Single agent and synergistic activity of the "first in class" dual PI3K/BRD4 inhibitor SF1126 with Sorafenib in hepatocellular carcinoma (original) (raw)

BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment

Cell Death & Disease

Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether the sorafenib response could be enhanced by combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively. We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhan...

Combination therapy for hepatocellular carcinoma: Additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib

Journal of Hepatology, 2012

Background & Aims-Hepatocellular carcinoma (HCC) is a heterogeneous cancer in which sorafenib is the only approved systemic therapy. Histone deacetylases (HDAC) are commonly dysregulated in cancer and therefore represent promising targets for therapies, however their role in HCC pathogenesis is still unknown. We analyzed the expression of 11 HDACs in human HCCs and assessed the efficacy of the pan-HDAC inhibitor panobinostat alone and in combination with sorafenib in preclinical models of liver cancer. Methods-Gene expression and copy number changes were analyzed in a cohort of 334 human HCCs, while the effects of panobinostat and sorafenib were evaluated in 3 liver cancer cell lines and a murine xenograft model. Results-Aberrant HDAC expression was identified and validated in 91 and 243 HCCs, respectively. Upregulation of HDAC3 and 5 mRNAs were significantly correlated with DNA copy number gains. Inhibiting HDACs with panobinostat led to strong anti-tumoral effects in vitro and vivo, enhanced by the addition of sorafenib. Cell viability and proliferation declined, while apoptosis and autophagy increased. Panobinostat increased Histone H3 and HSP90 acetylation, downregulated BIRC5 (survivin) and upregulated CDH1. Combination therapy with panobinostat

Targeted therapy for hepatocellular carcinoma: current status and future direction

Clinical Investigation, 2013

Following the proof of evidence on the use of sorafenib in patients with advanced hepatocellular carcinoma (HCC), targeted therapy has become an important element in management of advanced HCC. Novel targeted therapies are designed to inhibit the aberrant signaling pathways or oncogenic mechanism at a molecular level with an aim to improve the clinical outcome. An increasing number of targeted agents have been tested in HCC in the clinical setting in the past few years. This review aims to summarize the current status of clinical development of targeted therapy in HCC focusing on novel agents targeting angiogenesis, signal transduction and epigenetic dysregulation of tumors. The future direction of drug development for HCC will also be explored.

Molecular Targeted Therapy in Hepatocellular Carcinoma: Present Achievements and Future Challenges

Digestive Diseases, 2012

Therapeutic options in advanced stage hepatocellular carcinoma have been very poor until the discovery of new therapeutic agents that target the molecular pathways involved in hepatocarcinogenesis. In this paper we try to review the most important molecular agents in development, with a specific focus on sorafenib’s role and safety profile, especially in the treatment of patients with suboptimal liver function.

Sorafenib, a systemic therapy for hepatocellular carcinoma

Annals of hepatology

Hepatocellular carcinoma is a lethal disease that requires a multidisciplinary approach and management. Surgical therapy offers long-term survival; however, few patients are candidates. There has been no accepted systemic therapy for this disease until recently. This article briefly discusses the role of RAS/RAF/MEK/ERK signaling pathway in the pathogenesis of the disease and the promising role of sorafenib for advanced disease.

Induction of Bim Expression Contributes to the Antitumor Synergy Between Sorafenib and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase Inhibitor CI-1040 in Hepatocellular Carcinoma

Clinical Cancer Research, 2009

Purpose: Sorafenib has proved survival benefit for patients with advanced hepatocellular carcinoma (HCC). This study explored whether the efficacy of sorafenib can be improved by adding the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor CI-1040 to vertically block the Raf/MEK/ERK pathway. Experimental Design: The growth inhibitory effects of sorafenib and CI-1040 were tested in HCC cell lines (Huh-7 and Hep3B) and human umbilical vascular endothelial cells (HUVEC). The potential synergistic growth inhibitory effects were measured by median effect analysis. Apoptosis was measured by flow cytometry. The effects on ERK phosphorylation and levels of apoptosis regulatory proteins were measured by Western blotting. The in vivo antitumor activity of sorafenib and CI-1040 were tested in xenograft HCC models. Results: Combination of sorafenib and CI-1040 synergistically inhibited ERK phosphorylation and cell growth and induced apoptosis in...

Advanced hepatocellular carcinoma. Review of targeted molecular drugs

Annals of Hepatology, 2011

Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world in terms of incidence, accounting for approximately 630 thousand new cases per year; in addition, HCC is the third most common cause of cancer death. Worldwide, the greatest risk factors for HCC are the infections caused by hepatitis B and C viruses, which increase the risk of developing the disease by about 20 times. The standard treatment in the early stages of the disease, such as surgical resection, local ablation and liver transplantation, are able to cure a proportion of patients, but most cases of HCC present in advanced stages, precluding the use of such treatments with curative intent. In these advanced stages, systemic treatments are commonly used. Unfortunately, chemotherapy with conventional cytotoxic agents is ineffective and does not seem to modify the natural history of disease. Treatment options for patients with advanced HCC are extremely limited, but the identification of signaling pathways, and the recognition of the role of these pathways in the pathogenesis of the disease resulted in the development of drugs directed at specific therapeutic targets. One such drug is Sorafenib, a kinase inhibitor with antiangiogenic and antiproliferative properties. In conclusion, Sorafenib has demonstrated survival benefits in patients with advanced HCC, thus representing a new standard reference for systemic treatment in these cases.

Targeted Therapies for Hepatocellular Carcinoma

Gastroenterology, 2011

Unlike most solid tumors, incidence and mortality of hepatocellular carcinoma (HCC) have increased in the US and Europe in the last decade. Most patients are diagnosed at advanced stages, so there is an urgent need for new systemic therapies. Sorafenib, a tyrosine kinase inhibitor (TKI), has demonstrated clinical efficacy in patients with HCC. Studies in patients with lung, breast, or colorectal cancers indicated that the genetic heterogeneity of cancer cells within a tumor affect its response to therapeutics designed to target specific molecules. When tumor progression requires alterations in specific oncogenes (oncogene addiction), drugs that selectively block their products might slow tumor growth. However, no specific oncogene alterations are yet known to be implicated in HCC progression, so it is important to improve our understanding of its molecular pathogenesis. There are currently many clinical trials evaluating TKIs for HCC, including those tested in combination with (e.g., erlotinib) or compared to (e.g., linifanib) sorafenib as a first-line therapy. For patients that do not respond or are intolerant to sorafenib, TKIs such as brivanib, everolimus, and monoclonal antibodies (e.g. ramucirumab) are being tested as second-line therapies. There are early-stage trials investigating the efficacy for up to 60 reagents for HCC. Together, these studies might change the management strategy for HCC, and combination therapies might be developed for patients with advanced HCC. Identification of oncogenes that mediate progression of HCC, and trials that monitor their products as biomarkers, might lead to personalized therapy; reagents that interfere with signaling pathways required for HCC progression might be used to treat selected populations, and thereby maximize the efficacy and cost-benefit.