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RTP, NC, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 289.93K | Year: 2013

DESCRIPTION (provided by applicant): Characterization of human tumor samples and cell lines in combination with inhibitor studies in animal models has established a central role for the Hh pathway in a vast array of cancer types, including small-cell lung, pancreatic, oesophageal, prostate, breast, colon, liver and ovarian cancers. Hh signaling is now implicated in approximately 20-25% of all cancers. GLI1 is the downstream effector in the Hh signaling pathway, and has emerged as a valid therapeutic target. It has been suggested that due to the complexity of signaling inputs in the Hh pathway, targeting GLI1 may provide a more comprehensive strategy for treating both canonical and noncanonical Hh-pathway dependent cancers. This is especially true in light of the acquired resistance to inhibitors of SMO in patients. Screens utilizing GLI1-dependent transcriptional reporter cell-based assays have yielded inhibitors targeting the Hh pathway downstream of SMO including small molecule and natural product compounds that act by targeting GLI1 through differing mechanisms of action. Targeting at the level of GLI1 with small molecules has been effective in a number of cancer model systems including colon, CLL and breast cancer. However, these compounds have only micromolar potencies in vitro, and a subset (GANT61 and ATO) has shown only modest efficacy in in vivo cancer models. These studies suggest that GLI1 is pharmacologically targetable, and that the use of GLI1 inhibitors is a valid and promising approach for targeting GLI1-dependent cancers. Unfortunately, current GLI1 inhibitors are hampered by low potency and a lack of in vivo efficacy and hence are not viable clinical candidates. There are no GLI1-targeted inhibitors in the clinic. Using a novel high throughput, high content cell-based imaging platform, we will screen a diverse collection of small molecules to identify potent inhibitors of GLI1 (Aim 1). Compounds that show inhibitory activity will be further validated in a focused panel of cell-based assays which will incorporate cells derived from primary human breast tumors. These assays will also examine selectivity of the compounds as well as their effects on motility/invasiveness (Aim 2). Promising compounds discovered in Aims 1 and 2 will be subjected to extensive structure-activity relationship to optimize the novel GLI1 inhibitors (Aim 3). PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: A central role for the Hedgehog (Hh) pathway has been established in a vast array of cancer types and it hasbeen implicated in approximately 20-25% of all cancers. GLI1 is a downstream mediator of Hh signaling, making GLI1 a very attractive therapeutic target. A limited number of small molecule inhibitors of GLI1 have been identified; however none of them are clinically viable. In this application we describe a highly innovative cell-based drug screen that will be applied to identifying novel, potent and selective inhibitors o GLI1 as potential cancer therapeutics.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.32K | Year: 2015

DESCRIPTION provided by applicant The activation and recruitment of brown adipose tissue has become an exciting target in the fight against obesity and its related metabolic diseases Brown adipose tissue differs from white adipose tissue in its critical ability to burn energy as heat through UCP driven adaptive thermogenesis Expression of mitochondrial UCP uncouples oxidative phosphorylation resulting in accelerated substrate oxidation but low ATP production The resulting dissipation of energy is associated with plasma triglyceride clearance a key factor in weight loss The brown adipose depot has long been known to exist in rodents as well as in human infants However recent evidence has demonstrated the existence of active brown adipose tissue in human adults These findings prompted a resurgence of research focusing on both the activation of brown adipose tissue and the andquot browningandquot of white adipose tissue a phenomenon wherein UCP mediated mitochondrial uncoupling is induced by stimuli Studies using rodent models have demonstrated that brown fat activation or induction of browning can promote beneficial metabolic effects and promising therapeutic targets have been identified However the therapeutic potential of these targets has not been confirmed due to the lack of a widely available human brown adipocyte model Therefore there is a pronounced need to validate existing therapeutic targets in the human system ZenBio will address this need by providing both a primary and immortalized human brown adipocyte cell culture system to the research community and will utilize these tools to establish a screen to identify activators of human brown adipogenesis The principal goal of this project is to generate and characterize a human adult brown adipocyte cell system We will achieve this in a stepwise fashion beginning with an initial feasibility study focused on human fetal brown adipocytes Aim I will use functional and genomic analyses to generate a widely available fetal brown adipocyte model which will be used as a tool to establish the adult cell system The fetal model will be developed first due to the comparative ease of detecting fetal brown adipose tissue and its ready availability through existing procurement agencies The second aim is to generate and characterize an immortalized fetal brown adipocyte system for high throughput high content screening These cells will circumvent the limited material and lifespan of primary cells and allow for the development of a high throughput screening platform to identify novel targets of brown adipocyte activation Phase I will be expanded in Phase II with the goal of characterizing and commercializing the human adult brown adipocyte system from donors of differing BMI age gender and diabetic state These studies will generate both primary and immortalized human adult adipocyte cells which will be used to identify novel targets of brown adipocyte energy expenditure for the treatment of obesity PUBLIC HEALTH RELEVANCE The worldwide prevalence of obesity and its related diseases is at epidemic proportions necessitating novel therapeutic approaches The recent identification of human adult brown fat has led researchers to investigate new ways to increase this beneficial adipose tissue to deter obesity related diseases We will generate human brown adipocyte systems that can be used to discover and validate novel therapeutic modalities


