The challenges and molecular approaches surrounding interleukin-2-based therapeutics in cancer
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ABSTRACT:
SUBMITTER: Tang A
PROVIDER: S-EPMC7885892 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
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Project description:Nucleic acid-based therapeutics that regulate gene expression have been developed towards clinical use at a steady pace for several decades, but in recent years the field has been accelerating. To date, there are 11 marketed products based on antisense oligonucleotides, aptamers and small interfering RNAs, and many others are in the pipeline for both academia and industry. A major technology trigger for this development has been progress in oligonucleotide chemistry to improve the drug properties and reduce cost of goods, but the main hurdle for the application to a wider range of disorders is delivery to target tissues. The adoption of delivery technologies, such as conjugates or nanoparticles, has been a game changer for many therapeutic indications, but many others are still awaiting their eureka moment. Here, we cover the variety of methods developed to deliver nucleic acid-based therapeutics across biological barriers and the model systems used to test them. We discuss important safety considerations and regulatory requirements for synthetic oligonucleotide chemistries and the hurdles for translating laboratory breakthroughs to the clinic. Recent advances in the delivery of nucleic acid-based therapeutics and in the development of model systems, as well as safety considerations and regulatory requirements for synthetic oligonucleotide chemistries are discussed in this review on oligonucleotide-based therapeutics.
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Project description:The discovery of microRNAs (miRNAs) in 1993 has challenged the dogma of gene expression regulation. MiRNAs affect most of cellular processes from metabolism, through cell proliferation and differentiation, to cell death. In cancer, deregulated miRNA expression leads to tumor development and progression by promoting acquisition of cancer hallmark traits. The multi-target action of miRNAs, which enable regulation of entire signaling networks, makes them attractive tools for the development of anti-cancer therapies. Hence, supplementing downregulated miRNA by synthetic oligonucleotides or silencing overexpressed miRNAs through artificial antagonists became a common strategy in cancer research. However, the ultimate success of miRNA therapeutics will depend on solving pharmacokinetic and targeted delivery issues. The development of a number of nanocarrier-based platforms holds significant promises to enhance the cell specific controlled delivery and safety profile of miRNA-based therapies. In this review, we provide among the most comprehensive assessments to date of promising nanomedicine platforms that have been tested preclinically, pertaining to the treatment of selected solid tumors including lung, liver, breast, and glioblastoma tumors as well as endocrine malignancies. The future challenges and potential applications in clinical oncology are discussed.
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Project description:Understanding mediation is useful for identifying intermediates lying between an exposure and an outcome which, when intervened upon, will block (some or all of) the causal pathway between the exposure and outcome. Mediation approaches used in conventional epidemiology have been adapted to understanding the role of molecular intermediates in situations of high-dimensional omics data with varying degrees of success. In particular, the limitations of observational epidemiological study including confounding, reverse causation and measurement error can afflict conventional mediation approaches and may lead to incorrect conclusions regarding causal effects. Solutions to analysing mediation which overcome these problems include the use of instrumental variable methods such as Mendelian randomization, which may be applied to evaluate causality in increasingly complex networks of omics data.
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Project description:RNA interference (RNAi) is an evolutionarily conserved, endogenous process for post-transcriptional regulation of gene expression. Although RNAi therapeutics have recently progressed through the pipeline toward clinical trials, the application of these as ideal, clinical therapeutics requires the development of safe and effective delivery systems. Inspired by the immense progress with nanotechnology in drug delivery, efforts have been dedicated to the development of nanoparticle-based RNAi delivery systems. For example, a precisely engineered, multifunctional nanocarrier with combined passive and active targeting capabilities may address the delivery challenges for the widespread use of RNAi as a therapy. Therefore, in this review, we introduce the major hurdles in achieving efficient RNAi delivery and discuss the current advances in applying nanotechnology-based delivery systems to overcome the delivery hurdles of RNAi therapeutics. In particular, some representative examples of nanoparticle-based delivery formulations for targeted RNAi therapeutics are highlighted.
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Project description:Aminoacyl-tRNA synthetases (ARSs) are universal enzymes that catalyze the attachment of amino acids to the 3' ends of their cognate tRNAs. The resulting aminoacylated tRNAs are escorted to the ribosome where they enter protein synthesis. By specifically matching amino acids to defined anticodon sequences in tRNAs, ARSs are essential to the physical interpretation of the genetic code. In addition to their canonical role in protein synthesis, ARSs are also involved in RNA splicing, transcriptional regulation, translation, and other aspects of cellular homeostasis. Likewise, aminoacylated tRNAs serve as amino acid donors for biosynthetic processes distinct from protein synthesis, including lipid modification and antibiotic biosynthesis. Thanks to the wealth of details on ARS structures and functions and the growing appreciation of their additional roles regulating cellular homeostasis, opportunities for the development of clinically useful ARS inhibitors are emerging to manage microbial and parasite infections. Exploitation of these opportunities has been stimulated by the discovery of new inhibitor frameworks, the use of semi-synthetic approaches combining chemistry and genome engineering, and more powerful techniques for identifying leads from the screening of large chemical libraries. Here, we review the inhibition of ARSs by small molecules, including the various families of natural products, as well as inhibitors developed by either rational design or high-throughput screening as antibiotics and anti-parasitic therapeutics.
