Sorafenib is the first systemic tlierapy witii proven efficacy against liepatoceilular carcinoma (HCC). However, since HCCs evolve rapidly to circumvent sorafenib's effects, survival in HCC patients is prolonged only about 2 months. Although the anti-tumor effect of sorafenib was initially attributed to inhibition of RAF/IVIEK/ERK and vascular endothelial growth factor (VEGF) receptor pathways, recent clinical trials have challenged this hypothesis by showing inconsistent results with even more potent and/or selective MEK and VEGF inhibitors. The limited efficacy of these agents emphasizes the need to understand how HCCs evade sorafenib treatment. We show that HCC cells that survive sorafenib treatment harbor activated l /!EK and ERK, and that ERK activation mediates their viability after treatment.
In Aim 1 we will investigate the role of MEK/ERK activation-consistently seen in all the HCC cell lines we have tested-as a cell autonomous mechanism of evasion from sorafenib. The evasion from VEGF blockade also emphasizes the need to test whether sorafenib induces changes in tumor stroma (e.g., hypoxia) that facilitate HCC growth after treatment. We found that hypoxia levels, stromal- derived factor 1a (SDFIa) expression, Gr-1+ bone marrow-derived cells (BMDCs) number and fibrosis are all increased after sorafenib treatment in HCC. We will examine tumor stromal mechanisms of evasion from sorafenib treatment in HCC, and dissect the causal links between SDFIa upregulation, BMDC recruitment and tumor fibrosis in HCC in Aim 2. Finally, our preliminary data suggest that adding MEK/ERK or SDF1a/CXCR4 inhibitors to sorafenib significantly delays HCC growth compared to sorafenib alone.
In Aim 3, we will evaluate tumor response and toxicity after combining pharmacologic inhibitors of MEK or CXCR4 with sorafenib in (syngeneic and spontaneous) orthotopic HCC models in immunocompetent mice. The goals of this project will be achieved in close collaboration with the multidisciplinary PPG team.
We have designed a comprehensive approach to determine the underpinnings of hepatocellular carcinoma evasion from standard sorafenib therapy. We will examine two distinct pathways of evasion that emerged from our preclinical and clinical studies in hepatocellular carcinoma. Our research will generate critical data for the formulation of novel combination therapy approaches to improve the treatment of hepatocellular carcinoma.
|Jain, Rakesh K; Martin, John D; Stylianopoulos, Triantafyllos (2014) The role of mechanical forces in tumor growth and therapy. Annu Rev Biomed Eng 16:321-46|
|Chen, Yunching; Huang, Yuhui; Reiberger, Thomas et al. (2014) Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology 59:1435-47|
|Hong, Theodore S; Ryan, David P; Borger, Darrell R et al. (2014) A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys 89:830-8|
|Duda, Dan G; Ancukiewicz, Marek; Isakoff, Steven J et al. (2014) Seeds and soil: unraveling the role of local tumor stroma in distant metastasis. J Natl Cancer Inst 106:|
|Emblem, Kyrre E; Farrar, Christian T; Gerstner, Elizabeth R et al. (2014) Vessel caliber--a potential MRI biomarker of tumour response in clinical trials. Nat Rev Clin Oncol 11:566-84|
|Chen, Ou; Riedemann, Lars; Etoc, Fred et al. (2014) Magneto-fluorescent core-shell supernanoparticles. Nat Commun 5:5093|
|Hato, Tai; Goyal, Lipika; Greten, Tim F et al. (2014) Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology 60:1776-82|
|Jain, Rakesh K (2014) Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26:605-22|
|Pinho, Marco C; Polaskova, Pavlina; Kalpathy-Cramer, Jayashree et al. (2014) Low incidence of pseudoprogression by imaging in newly diagnosed glioblastoma patients treated with cediranib in combination with chemoradiation. Oncologist 19:75-81|
|Chauhan, Vikash P; Martin, John D; Liu, Hao et al. (2013) Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun 4:2516|
Showing the most recent 10 out of 169 publications