Sorafenib is the first systemic tlierapy with 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.
|Ina Ly, K; Vakulenko-Lagun, Bella; Emblem, Kyrre E et al. (2018) Probing tumor microenvironment in patients with newly diagnosed glioblastoma during chemoradiation and adjuvant temozolomide with functional MRI. Sci Rep 8:17062|
|Nowak-Sliwinska, Patrycja; Alitalo, Kari; Allen, Elizabeth et al. (2018) Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis 21:425-532|
|Zhao, Yingchao; Liu, Pinan; Zhang, Na et al. (2018) Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models. Proc Natl Acad Sci U S A 115:E2077-E2084|
|Hong, Theodore S; Grassberger, Clemens; Yeap, Beow Y et al. (2018) Pretreatment plasma HGF as potential biomarker for susceptibility to radiation-induced liver dysfunction after radiotherapy. NPJ Precis Oncol 2:22|
|Pinter, Matthias; Kwanten, Wilhelmus J; Jain, Rakesh K (2018) Renin-Angiotensin System Inhibitors to Mitigate Cancer Treatment-Related Adverse Events. Clin Cancer Res 24:3803-3812|
|Arvanitis, Costas D; Askoxylakis, Vasileios; Guo, Yutong et al. (2018) Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption. Proc Natl Acad Sci U S A 115:E8717-E8726|
|Khandekar, Melin J; Jain, Rakesh (2018) Smooth sailing for immunotherapy for unresectable stage III non-small cell lung cancer: the PACIFIC study. Transl Cancer Res 7:S16-S20|
|Stylianopoulos, Triantafyllos; Munn, Lance L; Jain, Rakesh K (2018) Reengineering the Tumor Vasculature: Improving Drug Delivery and Efficacy. Trends Cancer 4:258-259|
|Grassberger, Clemens; Hong, Theodore S; Hato, Tai et al. (2018) Differential Association Between Circulating Lymphocyte Populations With Outcome After Radiation Therapy in Subtypes of Liver Cancer. Int J Radiat Oncol Biol Phys 101:1222-1225|
|Zhang, Na; Chen, Jie; Ferraro, Gino B et al. (2018) Anti-VEGF treatment improves neurological function in tumors of the nervous system. Exp Neurol 299:326-333|
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