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Antisense oncology

Roberto Gambari, Eleonora Brognara, Demetrios A Spandidos, Enrica Fabbri
MicroRNA (miRNA or miR) therapeutics in cancer are based on targeting or mimicking miRNAs involved in cancer onset, progression, angiogenesis, epithelial-mesenchymal transition and metastasis. Several studies conclusively have demonstrated that miRNAs are deeply involved in tumor onset and progression, either behaving as tumor-promoting miRNAs (oncomiRNAs and metastamiRNAs) or as tumor suppressor miRNAs. This review focuses on the most promising examples potentially leading to the development of anticancer, miRNA-based therapeutic protocols...
July 2016: International Journal of Oncology
Ammad Ahmad Farooqi, Sundas Fayyaz, Iryna Shatynska-Mytsyk, Zeeshan Javed, Saima Jabeen, Ilhan Yaylim, Maria Luisa Gasparri, Pierluigi Benedetti Panici
Overwhelmingly increasing advancements in miRNA biology have opened new avenues for pharmaceutical companies to initiate studies on designing effective, safe, and therapeutically active candidates using miRNA mimetics and miRNA inhibitors. In accordance with this approach, development of miravirsen and SPC3649, an LNA-based (locked nucleic acid) antisense molecule against miR-122, to treat hepatitis C has sparked interest in identifying most efficient microRNAs for journey from bench-top toward pharmaceutical industry and breakthroughs in delivery technology will pave the way to 'final frontier'...
March 2016: Chemical Biology & Drug Design
Frank Jaschinski, Hanna Korhonen, Michel Janicot
Transforming growth factor beta isoforms (TGF-β1, -β2, and -β3) are cytokines associated with a wide range of biological processes in oncology including tumor cell invasion and migration, angiogenesis, immunosuppression, as well as regulation of tumor stem cell properties. Hence, blocking the TGF-β signaling pathways may have a multifold therapeutic benefit for the treatment of solid tumors. Here, we describe the identification and selection processes for the development of highly potent and selective chemically modified antisense oligodeoxynucleotides (fully phosphorothioate locked nucleic acid gapmers) allowing effective and selective suppression of TGF-β isoform expression in cell-based assays and in vivo preclinical models...
2015: Methods in Molecular Biology
Ronald Natale, Fiona Blackhall, Dariusz Kowalski, Rodryg Ramlau, Gerold Bepler, Francesco Grossi, Christian Lerchenmüller, Mary Pinder-Schenck, Jörg Mezger, Sarah Danson, Shirish M Gadgeel, Yvonne Summers, Sophie Callies, Valérie André, Mayukh Das, Michael Lahn, Denis Talbot
Chemoresistance is mediated, in part, by the inhibition of apoptosis in tumor cells. Survivin is an antiapoptotic protein that blocks chemotherapy-induced apoptosis. To investigate whether blocking survivin expression enhances docetaxel-induced apoptosis in patients with non-small-cell lung cancer (NSCLC), we compared the antitumor activity of the survivin inhibitor LY2181308 plus docetaxel with docetaxel alone. We used change in tumor size (CTS) as a primary endpoint to assess its use in early decision-making for this and future studies of novel agents in NSCLC...
November 2014: Journal of Thoracic Oncology
Ammad Ahmad Farooqi, Zia Ur Rehman, Jordi Muntane
There is increasing progress in translational oncology and tremendous breakthroughs have been made as evidenced by preclinical and clinical trials. Data obtained from high-throughput technologies are deepening our understanding about the molecular and gene network in cancer cells and rapidly emerging in vitro and in vivo evidence is highlighting the role of antisense agents as specific inhibitors of the expression of target genes, thus modulating the response of cancer cells to different therapeutic strategies...
2014: OncoTargets and Therapy
Paloma Del C Monroig, Lu Chen, Shuxing Zhang, George A Calin
One of the most fascinating discoveries in molecular oncology has been that cancer represents a disease in which genetic alterations in protein-coding, but also in non-coding genes complement each other. MicroRNAs (miRNAs) are a type of non-coding RNA (ncRNA) transcripts that can regulate gene expression primarily by disrupting messenger RNA (mRNA) translation and/or stability, or alternatively by modulating the transcription of target mRNAs. For the last decade, miRNAs have shown to be pivotal characters of every single one of the cancer hallmarks...
January 2015: Advanced Drug Delivery Reviews
Enrico P Spugnini, Alfonso Baldi
Electroporation is a delivery technique that is gaining popularity among the veterinary community due to its low cost, ease of application, and flexibility. It combines the administration of pharmaceutical compounds such as chemotherapy agents, antisense, and plasmids to the application of permeabilizing pulses. This chapter reviews the veterinary results obtained through the delivery of anticancer drugs (electrochemotherapy) and genes (electro-gene therapy).
