New Therapeutic Options for the Treatment of Sickle Cell Disease.
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ABSTRACT:
SUBMITTER: Matte A
PROVIDER: S-EPMC6328043 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
New Therapeutic Options for the Treatment of Sickle Cell Disease.
Matte Alessandro A Zorzi Francesco F Mazzi Filippo F Federti Enrica E Olivieri Oliviero O De Franceschi Lucia L
Mediterranean journal of hematology and infectious diseases 20190101 1
Sickle cell disease (SCD; ORPHA232; OMIM # 603903) is a chronic and invalidating disorder distributed worldwide, with high morbidity and mortality. Given the disease complexity and the multiplicity of pathophysiological targets, development of new therapeutic options is critical, despite the positive effects of hydroxyurea (HU), for many years the only approved drug for SCD. New therapeutic strategies might be divided into (1) pathophysiology-related novel therapies and (2) innovations in curati ...[more]
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Project description:Sickle cell disease (SCD) is a genetic hematologic disorder that is characterized by a variety of potentially life threatening acute and chronic complications. Currently, hydroxyurea is the only clinically approved pharmacological therapy for the treatment of SCD, and the continued prevalence of severe disease complications underscores the desperate need for the development of new therapeutic agents. Central features of the sickle cell disease milieu, including hypoxia, oxidative stress, and thrombosis, are established enhancers of endothelin-1 (ET-1) synthesis. This conceptual connection between ET-1 and SCD was confirmed by multiple studies that demonstrated markedly elevated plasma and urinary levels of ET-1 in SCD patients. Direct evidence for the involvement of ET-1 signaling in the development of SCD pathologies has come from studies using endothelin receptor antagonists in SCD mice. This review summarizes recent studies that have implicated ET-1 signaling as a mechanistic contributor to renal, vascular, pulmonary, and nociceptive complications of sickle cell disease and discusses the potential for the use of ET receptor antagonists in the treatment of SCD.
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Project description:Surgery and cisplatin-based treatment of hepatoblastoma (HB) currently guarantee the survival of 70-80% of patients. However, some important challenges remain in diagnosing high risk tumors and identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of hepatoblastoma tumors have been described, namely C1 and C2; C2 being the subgroup with the poorest prognosis, a more advanced tumor stage and the worst overall survival rate. An associated 16-gene signature to discriminate the two tumoral subgroups was proposed but it has not been transferred into clinical routine. To address these issues we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A and C2B, identifiable by a concise four-gene signature: HSD17B6, ITGA6, TOP2A and VIM, with TOP2A being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by RT-qPCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in Fanconi Anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, an FDA-approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway associated double-strand DNA repair and significantly impedes HB growth in vivo. In conclusion, the highly proliferating C2A subtype is characterized by TOP2A gene up-regulation and FA pathway activation and HB therapeutic arsenal could include Bortezomib for the treatment of patients with the most aggressive tumors.
2017-11-21 | GSE104766 | GEO
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Project description:Background:Sickle cell disease causes significant morbidity and mortality and affects the economic and healthcare status of many countries. Yet historically, the disease has not had commensurate outlays of funds that have been aimed at research and development of drugs and treatment procedures for other diseases. Methods:This review examines several treatment modalities and new drugs developed since the late 1990s that have been used to improve outcomes for patients with sickle cell disease. Results:Targeted therapies based upon the pathophysiologic mechanisms of sickle cell disease that result in organ dysfunction and painful episodes include hydroxyurea, L-glutamine, crizanlizumab, and other drugs that are currently on the market or are on the verge of becoming available. These agents have the potential to improve survival and quality of life for individuals with sickle cell disease. Also discussed is stem cell transplantation that, to date, is the only curative approach for this disease, as well as the current status of gene therapy. Conclusion:These examples demonstrate how the current knowledge of sickle cell disease pathophysiology and treatment approaches intersect. Although interest in sickle cell research has blossomed, many more clinical trials need to be initiated and subjected to more strenuous examination and analysis than have been used in the past.
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