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Project description:Glaucoma, a heterogeneous ocular disorder affecting ?60 million people worldwide, is characterized by painless neurodegeneration of retinal ganglion cells (RGCs), resulting in irreversible vision loss. Available therapies, which decrease the common causal risk factor of elevated intraocular pressure, delay, but cannot prevent, RGC death and blindness. Notably, it is changes in the anterior segment of the eye, particularly in the drainage of aqueous humor fluid, which are believed to bring about changes in pressure. Thus, it is primarily this region whose properties are manipulated in current and emerging therapies for glaucoma. Here, we focus on the challenges associated with developing treatments, review the available experimental methods to evaluate the therapeutic potential of new drugs, describe the development and evaluation of emerging Rho-kinase inhibitors and adenosine receptor ligands that offer the potential to improve aqueous humor outflow and protect RGCs simultaneously, and present new targets and approaches on the horizon.
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Project description:BackgroundThyroid cancer, as with other types of cancer, is dependent on angiogenesis for its continued growth and development. Interestingly, estrogen has been shown to contribute to thyroid cancer aggressiveness in vitro, which is in full support of the observed increased incidence of thyroid cancer in women over men. Provided that estrogen has been observed to contribute to increased angiogenesis of estrogen responsive breast cancer, it is conceivable to speculate that estrogen also contributes to angiogenesis of estrogen responsive thyroid cancer.MethodsIn this study, three human thyroid cancer cells (B-CPAP, CGTH-W-1, ML-1) were treated with estrogen alone or estrogen and anti-estrogens (fulvestrant and 3,3'-diindolylmethane, a natural dietary compound) for 24 hours. The cell culture media was then added to human umbilical vein endothelial cell (HUVECs) and assayed for angiogenesis associated events. Vascular endothelial growth factor (VEGF) levels were also quantified in the conditioned media so as to evaluate if it is a key player involved in these observations.ResultsConditioned medium from estrogen treated thyroid cancer cells enhanced phenotypical changes (proliferation, migration and tubulogenesis) of endothelial cells typically observed during angiogenesis. These phenotypic changes observed in HUVECs were determined to be modulated by estrogen induced secretion of VEGF by the cancer cells. Lastly, we show that VEGF secretion was inhibited by the anti-estrogens, fulvestrant and 3,3'-diindolylmethane, which resulted in diminished angiogenesis associated events in HUVECs.ConclusionOur data establishes estrogen as being a key regulator of VEGF secretion/expression in thyroid cells which enhances the process of angiogenesis in thyroid cancer. These findings also suggest the clinical utility of anti-estrogens as anti-angiogenic compounds to be used as a therapeutic means to treat thyroid cancer. We also observed that 3,3'-diindolylmethane is a promising naturally occurring anti-estrogen which can be used as a part of therapeutic regimen to treat thyroid cancer.
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Project description:The emergence of the "precision-medicine" paradigm in oncology has ushered in tremendous improvements in patient outcomes in a wide variety of malignancies. However, pancreas ductal adenocarcinoma (PDAC) has remained an obstinate challenge to the oncology community and continues to be associated with a dismal prognosis with 5-year survival rates consistently less than 5%. Cytotoxic chemotherapy with gemcitabine-based regimens has been the cornerstone of treatment in PDAC especially because most patients present with inoperable disease. But in recent years remarkable basic science research has improved our understanding of the molecular and genetic basis of PDAC. Whole genomic analysis has exemplified the genetic heterogeneity of pancreas cancer and has led to ingenious efforts to target oncogenes and their downstream signaling cascades. Novel stromal depletion strategies have been devised based on our enhanced recognition of the complex architecture of the tumor stroma and the various mechanisms in the tumor microenvironment that sustain tumorigenesis. Immunotherapy using vaccines and immune checkpoint inhibitors has also risen to the forefront of therapeutic strategies against PDAC. Furthermore, adoptive T cell transfer and strategies to target epigenetic regulators are being explored with enthusiasm. This review will focus on the recent advances in molecularly targeted therapies in PDAC and offer future perspectives to tackle this lethal disease.
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