The Mount Sinai journal of medicine, New York
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Malignant gliomas are the most common primary brain tumors in adults and carry a dismal prognosis. Despite aggressive therapy with maximal safe surgical resection, radiation and chemotherapy, these tumors invariably are refractory to or become resistant to treatment and recur. Gliomas are highly infiltrative cancers and display remarkable genetic heterogeneity making them challenging to treat. ⋯ In addition, the growing body of research in cancer immunology as well as cancer stem cells has made inroads in our understanding of tumorgenesis. Translational research has been particularly crucial to the development of these therapies as much preclinical and clinical work is needed to develop the rationale for treatments, to develop biomarkers of drug activity and to elucidate mechanisms of resistance. This brief overview will discuss some of the pivotal advances made in the pursuit of improved outcomes and survival for patients with this devastating disease.
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Review
Drug-based therapies for vascular disease in Marfan syndrome: from mouse models to human patients.
Marfan syndrome is a congenital disorder of the connective tissue with a long history of clinical and basic science breakthroughs that have forged our understanding of vascular-disease pathogenesis. The biomedical importance of Marfan syndrome was recently underscored by the discovery that the underlying genetic lesion impairs both tissue integrity and transforming growth factor-beta regulation of cell behavior. This discovery has led to the successful implementation of the first pharmacological intervention in a connective-tissue disorder otherwise incurable by either gene-based or stem cell-based therapeutic strategies. More generally, information gathered from the study of Marfan syndrome pathogenesis has the potential to improve the clinical management of common acquired disorders of connective-tissue degeneration.
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G-protein-coupled receptors are important molecular targets in drug discovery. These receptors play a pivotal role in physiological signaling pathways and are targeted by nearly 50% of currently available drugs. Mounting evidence suggests that G-protein-coupled receptors form dimers, and various studies have shown that dimerization is necessary for receptor maturation, signaling, and trafficking. ⋯ Such antibodies could be used as tools for characterization of heteromer-specific function; as reagents for their purification, tissue localization, and regulation in vivo; and as probes for mapping their functional domains. In addition, such antibodies could serve as alternative ligands for G-protein-coupled receptor heteromers. Thus, heteromer-specific antibodies represent novel tools for the exploration and manipulation of G-protein-coupled receptor-dimer pharmacology.
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The drug discovery and development enterprise, traditionally an industrial juggernaut, has spanned into the academic arena that is partially motivated by the National Institutes of Health Roadmap highlighting translational science and medicine. Because drug discovery and development represents a pipeline of basic to clinical investigations, it meshes well with the "bench to the bedside" prime directive of translational medicine. ⋯ One area that has received limited attention concerns the use of pharmacokinetic and pharmacodynamic studies in the drug-development process. Using anticancer drug development as a focus, this review will address past and current deficencies in how pharmacokinetic/pharmacodynamic studies are conducted and offer new strategies that might bridge the gap between preclinical and clinical trials.
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Over the past 2 decades, our increased understanding of tumor biology has resulted in the delivery of a new generation of molecularly targeted cancer drugs with greater efficacy and less toxicity. This understanding has also provided pharmaceutical and academic institutions with a greater appreciation for the complexities and challenges associated with discovering and developing molecularly targeted drugs. ⋯ Cooperative efforts by industry and academia have also provided important insights to optimize the use of such agents in the clinic. This review aims to emphasize the need for academic/industrial collaborations for success and efficiency through the drug discovery and development continuum, and will highlight several examples of collaborations between academic and industrial scientists that facilitated the development of molecularly targeted antitumor agents into the clinic.