2014: Methods in Molecular Biology
Sebastien A Burel, So-Ri Han, Hong-Soo Lee, Daniel A Norris, Byoung-Seok Lee, Todd Machemer, Shin-Young Park, Tianyuan Zhou, Guobin He, Youngsoo Kim, A Robert MacLeod, Brett P Monia, Shirley Lio, Tae-Won Kim, Scott P Henry
ISIS 481464 is a constrained ethyl (cEt) modified phosphorothioate antisense oligonucleotide (ASO) targeting signal transducer and activator of transcription 3 (STAT3) studied in mice and monkey to support oncology clinical trials. Six-week toxicology studies were performed in mice and cynomolgus monkey (up to 70 and 30 mg/kg/week respectively). Reduction in STAT3 protein up to 90% of control was observed in monkey. Cynomolgus monkey was considered the most relevant species to human with respect to pharmacokinetic properties, but mice are useful in their relative sensitivity to the potential proinflammatory and hepatic effects of oligonucleotides...
June 2013: Nucleic Acid Therapeutics
Sohaib Al-Asaaed, Eric Winquist
Adenocarcinoma of the prostate is the most common cancer in men in the Western Hemisphere. This diagnosis includes a clinicopathologically diverse collection of disease entities, encompassing a spectrum from early localized disease to advanced-stage castration-sensitive and ultimately metastatic, castration-resistant states. Although early-stage disease is treatable and potentially curable, treatment options for castration-resistant prostate cancer, the common pathway to prostate cancer death, remain limited and palliative in nature...
April 2013: Current Oncology Reports
Erin C Connolly, Julia Freimuth, Rosemary J Akhurst
Many advanced tumors produce excessive amounts of Transforming Growth Factor-β (TGF-β) which, in normal epithelial cells, is a potent growth inhibitor. However, in oncogenically activated cells, the homeostatic action of TGF-β is often diverted along alternative pathways. Hence, TGF-β signaling elicits protective or tumor suppressive effects during the early growth-sensitive stages of tumorigenesis. However, later in tumor development when carcinoma cells become refractory to TGF-β-mediated growth inhibition, the tumor cell responds by stimulating pathways with tumor progressing effects...
2012: International Journal of Biological Sciences
Dario C Altieri
With almost 4000 citations in Medline in a little over 10 years, survivin has certainly kept scores of investigators busy worldwide. Tangible progress has been made in revealing the multiple functions of survivin, uncovering their wirings as integrated cellular networks, and mapping their exploitation in virtually every human tumor, in vivo. Considering the normally long and excruciating timeline of oncology drug discovery, it is clearly a resounding success that a better understanding of survivin biology has led to several clinical trials of survivin-based therapeutics in cancer patients...
May 28, 2013: Cancer Letters
V Baylot, C Andrieu, M Katsogiannou, D Taieb, S Garcia, S Giusiano, J Acunzo, J Iovanna, M Gleave, C Garrido, P Rocchi
Despite many advances in oncology, almost all patients with pancreatic cancer (PC) die of the disease. Molecularly targeted agents are offering hope for their potential role in helping translate the improved activity of combination chemotherapy into improved survival. Heat shock protein 27 (Hsp27) is a chaperone implicated in several pathological processes such as cancer. Further, Hsp27 expression becomes highly upregulated in cancer cells after chemotherapy. Recently, a modified antisense oligonucleotide that is complementary to Hsp27 (OGX-427) has been developed, which inhibits Hsp27 expression and enhances drug efficacy in cancer xenograft models...
2011: Cell Death & Disease
Pooja P Advani, Aneel Paulus, Ayesha Masood, Taimur Sher, Asher Chanan-Khan
INTRODUCTION: Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the western hemisphere. Developing new therapies remains a priority as present treatment options do not offer a cure. BCL-2 overexpression in CLL is associated with aggressive disease features and resists chemotherapy. Oblimersen sodium (G3139) is a phosphorothioate oligonucleotide antisense drug targeting the BCL-2 mRNA and is the first antisense to reach advanced clinical testing in oncology. Preclinical evaluation has demonstrated good antineoplastic effect in B-cell cancers; several clinical trials have confirmed its safety and efficacy both alone and in combination with other therapeutics...
