Begell House Inc.
Onco Therapeutics
OT
2694-4642
5
3-4
2014
Preface: Advances in Molecular Targets for Therapeutics in Resistant Cancers
v-vi
10.1615/ForumImmunDisTher.2015014075
Melchiorre
Cervello
Institute for Biomedical Research and Innovation, Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR) Palermo, Italy
Natale
D'Alessandro
Pharmacology Unit, University of Palermo Department of Health Sciences and Mother and Child Care "Giuseppe D'Alessandro" Palermo, Italy
Epidemiology, Diagnosis, and Non-Pharmacological Treatment of HCC
115-136
10.1615/ForumImmunDisTher.2015014080
Maurizio
Soresi
Department of Health Promotion Sciences Maternal and Infantile Care, Biomedical Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo, Italy
Lydia
Giannitrapani
Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy; Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Italy
Walter
Grana
Biomedical Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo, Italy
Anna
Licata
Biomedical Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo, Italy
Giuseppe
Montalto
Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy; Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Italy
Hepatocellular carcinoma
epidemiology
diagnosis
treatment
Hepatocellular carcinoma (HCC) is still one of the most common tumors, ranking first among all cancers in relation to its frequency and mortality. Only very recently has there been a deceleration in the incidence and mortality of this neoplasia, which suggests that we may be close to the peak of the HCC epidemic, at least in the Western population. Risk factors are well known, and the hepatitis B and hepatitis C viruses are the main etiologic factors. Indeed, liver cirrhosis (LC) of any etiology is the main cause of predisposition to the neoplastic degeneration of the liver; an underlying LC is present in most cases of HCC. For this reason, a surveillance program has been established by the main associations for the study of the liver, and an ultrasound examination of the liver every 6 months has been codified as a recommendation to facilitate discovery of a neoplastic lesion at an early stage, which allows patients the opportunity to access more efficacious treatments. The actual therapy, in fact, is based on the stratification of patients according to the number of lesions, diameter of the lesions, and the evaluation of the underlying liver cirrhosis and general conditions. According to this (prevalently physical) stratification, patients are allocated to receive liver transplantation, resection, or ablative therapy of the lesion if they are at an early stage. Transarterial chemoembolization is indicated for patients at an intermediate stage, and systemic therapy with sorafenib is recommended only for advanced tumors. The prognosis of HCC is being ameliorated in time with a better selection of patients and with a better performance of the therapeutic equipment; however, current efforts should be directed toward the primary prevention of cirrhosis, together with the very early diagnosis of HCC. In this respect, it seems that with the spreading of hepatitis B virus (HBV) vaccination in highly endemic countries and with the treatments of hepatitis C virus (HCV) with the new direct-acting antiviral drugs, both the HCC frequency and mortality will decrease in the near future.
The Role of HSP70 in the Diagnosis of HCC
137-143
10.1615/ForumImmunDisTher.2015013939
Lydia
Giannitrapani
Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy; Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Italy
Gabriele
Multhoff
Technische Universitat Munchen (TUM), TUM School of Medicine, Ismaninger Strasse 22, München, Germany
Diagnosis of HCC
Hsp70
liquid biopsy
tumor biomarker
Hepatocellular carcinoma (HCC) is a common tumor with a fatal clinical outcome if not diagnosed at an early stage. To date there is still a lack of reliable tumor biomarkers to detect asymptomatic precursor lesions in early HCC. Conventional pathological analysis also often fails to achieve sufficient sensitivity and specificity to diagnose early HCC. Genetic, proteomic, immunohistochemical, and liquid biopsy analysis indicate a role for members of the heat-shock protein 70 (HSP70) family as potential tumor-specific markers for HCC. The aim of this review is to revisit the existing literature and to specifically explore HSP70 as a molecular tumor biomarker for the detection of HCC and its potential use as a tumor-specific target for future anticancer therapies in HCC.
