ABSTRACT
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death in Korea. Curative treatment is only possible when the disease is diagnosed at the early stage. The prognosis of patients with HCC is even dismal in advanced stages. No systemic cytotoxic chemotherapy has proven to be beneficial in overall survival. Recently, the understanding of the molecular pathogenesis led to the development of new therapies. With the evidence of dysregulation of critical genes associated with cellular proliferation, growth factor signaling, cell cycling, apoptosis, and angiogenesis in HCC, a number of molecular target agents are under clinical trials. Sorafenib is the first systemic anticancer drug which has proven to gain survival benefit in the global as well as Asia-Pacific trials. However, the survival gain is still modest, and further efforts to improve outcomes in patients with HCC are necessary by developing novel drugs or combining other forms of therapies. This article will review signaling pathways in HCC and introduce molecular target agents under investigation currently.
Subject(s)
Humans , Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Molecular Targeted Therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Receptor, IGF Type 1/antagonists & inhibitors , Signal Transduction , TOR Serine-Threonine Kinases/antagonists & inhibitors , Wnt Proteins/antagonists & inhibitorsABSTRACT
Pancreatic ductal adenocarcinoma is one of the most dreaded malignancies and the 5th leading cause of cancer-related death in Korea. Late diagnosis and unfavorable response to both chemotherapy and radiotherapy result in exceptionally poor prognosis. Recently, the rapid advances of molecular biology allowed an in-depth understanding of pancreatic carcinogenesis, and there are many attempts to modulate signal pathway using specific targeted agent. However, the most of them have so far failed to improve survival significantly except erlotinib. The real challenge is now how these impressive advances of molecular biology could be successfully integrated into better clinical implications. Herein, we summarize the latest insights into the carcinogenesis, and their repercussions for novel targeted agents for pancreatic cancer, and provide a review of recent clinical trials using molecular targeted therapy.
Subject(s)
Humans , Antineoplastic Agents/therapeutic use , Epigenesis, Genetic , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Molecular Targeted Therapy , Pancreatic Neoplasms/drug therapy , Poly(ADP-ribose) Polymerases/antagonists & inhibitors , ErbB Receptors/antagonists & inhibitors , Receptor, IGF Type 1/antagonists & inhibitors , Vascular Endothelial Growth Factor A/antagonists & inhibitorsABSTRACT
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death in Korea. Curative treatment is only possible when the disease is diagnosed at the early stage. The prognosis of patients with HCC is even dismal in advanced stages. No systemic cytotoxic chemotherapy has proven to be beneficial in overall survival. Recently, the understanding of the molecular pathogenesis led to the development of new therapies. With the evidence of dysregulation of critical genes associated with cellular proliferation, growth factor signaling, cell cycling, apoptosis, and angiogenesis in HCC, a number of molecular target agents are under clinical trials. Sorafenib is the first systemic anticancer drug which has proven to gain survival benefit in the global as well as Asia-Pacific trials. However, the survival gain is still modest, and further efforts to improve outcomes in patients with HCC are necessary by developing novel drugs or combining other forms of therapies. This article will review signaling pathways in HCC and introduce molecular target agents under investigation currently.
Subject(s)
Humans , Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Molecular Targeted Therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Receptor, IGF Type 1/antagonists & inhibitors , Signal Transduction , TOR Serine-Threonine Kinases/antagonists & inhibitors , Wnt Proteins/antagonists & inhibitorsABSTRACT
Pancreatic ductal adenocarcinoma is one of the most dreaded malignancies and the 5th leading cause of cancer-related death in Korea. Late diagnosis and unfavorable response to both chemotherapy and radiotherapy result in exceptionally poor prognosis. Recently, the rapid advances of molecular biology allowed an in-depth understanding of pancreatic carcinogenesis, and there are many attempts to modulate signal pathway using specific targeted agent. However, the most of them have so far failed to improve survival significantly except erlotinib. The real challenge is now how these impressive advances of molecular biology could be successfully integrated into better clinical implications. Herein, we summarize the latest insights into the carcinogenesis, and their repercussions for novel targeted agents for pancreatic cancer, and provide a review of recent clinical trials using molecular targeted therapy.
Subject(s)
Humans , Antineoplastic Agents/therapeutic use , Epigenesis, Genetic , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Molecular Targeted Therapy , Pancreatic Neoplasms/drug therapy , Poly(ADP-ribose) Polymerases/antagonists & inhibitors , ErbB Receptors/antagonists & inhibitors , Receptor, IGF Type 1/antagonists & inhibitors , Vascular Endothelial Growth Factor A/antagonists & inhibitorsABSTRACT
We addressed the effect of targeting type I insulin-like growth factor receptor (IGF-IR), with antisense strategies in in vivo growth of breast cancer cells. We used C4HD tumors from an experimental model of hormonal carcinogenesis in which medroxyprogesterone acetate induced mammary adenocarcinomas in Balb/c mice. Intratumor or systemic administration of phosphorothiolated antisense oligodeoxynucleotides (AS[S]ODN) to IGF-IR mRNA resulted in a significant inhibition of C4HD tumor growth. The antitumor effect was specific since inhibition of tumor growth was dose-dependent and no effect was observed in mice treated with sense S[S]ODN. Tumors from AS[S]ODN-treated mice showed a decrease in IGF-IR expression and in insulin receptor substrate-1 tyrosine phosphorylation. Activation of PI-3K/Akt, p42/p44 MAPK and ErbB-2 was abolished in tumors treated with AS[S]ODN. Progesterone receptor expression or activity remained invariable. This is the first demonstration that breast cancer growth can be inhibited by direct in vivo administration of IGF-IR AS[S]ODN.
Evaluamos el efecto del bloqueo de la expresión del receptor del factor de crecimiento semejante a lainsulina tipo I (IGF-IR) sobre el crecimiento in vivo de cáncer de mama empleando una estrategiaantisentido. Utilizamos el adenocarcinoma mamario murino progestágeno-dependiente C4HD. La administración intratumoral o sistémica de oligodeoxinucleótidos antisentido fosfotiolados al ARNm del IGF-IR (AS[S]ODN) inhibió el crecimiento tumoral. El efecto antitumoral fue específico debido a su dosis-dependencia y a la faltade efecto en ratones tratados con el S[S]ODN sentido. Los tumores obtenidos de ratones tratados con AS[S]ODN mostraron: disminución en la expresión de IGF-IR y en la fosforilación del sustrato del receptor de insulina-1, inhibición de la activación de PI-3K/Akt, p42/p44MAPK y ErbB-2, mientras que la expresión y activación del receptor de progesterona no se afectó. Es la primera demostración que el