Prospects For Clinical Translation Research Articles

Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation. Medium-throughput results were scrutinized and extensively analyzed for sensitivity patterns, synergy, anticancer activity, and were validated in low-throughput experiments. Principal component analysis revealed that a fraction of all upregulated or downregulated genes of a particular targeted pathway could partly explain cell sensitivity toward agents targeting that pathway. Combination therapies deemed immediately tractable to translation included ABT-263/crizotinib, ABT-263/paclitaxel, paclitaxel/JQ1, ABT-263/XL-184, and paclitaxel/nutlin-3, all of which exhibited synergistic antiproliferative and apoptotic activity in multiple TNBC backgrounds. Mechanistic investigations of the ABT-263/crizotinib combination offering a potentially rapid path to clinic demonstrated RTK blockade, inhibition of mitogenic signaling, and proapoptotic signal induction in basal and mesenchymal stem-like TNBC. Our findings provide preclinical proof of concept for several combination treatments of TNBC, which offer near-term prospects for clinical translation. Cancer Res; 77(2); 566-78. ©2016 AACR.

'Off-the-shelf' immunotherapy with iPSC-derived rejuvenated cytotoxic Tlymphocytes.

Adoptive T-cell therapy to target and kill tumor cells shows promise and induces durable remissions in selected malignancies. However, for most cancers, clinical utility is limited. Cytotoxic T lymphocytes continuously exposed to viral or tumor antigens, with long-term expansion, may become unable to proliferate ("exhausted"). To exploit fully rejuvenated induced pluripotent stem cell (iPSC)-derived antigen-specific cytotoxic T lymphocytes is a potentially powerful approach. We review recent progress in engineering iPSC-derived T cells and prospects for clinical translation. We also describe the importance of introducing a suicide gene safeguard system into adoptive T-cell therapy, including iPSC-derived T-cell therapy, to protect from unexpected events in first-in-humans clinical trials.

Toward Clinical Application and Molecular Understanding of the Mechanobiology of Bone Healing

Bone healing is sensitive to mechanical loading. Study of the mechanisms by which mechanical loads modulate healing can yield new strategies for the treatment of bone injuries. This article reviews the basic biological and biomechanical stages of bone healing and then summarizes the phenomenological evidence of the mechanosensitivity of the healing process. We then turn our focus to more mechanistic studies. Noting that the puzzle of bone-healing mechanobiology is multi-scale—spanning from the scale of bone as an organ system down to subcellular components—we review these studies according to this hierarchy of length scales and thus highlight how little is known about cellular and subcellular mechanobiology during bone healing. Progress in filling this gap in knowledge, so as to develop a more molecular-based understanding of bone-healing mechanobiology, is discussed, along with prospects for clinical translation.

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders.

Research into the causes of psychopathology has largely focused on two broad etiologic factors: genetic vulnerability and environmental stressors. An important role for familial/heritable factors in the etiology of a broad range of psychiatric disorders was established well before the modern era of genomic research. This review focuses on the genetic basis of three disorder categories-posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and the anxiety disorders-for which environmental stressors and stress responses are understood to be central to pathogenesis. Each of these disorders aggregates in families and is moderately heritable. More recently, molecular genetic approaches, including genome-wide studies of genetic variation, have been applied to identify specific risk variants. In this review, I summarize evidence for genetic contributions to PTSD, MDD, and the anxiety disorders including genetic epidemiology, the role of common genetic variation, the role of rare and structural variation, and the role of gene-environment interaction. Available data suggest that stress-related disorders are highly complex and polygenic and, despite substantial progress in other areas of psychiatric genetics, few risk loci have been identified for these disorders. Progress in this area will likely require analysis of much larger sample sizes than have been reported to date. The phenotypic complexity and genetic overlap among these disorders present further challenges. The review concludes with a discussion of prospects for clinical translation of genetic findings and future directions for research.

Mechanical properties of α-tricalcium phosphate-based bone cements incorporating regenerative biomaterials for filling bone defects exposed to low mechanical loads.

Calcium phosphate-based cements with enhanced regenerative potential are promising biomaterials for the healing of bone defects in procedures such as percutaneous vertebroplasty. With a view to the use of such cements for low load bearing applications such as sinus augmentation or filling extraction sites. However, the inclusion of certain species into bone cement formulations has the potential to diminish the mechanical properties of the formulations and thereby reduce their prospects for clinical translation. Consequently, we have prepared α-tricalcium phosphate (α-TCP)-based bone cements including materials that we would expect to improve their regenerative potential, and describe the mechanical properties of the resulting formulations herein. Formulations incorporated α-TCP, hydroxyapatite, biopolymer-thickened wetting agents, sutures, and platelet poor plasma. The mechanical properties of the composites were composition dependent, and optimized formulations had clinically relevant mechanical properties. Such calcium phosphate-based cements have potential as replacements for cements such as those based on polymethylmethacrylate.

