Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 11, Issue 6, 2011

This special issue focuses on hepatocellular carcinoma (HCC), the predominant form of adult liver cancer, and also the third most common cause of cancer deaths worldwide. Despite well defined major etiologies and risk factors, and recent scientific advances in understanding hepatocarcinogenesis, survival of patients has not improved greatly over the past three decades. This is in part due to presentation and diagnosis of HCC at the advanced stages, when most potentially curative therapies such as resection, transplantation, or percutaneous and transarterial interventions are of limited efficacy. It is intrinsically resistant to conventional chemotherapy, and is rarely amenable to radiotherapy, leaving patients with no effective therapeutic options and a very poor prognosis. The development of more effective therapeutic agents and strategies is therefore much needed to improve the clinical management and prognosis of millions of HCC patients. HCCs are phenotypically and genetically heterogeneous tumors that commonly emerge on a background of cirrhosis (often caused by viral hepatitis or other chronic liver diseases). Recent insights into the biology of HCC suggest that certain signaling pathways and molecular alterations are likely to play essential roles in HCC development by promoting cell growth and survival. The malignant transformation of hepatocytes is a multistep process associated with preneoplastic changes in gene expression, resulting from altered methylation of genes, the actions of hepatitis B and C viruses, and point mutations or loss of heterozygosity. Improved knowledge in these critical areas has led to the identification of several potential therapeutic targets and has driven the development of molecularly targeted therapies. In this special issue, we first present an introduction to the basic molecular mechanisms underlying HCC development, including emerging areas of research such as small non-coding RNA molecules microRNAs and stem cells in liver cancer that hold great promise for future therapeutic applications, followed by reviewing several promising approaches and molecular targets for the treatment of HCC. Taken together, these molecular approaches offer novel and potentially more efficacious avenues to improve the clinical management and prognosis of HCC patients. The first article, “Molecular mechanisms of liver cancer”, by Dr. Wendong Huang's group, discussed important signaling molecules regulating hepatic inflammation and liver injury and their involvement in the development of liver cancer. The second article, “MicroRNA involvement in hepatocellular carcinoma”, by Dr. Massimo Negrini and his colleagues, provided a comprehensive overview of the role of small non-coding RNA microRNAs (miRNAs) in HCC. The article summarized the regulatory roles of miRNA on cell cycle, apoptosis, invasion and metastasis, and the β-catenin pathway, and also highlighted the value of using miRNA expression profile for HCC classification and prognostic stratification, and their blood circulating levels as HCC biomarkers. Lastly, the therapeutic potential of miRNA for HCC therapy was discussed. In the following article by Dr. Zhen Fan Yang's group, “Role of Stem cells in normal liver and cancer”, the authors introduced normal stem cells and putative cancer stem cells (CSCs) in the liver, and discussed signaling pathways, including the Bmil, Wnt/- βcatenin, Notch, PTEN, TGF-β, and sonic hedgehog pathways, that regulate pathophysiological activities of liver CSCs and the therapeutic potential by targeting CSCs in liver cancer. Nuclear receptors (NRs) are ligand-activated transcription factors regulating a wide variety of physiological and pathological functions in the liver, including hepatocarcinogenesis. The next article by Drs. Guodong Li and Grace Guo, entitled “Role of class II nuclear receptors in liver carcinogenesis”, summarized the roles of class II NRs, including PPARα, PPARβ/δ, PPARγ, RARs, FXR, CAR, PXR, LXRs, TRs, and VDR, in liver carcinogenesis and their potential application in the prevention and treatment of HCC. The poor prognosis of HCC patients is in part due to inaccurate diagnosis of HCC at an early stage. In the quest for more specific and sensitive HCC tumor markers, researchers have identified glypican-3 (GPC3) as being specifically over-expressed in HCC tumors but not in normal liver or other benign liver lesions. The article “Therapeutic potential of targeting glypican-3 in hepatocellular carcinoma” by Dr. Mark Allegretta provided the rationale for targeting GPC3 in HCC, and suggested strategies in which the functions of GPC3 can be inhibited to achieve therapeutic effects in HCC. As alluded to by Dr. Allegretta, the relationship between GPC3 and the Wnt pathway offers exciting opportunities to target these pathways in concert for more effective, broad-spectrum therapeutic intervention. In the contribution “Points of therapeutic intervention along the Wnt signaling pathway in hepatocellular carcinoma”, Dr. Miran Kim provided a comprehensive review of the many possibilities that various components of this pathway can be exploited for the treatment of HCC. Besides the critical Wnt signaling pathway, several other pathways are also major contributors towards cell proliferation, survival, metastasis, and angiogenesis in HCC development. These include the components of the receptor tyrosine kinase-activated pathways, such as the Raf, mitogen-activated protein extracellular kinase (MEK) and extracellular signal-regulated kinase (ERK) (Raf/MEK/ERK) pathway, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, the angiopoietins/Tie2 (Ang/Tie2) system, and the Janus kinase (Jak)-signal transducer/activator of transcription factor (Stat) (Jak/Stat) pathway. These pathways lie downstream of many important growth factors and their receptors that have been implicated in the development and progression of HCC. In his review entitled “Targeting receptor tyrosine kinase pathways in hepatocellular carcinoma”, Dr. Hung Huynh provided the latest pre-clinical and clinical developments on the efficacy of the emerging tyrosine kinase inhibitors, as well as the rationale for combination therapies for the treatment of advanced HCC. Next, an article by Dr. Jordi Muntané on “Targeting cell death and survival receptors in hepatocellular carcinoma” discussed the importance of death receptor (DR)-mediated cell signaling in HCC, and how the most important DRs in HCC (such as TNF-R1, CD95, and TRAIL-R1 and TRAIL-R2) can be targeted for enhanced therapeutic intervention. Lastly, HCC tumors have been reported to over-express the molecular target, ribonucleotide reductase M2 (RRM2), which is fundamentally involved in DNA synthesis. The function of RRM2 is dependent on iron, and can be competitively inhibited by gallium, which is chemically equivalent to iron. In his article “Hepatocellular carcinoma detection by gallium scan and subsequent treatment by gallium maltolate: Rationale and case study”, Dr. Lawrence Bernstein discussed the rationale for using an oral gallium compound, gallium maltolate, for the treatment of HCC, and presented a case study demonstrating the effectiveness of combining a 67Ga-scan with subsequent treatment of a patient's gallium-avid HCC. In conclusion, improved understanding of the molecular bases contributing to HCC, as well as the targets and strategies presented in this hot topic issue provide optimism for improved clinical management of HCC in the future, which will hopefully translate into prolonged patient survival for this typically fatal malignancy. The heterogeneous pathology of HCC, evidenced by the complex interplay of multiple essential pathways underlying HCC development, suggests that rational combination therapies will likely provide synergistic anti-tumor effects and better outcome.

