than S or N alone, suggesting that inhibition of the PI3K/AKT/mTOR pathway, and perhaps of mTORC1/2 in particular, is important to effectively radiosensitize HCC. Synergistic radiosensitization was not observed for any 2-drug combination. Further confirmation of these results in additional HCC cell lines and elucidation of possible molecular mechanisms are necessary future steps that are currently underway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1469. doi:1538-7445.AM2012-1469