Re-growth of the adult heart by stem cells?

The potential of the human heart to regenerate cells in tissue in adult life by local replacement of cells either by cell division or by differentiation of cardiovascular or mesenchymal progenitor cells (here referred to as stem cells) has been a subject of major controversial discussion in the last 10 years [1]. The debate and studies to understand physiological and pathological regulation of cell turnover in different parts of the heart organ is currently ongoing. Basic science is gradually evolving data on cell turnover and replacement in cardiac tissue with respect to considerable differences between the various cell types of the heart as well as to the generation and turnover of cardiac extracellular matrix components. Different kinetics of cell turnover have been discussed for endothelial cells and myofibroblasts to be at least in part derived from bone marrow stem cells and cardiomyocytes to be potentially derived from resident cardiac stem cells. First reliable human data on cell turnover and cardiomyocyte replacement has been generated by Bergmann et al. [2], observing a slow physiological replacement of cardiomyocytes throughout adult life. The source of supply of new cells either by cell division of cardiac stem cells or by cardiomyocytes is currently under debate in recently published papers. The three possible modes of replacement are (i) cell division of mononuclear cardiomyocytes [3] vs (ii) replacement by resident cardiac (progenitor) stem cells [4, 5] vs (iii) dedifferentiation and proliferation of cardiomyocytes [6]. All three proposed mechanisms remain speculative to be involved in human hearts disease. This is reflected by the divergence of the calculated rate of annual replacement of cardiomyocytes in adult human hearts ranging from 1 [2] to 40% [4]. The potential to stimulate cardiomyocyte growth by periostinbased integrin stimulation discovered by Kuhn et al. [7] fostered research on pathways for therapeutical use. Another interesting advance is coming from cell programming technology, raising prospects for clinical translation. Qian et al. [8] and Song et al. [9] have demonstrated the direct intracardiac programming of fibroblasts to cardiomyocytes by the use of a combination of transcription factors. Actually, this has been complemented by a paper by Eulalio et al. [10], demonstrating the induction by cardiomyocyte proliferation by specific microRNA. The generation of autologous cardiomyocytes from induced pluripotent stem cells (iPS) [11] for myocardial transplantation has been demonstrated to be another promising option for myocardial transplantation of cells or myocardial sheets and to induce cardiac recovery [12]. Thus, a number of tools for cell manipulation and site-directed application in cardiac disease have been discovered and can be developed for preclinical evaluation. Taken together, however, basic science understanding of the mechanism and control of cardiac growth, especially with respect to cardiomyocytes, is still quite limited to open the road for rapid clinical translation in the near future. The use of extracardiac or cardiac stem cells for therapeutic approaches to induce angiogenesis and cardiac growth, however, has gained some early advance in clinical translation, reaching clinical trial level since 2001 [13–15].

Adoptive T cell therapy for cancer in the clinic

The transfusion of lymphocytes, referred to as adoptive T cell therapy, is being tested for the treatment of cancer and chronic infections. Adoptive T cell therapy has the potential to enhance antitumor immunity, augment vaccine efficacy, and limit graft-versus-host disease. This form of personalized medicine is now in various early- and late-stage clinical trials. These trials are currently testing strategies to infuse tumor-infiltrating lymphocytes, CTLs, Th cells, and Tregs. Improved molecular biology techniques have also increased enthusiasm and feasibility for testing genetically engineered T cells. The current status of the field and prospects for clinical translation are reviewed herein.

Gene therapy progress and prospects: Hydrodynamic gene delivery

Over the last few years, hydrodynamic tail vein delivery has established itself as a simple, yet very effective method for gene transfer into small rodents. Hydrodynamic delivery of plasmid DNA expression vectors or small interfering RNA allows for a broad range of in vivo experiments, including the testing of regulatory elements, antibody generation, evaluation of gene therapy approaches, basic biology and disease model creation (non-heritable transgenics). The recent development of the hydrodynamic limb vein procedure provides a safe nucleic acid delivery technique with equally high efficiency in small and large research animals and, importantly, the prospects for clinical translation.