Project Details

Description

Background: Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer, and it represents the second leading cause of cancer-related mortality in the United States. Sorafenib was recently approved as the first systemic treatment for patients with advanced HCC. However, most patients rapidly develop resistance to sorafenib and relapse. Therefore, understanding the mechanisms of emergence of resistance to sorafenib is critical for the clinical management of HCC. Our proposed research addresses the Fiscal Year 2015 Peer Reviewed Cancer Research Program Topic Area 'Liver cancer' and the Military Relevance Focus Area 'Gaps in cancer prevention, screening, early detection, diagnosis, treatment, and/or survivorship that may affect the general population but have a particularly profound impact on the health and well-being of military members, Veterans, and their beneficiaries.'Hypothesis/Objective: The objective of this project is to comprehensively define cell- and non-cell-autonomous molecular mechanisms of resistance to sorafenib in human HCC, to model their behavior in three-dimensional (3D) organoids and in vivo models, and to establish a platform for identifying and validating novel antagonists to these drivers in patient-derived xenografts (PDXs). Successful completion of this project will identify novel mechanisms of acquired resistance to sorafenib in HCC and therapeutic strategies for first-line combination therapies with sorafenib and for second-line treatment of sorafenib-resistant HCC.Specific Aims: We propose four interrelated aims to identify the drivers of sorafenib resistance in HCC. We will first identify the molecular mechanisms underlying resistance to sorafenib by studying biopsies from HCC patients that develop resistance to sorafenib (Aim 1). We will then validate actionable drivers of sorafenib resistance by using RNA interference technology in sorafenib-resistant HCC organoids (Aim 2). We will also explore the role of tumor microenvironment on resistance to sorafenib by analyzing tumor stroma samples and a sophisticated in vivo model of sorafenib resistance (Aim 3). Lastly, we will validate candidates for second-line clinical trials in sorafenib-resistant PDXs.Study Design: The aims will be achieved by (1) studying the molecular changes associated with resistance to sorafenib by performing exome-sequencing, RNA-seq, DNA methylation studies and copy number variation analysis in HCC patient samples, before and after developing resistance to sorafenib. (2) We will establish 3D organoids from biopsies from sorafenib-resistant HCC patients and perform an shRNA (short-hairping RNA) screen to identify drug targets that can overcome resistance to sorafenib. (3) We will study the molecular and cellular changes in the tumor stroma associated with sorafenib resistance and explore the potential of targeting the stroma or the immune system to overcome resistance to sorafenib. (4) We will establish PDXs from sorafenib-resistant patients and validate actionable candidates from Aims 1 and 2 for second-line clinical trials.Collaboration/Translational Aspects: This translational team exploits the synergistic talents of three senior and two early-career investigators from two leading institutions to address a vitally important unmet need in liver cancer. The physical closeness of both institutions will facilitate meetings and exchange of materials. Dr. Friedman is an expert in liver fibrosis and tumor microenvironment and as Dean for Therapeutic Discovery will play a critical role at prioritizing therapeutic targets. Dr. Llovet established sorafenib as the standard of care in HCC and has led sequencing efforts to characterize HCC. Dr. Lowe has pioneered the use of RNA interference to identify therapeutic targets and innovative models of cancer, including organoids. Dr. Villanueva has identified drivers of tumor progression in HCC and established clinically relevant models. Dr. Lujambio has explored the role of microenvironment in HCC initiation.Military Relevance and Impact: The incidence of HCC is increasing in the United States, specially within the US Military and US Veterans community. Among the main risk factors for HCC development, we find alcohol consumption, hepatitis B and C infection, obesity, and male gender, all of which are over-represented in the US Military and US Veterans community. Here, we will identify the mechanisms of resistance to sorafenib, the standard of care for HCC treatment, and validate therapeutic strategies to overcome this resistance. These studies will improve the lives of American citizens in general and US military and Veterans in particular.Innovation: Most strategies to identify mechanisms of drug resistance in cancer rely on the use of models that fail to recapitulate features of human cancer and/or lack the functional experiments needed to validate the findings. Here, we undertake a unique and comprehensive approach to identify cell-autonomous and non-cell-autonomous mechanisms of resistance to sorafenib by characterizing human HCC samples and by using 3D organoids, in vivo models of sorafenib resistance, and PDXs to validate therapeutic strategies to overcome resistance to sorafenib.

StatusFinished
Effective start/end date1/09/1631/08/19

Funding

  • Congressionally Directed Medical Research Programs: $406,800.00

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