June 2011: Expert Opinion on Drug Metabolism & Toxicology
Isabel Heidegger, Andreas Pircher, Helmut Klocker, Petra Massoner
During the last decades, changes in the insulin-like growth factor (IGF) signaling have been related to the pathogenesis of cancer. Therefore, IGFs became highly attractive therapeutic cancer targets. Several drugs including monoclonal antibodies (mAB), small molecule tyrosine kinase inhibitors (RTKIs), anti-sense oligonucleotids (ASOs) and IGF-binding proteins (IGFBPs) targeting the IGF axis were developed. With over 60 ongoing clinical trials, the IGF1 receptor (IGF1R) is currently one of the most studied molecular targets in the field of oncology...
April 15, 2011: Cancer Biology & Therapy
F Rödel, S Reichert, T Sprenger, U S Gaipl, J Mirsch, T Liersch, S Fulda, C Rödel
Alterations in the expression of apoptosis-related proteins, like the inhibitor of apoptosis (IAP) protein family, display a pivotal pathway by which cancer cells acquire resistance to therapeutic treatment. Among this family, survivin, the smallest and structural unique member, deserves growing attention due to its universal over-expression in human tumors, and its prominent role in disparate networks of cellular division, intracellular signaling and apoptosis. Several preclinical studies have demonstrated that targeting survivin expression by the use of small interfering RNAs, dominant negative mutants, antisense-oligonucleotides and small molecule repressors sensitized tumor cells towards chemotherapy and irradiation and reduced tumor growth potential...
2011: Current Medicinal Chemistry
Kim N Chi, Sebastien J Hotte, Evan Y Yu, Dongsheng Tu, Bernhard J Eigl, Ian Tannock, Fred Saad, Scott North, Jean Powers, Martin E Gleave, Elizabeth A Eisenhauer
PURPOSE: To determine the clinical activity of OGX-011, an antisense inhibitor of clusterin, in combination with docetaxel/prednisone in patients with metastatic castration-resistant prostate cancer. PATIENTS AND METHODS: Patients were randomly assigned 1:1 to receive docetaxel/prednisone either with (arm A) or without (arm B) OGX-011 640 mg intravenously weekly. The primary end point was the proportion of patients with a prostate-specific antigen (PSA) decline of ≥ 50% from baseline, with the experimental therapy being considered of interest if the proportion of patients with a PSA decline was more than 60%...
September 20, 2010: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Carmen S Dence, Richard Laforest, Xiankai Sun, Terry L Sharp, Michael J Welch, Robert H Mach
PURPOSE: The aim of the study was to develop a rapid and reproducible method to label LY2181308, an antisense oligonucleotide to Survivin, with carbon-11 in order to study its in vivo biodistribution and tumor uptake in rodents and its human dosimetry based on baboon data. METHODS: Randomly [¹¹C] methylated LY2181308 was produced with [¹¹C] methyl iodide. The biodistribution was performed in female Sprague-Dawley (SD) rats and EMT-6 tumor-bearing mice in the presence of nonradioactive LY2181308...
December 2010: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
William C S Cho
MicroRNAs have a revolutionary impact on cancer research over recent years. They emerge as important players in tumorigenesis, leading to a paradigm shift in oncology. The widespread and comprehensive use of microRNA microarrays has enabled the identification of a number of microRNAs as potential biomarkers for cancer. It is encouraging to report that microRNAs have remarkable stability in both formalin-fixed tissue and blood. Many microRNAs have been identified to act as oncogenes, tumor suppressors, or even modulators of cancer stem cells and metastasis...
August 2010: International Journal of Biochemistry & Cell Biology
Sneha Sundaram, Ruchit Trivedi, Chandrasekar Durairaj, Rajagopal Ramesh, Balamurali K Ambati, Uday B Kompella
PURPOSE: To evaluate the efficacy of a novel docetaxel derivative of deslorelin, a luteinizing hormone-releasing hormone (LHRH) agonist, and its combination in vivo with RGD peptide conjugated nanoparticles encapsulating an antiangiogenic, anti-vascular endothelial growth factor (VEGF) intraceptor (Flt23k; RGD-Flt23k-NP) in H1299 lung cancer cells and/or xenografts in athymic nude BALB/c mice. EXPERIMENTAL DESIGN: The in vitro and in vivo efficacy of the deslorelin-docetaxel conjugate was evaluated in H1299 cells and xenografts in athymic nude mice...
December 1, 2009: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Vivek Vijjan, Deepak Dubey
Androgen deprivation therapy has become the mainstay of the treatment of advanced prostate cancer, being used in every clinical setting of the disease, from neoadjuvant to metastatic disease. Despite success in controlling the disease in the majority of men, hormonal manipulations will eventually fail. New agents are being developed for patients with hormone refractory disease. Important advances in molecular oncology have improved our understanding regarding the cellular mechanisms that regulate cell death in the prostate...
January 2007: Indian Journal of Urology: IJU: Journal of the Urological Society of India
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