From Targets to Targeted Therapies in Hepatocellular Carcinoma
145-194
10.1615/ForumImmunDisTher.2015013982
Melchiorre
Cervello
Institute for Biomedical Research and Innovation, Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR) Palermo, Italy
Maria Rita
Emma
Institute for Biomedical Research and Innovation, Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy
Giuseppa
Augello
Institute for Biomedical Research and Innovation, Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy; Biomedical Department of internal Medicine and Specialties, University of Palermo, Via del Vespro 143, 90127
Daniele
Balasus
Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy
Antonina
Azzolina
Institute for Biomedical Research and Innovation, Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy
James A.
McCubrey
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA
Antonella
Cusimano
Institute for Biomedical Research and Innovation, Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy
HCC
targeted therapy
Ras/Raf/MEK/ERK
PI3K/AKT/PTEN/mTOR
signal transduction inhibitors
Prognosis in advanced hepatocellular carcinoma (HCC) remains poor, despite the great improvement in the knowledge of the mechanisms behind hepatocarcinogenesis in recent years. Therapeutic options in the advanced stage of disease were quite limited until the introduction of sorafenib, a multi-kinase inhibitor. Sorafenib is considered the first systemic therapy and the only approved drug in advanced HCC. Unfortunately, sorafenib efficacy is rather limited in terms of overall survival, especially compared to results obtained with targeted therapies in other solid tumors; this limited efficacy is probably related to the heterogeneity of HCC. Consequently, a molecular characterization of HCC is urgently needed to improve treatments for and the clinical outcomes of HCC patients. This review offers a summary of the major studies regarding the signaling pathways involved in HCC pathogenesis, and an overview of the most promising drug treatments, apart from sorafenib, and the potential for their application in new therapeutic interventions in HCC.
Druggable Targets in Pancreatic Adenocarcinoma
195-214
10.1615/ForumImmunDisTher.2015014118
Stefania
Nobili
Department of Health Sciences, University of Florence, Firenze, Italy
Renato
Tassi
Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy
Ida
Landini
Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy
Gabriele
Perrone
Department of Health Sciences, University of Florence, Firenze, Italy
Cristina
Napoli
Department of Health Sciences, University of Florence, Firenze, Italy
Enrico
Mini
Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy
PDAC hallmarks
PDAC target therapy
PDAC immunotherapy
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. It is often diagnosed at an advanced or metastatic stage and results of the approved systemic therapies are discouraging, making PDAC one of most lethal cancers in Western countries. In recent years, a better comprehension of PDAC unique biology has disclosed new potential targets for therapeutic interventions. Meanwhile, the development of conjugated agents, small molecules, antibodies, and immunoagents has opened therapeutic opportunities for drugs able to exert therapeutic effects on druggable targets of PDAC biology. Despite some failures, this approach is bringing meaningful results from bench to bedside, and more efficacious therapeutic opportunities may become available for PDAC treatment. In this review, we discuss the main hallmarks of PDAC biology as its microenvironment, cancer-driving proliferative pathways, growth suppression loops, and how PDAC evades immune system surveillance, as well as molecular aspects of each feature. The main preclinical and clinical results of each targeted intervention are also presented considering its biological rationale. Ongoing clinical trials provide evidence of the effectiveness of this approach and promising results in the treatment of PDAC.
Mechanisms of Raf-1 Kinase Inhibitor Protein Dysregulation in Triple-Negative Breast Cancers and Identification of Possible Novel Therapeutic Approaches for These Tumors
215-222
10.1615/ForumImmunDisTher.2015013936
Natale
D'Alessandro
Pharmacology Unit, University of Palermo Department of Health Sciences and Mother and Child Care "Giuseppe D'Alessandro" Palermo, Italy
Paola
Poma
Pharmacology Unit, Department of Health Sciences and Mother and Child Care "G. D'Alessandro", University of Palermo; Department of Biological, Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, Palermo, Italy
Manuela
Labbozzetta
Pharmacology Unit, Department of Health Sciences and Mother and Child Care "G. D'Alessandro", University of Palermo; Department of Biological, Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, Palermo, Italy
Nicoletta
Vivona
Pharmacology Unit, Department of Health Sciences and Mother and Child Care "G. D'Alessandro", University of Palermo; Palermo, Italy
Monica
Notarbartolo
Pharmacology Unit, Department of Health Sciences and Mother and Child Care "G. D'Alessandro", University of Palermo; Palermo, Italy
epigenetic therapy
NF-κB inhibition
Raf-1 kinase inhibitor protein
triple-negative breast cancers
Triple-negative breast cancers (TNBCs) are a heterogenous group of breast cancers characterized by poor prognosis because they are not amenable to targeted therapies. We have taken into account that altered expression of Raf-1 kinase inhibitor protein (RKIP), a tumor and metastasis suppressor and a promoter of drug-induced apoptosis, is frequent in TNBCs and may be involved in their aggressive biology. Interestingly, the analysis of the possible mechanisms of RKIP downregulation in TNBCs permits the identification and recapitulation of different possible approaches, including epigenetic modulation, e.g., by DNA demethylating agents or histone deacetylase inhibition, and NF-κB inhibition. These approaches are currently of great interest in the field of TNBC therapy.