Liver cancer, hepatocellular carcinoma (HCC) in particular, is one of the most deadly cancers worldwide, and the incidence of HCC is increasing rapidly in the United States and other developed countries. Epidemiological studies have identified major risk factors for HCC, including infection with hepatitis B and C virus (HBV and HCV), exposure to certain chemicals, high intake of alcohol, as well as metabolic diseases such as obesity and diabetes that are rapidly rising in the US. Although the etiologies for liver carcinogenesis are relatively well defined, the exact mechanism and pathways leading to cancer development are still unclear. Chronic liver injury, followed by inflammation and irregular liver regeneration has been suggested as an important step in hepatocarcinogenesis. Therefore, the identification of key factors that protect the liver from injury and inflammation could provide valuable insight into the development of HCC. In this review, we will summarize the recent findings in HCC studies, mainly focusing on the new molecular link among inflammation, liver repair and HCC.

The role of microRNAs (miRNAs) in human tumorigenesis has been demonstrated by gene profiling and functional studies. In hepatocellular carcinoma (HCC), consistently deregulated miRNAs were identified. Their aberrant expression revealed relations shared with other types of cancer and others unique to HCC, namely the down-regulation of miR-122. Most importantly, functional and molecular studies uncovered mechanisms that linked deregulated miRNAs to cancer-associated pathways, thereby placing their deregulation in a more rational framework. These results improved our knowledge concerning the molecular basis of HCC and helped to increase our understanding about the great clinical potential behind these small molecules. In fact, a number of studies proved that miRNAs may have clinical relevance as bio-pathologic markers for HCC classification, prognostic stratification, early diagnosis or follow-up of patients. Additionally, the demonstration that miRNAs themselves or anti-miRNA oligonucleotides could be successfully used for in vivo modulation of miRNA actions has shown significant potentials in molecularly targeted therapy. In this context, the liver represents an organ of election to test therapeutic possibilities associated with miRNAs.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality in the world because current treatments, including both surgical and non-surgical ones, cannot effectively cure this disease. Increasing evidence has revealed the importance of cancer stem cells (CSCs) in hepatocarcinogenesis, and the idea of targeting CSCs sheds light on more effective therapeutic strategies for HCC. In this review, normal stem cells and putative CSCs in the liver are briefly introduced. Studies about signaling pathways that regulate pathophysiological activities of liver CSCs and the therapeutic potential by targeting CSCs are also summarized and discussed.

Nuclear receptors (NRs) are ligand-activated transcription factors that are important to life by regulating a wide variety of physiological and pathological functions. There are three classes of NRs defined by ligands and heterodimer partners. The Class II NRs are involved in a broad range of pathophysiological functions in the liver, including cholesterol and bile acid homeostasis; lipid and glucose metabolism; inflammation; liver regeneration and hepatocellular carcinogenesis. Due to highly complicated molecular mechanisms in the development and progression of hepatocellular carcinoma (HCC), HCC is still one of the most common malignancies in the world. Given the pivotal functions of the Class II NRs in the liver, the roles of these NRs in hepatocellular carcinogenesis are emerging. This review summarizes the roles of Class II NRs in liver carcinogenesis and their potential application in the prevention and treatment of HCC.

