As a central coordinator of physiologic metabolism, adipose tissue has long been appreciated as a highly plastic organ that dynamically responds to environmental cues. Once thought of as a homogenous storage depot, recent advances have enabled deep characterizations of the underlying structure and composition of adipose tissue depots. As the obesity and metabolic disease epidemics continue to accelerate due to modern lifestyles and an aging population, elucidation of the underlying mechanisms that control adipose and systemic homeostasis are of critical importance. Within the past decade, the emergence of deep cell profiling at tissue- and, recently, single-cell level has furthered our understanding of the complex dynamics that contribute to tissue function and their implications in disease development. Although many paradigm-shifting findings may lie ahead, profound advances have been made to forward our understanding of the adipose tissue niche in both health and disease. Now widely accepted as a highly heterogenous organ with major roles in metabolic homeostasis, endocrine signaling, and immune function, the study of adipose tissue dynamics has reached a new frontier. In this review, we will provide a synthesis of the latest advances in adipose tissue biology made possible by the use of single-cell technologies, the impact of epigenetic mechanisms on adipose function, and suggest what next steps will further our understanding of the role that adipose tissue plays in systemic physiology.
BACKGROUND The MEK1/2 inhibitor selumetinib was recently approved for Neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas, but outcomes could be improved and its pharmacodynamic evaluation in other relevant tissues is limited. The aim of this study was to assess selumetinib tissue pharmacokinetics and pharmacodynamics using a minipig model of NF1. METHODS Eight wild type (WT) and eight NF1 +/- (NF1) minipigs received a single oral dose of 7.3 mg/kg selumetinib. Peripheral blood mononuclear cells (PBMCs), cerebral cortex, optic nerve, sciatic nerve, and skin were collected for pharmacokinetic analysis and pharmacodynamic analysis of extracellular regulated kinase phosphorylation (p-ERK) inhibition and transcript biomarkers (DUSP6 & FOS). RESULTS Key selumetinib pharmacokinetic parameters aligned with those observed in human patients. Selumetinib concentrations were higher in CNS tissues from NF1 compared to WT animals. Inhibition of ERK phosphorylation was achieved in PBMCs (mean 60% reduction), skin (95%) and sciatic nerve (64%) from all minipigs, whereas inhibition of ERK phosphorylation in cerebral cortex was detected only in NF1 animals (71%). Basal p-ERK levels were significantly higher in NF1 minipig optic nerve compared to WT and were reduced to WT levels (60%) with selumetinib. Modulation of transcript biomarkers was observed in all tissues. CONCLUSIONS Selumetinib reduces MAPK signaling in tissues clinically relevant to NF1, effectively normalizing p-ERK to WT levels in optic nerve but resulting in abnormally low levels of p-ERK in the skin. These results suggest that selumetinib exerts activity in NF1-associated central nervous system tumors by normalizing Ras/MAPK signaling and may explain common MEK inhibitor-associated dermatologic toxicities.
Glioblastoma (GBM) is the most common and malignant primary brain tumor. Novel therapeutic development for GBM is needed since the standard of care universally fails to cure patients and the five-year survival rate remains below 10%. GBM therapeutic development is hampered by the lack of relevant large animal models for preclinical studies. To mitigate this problem, we are developing a model of GBM in outbred, immune-proficient swine which have comparable brain size and anatomy to humans. We developed methods for introducing genome engineering tools to minipig brain cells in vivo by direct injection of gene delivery reagents to the lateral ventricle. Using this technique, we have delivered a combination of expression vectors for oncogenes and targeted nucleases to disrupt tumor suppressor genes commonly altered in human GBM to alter six major human GBM-associated signaling pathways in a cohort of minipigs (Ras, Pi3k, p53, Rb/E2F, Pdgf, and the alternative lengthening of telomeres (ALT) pathways). These minipigs are being monitored for tumorigenesis using a secreted reporter, detectable through a simple luminescence-based blood test. Resulting tumors will be examined molecularly to detect the pathway-associated alterations in tumor tissue and determine the resemblance to human GBM. We hypothesize that this somatic cell gene-modification platform we have developed in the minipig will facilitate the efficient production of brain tumors that histologically and genetically resemble human GBM. It will allow the production of tumors that are genetically heterogeneous, of specified molecular subclasses, containing therapeutic targets of interest, and in the context of genetic backgrounds of interest. This minipig model of GBM will be applied towards preclinical therapeutic studies, imaging studies using human clinical grade equipment, and surgical technique development, to improve clinical trial success rates and patient outcomes. Funding for this study is provided by the National Institutes of Health through SBIR grant # 1R43CA235837-01A1.
Glioblastoma (GBM) is the most common and malignant primary brain tumor. Novel therapeutic development for GBM is desperately needed, as the standard of care universally fails to cure patients and the 5-year survival rate remains extremely low. GBM therapeutic development is hampered by the lack of relevant preclinical models for preclinical studies. To mitigate this problem, we have developed a genetic model of GBM in outbred, immune-proficient swine which have comparable brain size and anatomy to humans. We developed methods for introducing genome engineering tools to minipig brain in vivo by direct injection of gene delivery reagents to the lateral ventricle, altering major signaling pathways frequently changed in human GBM. Using this technique, we have delivered a combination of expression vectors for oncogenes and targeted nucleases to disrupt tumor suppressor genes commonly altered in human GBM. We have altered six major human GBM-associated signaling pathways and modeled molecular GBM subclasses. We have also engineered a secreted tumor reporter that can be used to monitor tumor size through a simple blood test. This somatic cell gene-modification platform we have developed in the minipig allows us to reproduce the genetic heterogeneity seen in GBM and understand the impact of the tumor microenvironment, immune system, and response to therapy. This minipig model of GBM Is being used to test the standard of care against novel therapies in preclinical studies, and biopsy, surgical, imaging, and radiation therapy techniques are being optimized in this mode to improve clinical trial success rates and patient outcomes. Funding for this study is provided by the National Institutes of Health though SBIR grant # 1R43CA235837-01A1.
Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in the neurofibromin 1 (NF1) gene. NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. Using gene-editing technology, we have developed a minipig model of NF1 that exhibits clinical hallmarks of the disease, including café au lait macules, neurofibromas, and optic pathway glioma. We have conducted pharmacological studies in our NF1 minipigs to assess the pharmacokinetic and pharmacodynamic properties of MEK inhibitors for NF1. We have demonstrated that oral administration of several MEK inhibitors results in clinically relevant plasma concentrations and consequent inhibition of Ras signaling in immune cells, and certain MEK inhibitors can cross the blood brain barrier and have a pharmacodynamic effect, suggesting that they may be effective in treating NF1-associated brain tumors. Because over 20% of NF1 patients harbor NF1 nonsense mutations, we are assessing safety and efficacy of nonsense mutation suppressors that may be effective in treating NF1. We evaluated six drugs known to induce nonsense mutation suppression in several primary cell types isolated from NF1 minipigs and show that several of these drugs have the propensity to induce the production of full length neurofibromin protein, leading to a subsequent reduction in MAPK signaling. Information acquired from this NF1 minipig preclinical model will be leveraged towards initiating a clinical trial in NF1 patients. The NF1 minipig provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1 therapies.
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