Targeting PGE2 Signaling in Tumor Progression and Angiogenesis
223-232
10.1615/ForumImmunDisTher.2015014095
Sandra
Donnini
Department of Life Sciences, Via A. Moro, 2, 53100, University of Siena, Siena, Italy
Federica
Finetti
Department of Life Sciences, Via Aldo Moro, 2, University of Siena, 53100-Siena, Italy
Erika
Terzuoli
Department of Life Sciences, Via Aldo Moro, 2, University of Siena, 53100-Siena, Italy
Lorenzo
Bazzani
Department of Life Sciences, University of Siena, Siena, Italy
Marina
Ziche
Department of Medicine, Surgery and Neurosceinces, University of Siena, 53100 Siena, Italy
Angiogenesis
inflammation
mPGES-1
PGE2
RTK
Inflammatory milieu is associated with cancer progression and angiogenesis in different types of tumors, such as gastrointestinal, breast, prostate, and head and neck cancers. Among the inflammatory pathways, numerous evidence indicates that the cyclooxygenase-2/microsomal prostaglandin E synthase-1/prostaglandin E2/E Prostaglandin type receptor (COX-2/mPGES-1/PGE2/EPs) signaling supports epithelial tumor aggressiveness promoting cell growth, epithelial-mesenchymal transition (EMT), and sternness. Further, PGE2 modulates pro-oncogenic and pro-angiogenic pathways such as EGFR and FGFR-1. In this review, we discuss the role of PGE2 and its network of partner proteins in tumor progression and angiogenesis. We also discuss major COX-2/mPGES-1 and EPs therapeutic advances that have been made over the past few years in targeting tumorigenesis and angiogenesis.
Targeting Integrins in Cancer
233-241
10.1615/ForumImmunDisTher.2015013962
Chiara
Pazzagli
Department of Dermatology, Medical Center-University of Freiburg, Freiburg, Germany e Spemann Graduate School of Biology and Medicine (SGBM); Albert Ludwigs University Freiburg, Via Aldo Moro, 2, University of Siena, 53100-Siena, Italy
Sandra
Donnini
Department of Life Sciences, Via A. Moro, 2, 53100, University of Siena, Siena, Italy
Integrins
cancer cells
sternness
angiogenesis
drug resistance
Interactions between cancer cells and their surrounding cells are essential to determining tumor fate. Integrins, present on the surface of tumor and stromal cells, including endothelial cells, have a profound impact on the ability of cells to survive, expand, migrate, invade, and metastasize. Moreover, integrins facilitate tumor cell malignancy/stemness and resistance to therapeutic drugs by modulating intracellular signaling pathways through the recruitment and activation of specific kinases and signaling intermediates. Understanding how integrin expression and function are regulated during progression of tumor malignancy will enable the development of new therapeutic approaches to treating tumors and suppressing their metastatic phenotype. In this review, we discuss the role of integrins and their network of partner proteins in cancers. We also discuss major integrin-specific therapeutic advances that have been made over the past few years in targeting tumorigenesis and angiogenesis.
VOLUME 5 CONTENTS, 2014
243-245
10.1615/ForumImmunDisTher.v5.i3-4.90