Glypican-3 (GPC3) is a developmentally-regulated oncofetal protein that has been established as a clinically-relevant biomarker for early hepatocellular carcinoma (HCC). It is one of the first transcripts to appear during malignant hepatocyte transformation, and is expressed at the protein level in approximately half of high-grade dysplastic macronodules in cirrhotic liver. Several studies show it is expressed in most (75 to 100%) of HCCs confirmed by histopathology. The protein is anchored to the hepatocyte membrane by a glycosyl-phosphatidylinositol (GPI) anchor and shows consistent membrane immunostaining pattern, making it a viable target for immunotherapeutic approaches. Targeting GPC3 for therapeutic intervention is a promising approach for the clinical management of HCC and selected other tumors that express the marker.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. However, there is little known about targeted therapeutics for the treatment of this devastating tumor. Among the growth factor signaling cascades deregulated in HCC, evidences suggest that the WNT/Frizzled-mediated signaling pathway plays a key role in the hepatic carcinogenesis. Aberrant activation of the signaling in HCC is mostly due to deregulated expression of the Wnt/β-catenin signaling components. This leads to the activation of the β-catenin/TCF dependent target genes, which controls cell proliferation, cell cycle, apoptosis or motility. It has been shown that disruption of the Wnt/β-catenin signaling cascade displayed anti-cancer properties in HCC. Currently, no therapeutic molecules targeting the WNT pathway are available or under clinical evaluation for the treatment of HCC. This review will discuss the identified potential molecular targets related to the canonical WNT signaling pathway and their potential therapeutic usefulness.

Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide with 660,000 deaths annually. Studies of the molecular pathophysiology of HCC have shown that growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in HCC. Activation of these receptors and their downstream signaling pathways can lead to angiogenesis, cell proliferation, survival and metastasis of HCC. Hence, agents that specifically block their activation and signaling cascades would be valuable for treatment of HCC. Many small molecular tyrosine kinase inhibitors (TKIs) and antibodies have been tested in various phases of clinical trials. Although sorafenib has been shown to improve overall survival of patients with advanced HCC, the improvement is marginal and many patients eventually turn out to be refractory to this therapy. Thus, there is a pressing need to identify new drugs and effective treatments for this fatal disease. This review summarizes the pre-clinical and clinical data on the efficacy of the emerging tyrosine kinase inhibitors as well as the rationale for combination therapies for advanced HCC treatment. Understanding the mechanisms of action of these therapeutic agents and methods of combining these drugs may help to increase their efficacy, reduce toxicity, and improve overall survival and quality of life in patients with HCC.

Hepatocarcinoma (HCC) is the fifth most common neoplasia in the world, and the first cause of death by cancer in some areas. The clinical course of HCC patients has improved greatly owing to the use of the oral multikinase inhibitor, Sorafenib. The expression of receptors belonging to the superfamily of tumor necrosis factor receptors (TNF-R), such as TNF-R1, CD95 and TNF-related apoptosis inducing ligand (TRAIL) receptor -1 (TRAIL-R1) and -2 (TRAIL-R2) are altered in patients with HCC, especially those in advanced stages of de-differentiation. The disruption of death receptor (DR)-dependent cell signaling is related to poor survival in patients with HCC. These observations, together with the lack of antitumoral therapy alternatives, have stimulated research on DR-targeted therapies. The increasing research progress in cell death shows the intense crosstalk among DR and cell survival pathways in cancer cells. In consequence, new potential therapeutic strategies involving antibodies or small molecules specifically targeted to DR pathways either in monotherapy or in combination with other therapeutic strategies may be envisaged in the future to treat HCC.

Gallium is antiproliferative to many types of cancer, due primarily to its ability to act as a non-functional mimic of ferric iron (Fe3+). Because Fe3+ is needed for ribonucleotide reductase activity—and thus DNA synthesis—gallium can inhibit DNA production and cell division. Diagnostic gallium scans have shown that hepatocellular carcinoma (HCC) is commonly avid for gallium. Furthermore, in vitro studies have found that gallium nitrate, and particularly gallium maltolate (GaM), have dose-dependent antiproliferative activity against HCC cell lines. Rationale thus exists to use GaM, an orally active compound that has been well tolerated in Phase I clinical trials, to treat patients whose HCC is gallium-avid in a gallium scan. Because gallium absorbed from orally administered GaM is bound predominately to serum transferrin, which travels to all tissues in the body, GaM has the potential to treat even distant metastases. A patient with advanced HCC (20 x 10 cm primary tumor, ascites around liver and spleen, resistant to sorafenib (Nexavar®)), whose cancer was highly gallium-avid in a 67Ga-scan, was treated with oral gallium maltolate at 1500 mg/day q.d. After four weeks of treatment, the patient had a large reduction in pain, with greatly increased mobility and quality of life, and significantly lowered serum bilirubin and inflammation- related liver enzymes. At eight weeks, CT scans showed apparent necrosis of the tumor.