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.90K | Year: 2015

Not Available


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 363.20K | Year: 2010

DESCRIPTION (provided by applicant): Diabetes affects the lives of hundreds of millions of people worldwide and the incidence rate is continuing to rise. About 8% of the US population is estimated to have Type 1 or Type 2 diabetes, with the prevalence of Type 2 diabetes increasing with the rise in obesity. Even though the etiology of Type 1 and Type 2 diabetes is different, the end stages show a similar reduction or loss of pancreatic insulin secretion. This is caused by destruction of the pancreatic beta cells which produce and secrete insulin in response to serum glucose levels. Current diabetes therapies do not offer the degree of metabolic control needed to prevent the progression of the disease to the serious complications and mortality that occur when glucose control is lost. The potential for excellent, long-term glycemic control offered by a beta-like , insulin producing cell is the rationale for our proposal. This cell would release insulin in a physiologically controlled, glucose-dependent manner, responding minute-to-minute to acute changes in blood glucose levels. In this situation, diabetes would be completely controlled. We have obtained significant preliminary data suggesting that adipose-derived stem cells can be differentiated in culture to beta-like insulin producing cells, and propose to develop applications of these cells for use in cell therapy and drug development. It is our goal to identify and characterize an optimized adult stem cell population from human adipose tissue that has the therapeutic potential for the treatment of diabetes. PUBLIC HEALTH RELEVANCE: Current diabetes therapies do not offer the degree of metabolic control needed to prevent the progression of the disease to the serious complications and mortality that occur when glucose control is lost. Our objective is to identify and characterize an adult stem cell population from human adipose tissue that has the therapeutic potential to differentiate into insulin-secreting pancreatic beta-like cells. If successful, this work would offer the possibility for cell treatment and possible cure of type 1 and type 2 diabetes.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.29M | Year: 2010

DESCRIPTION (provided by applicant): Breast cancer is the second most common cancer among women. Roughly 190,000 women in the U.S. will be diagnosed with breast cancer in 2009, and 40,000 will die. The majority of breast cancers originate in the lobular or ductal cells of the milk-producing glands. In these structures, there are two main cell types: the inner luminal cells surrounded by basal myoepithelium. These cells types are distinct and are the precursors to various forms of breast cancer. As such, it is it is important to study these cell populations independently as well as in co-culture models systems. There are no commercial sources of quality-controlled, matched basal and luminal cells (from individual donors), forcing researchers to isolate and characterize the cells on their own. This process is time-consuming, requires access to human tissue, and introduces variation in the preparation and characterization of the cells. Primary cultured human mammary-derived cells are an ideal model currently used to investigate the genesis and understanding of human breast cancer. Because a consistent commercial source of primary human cultured breast-derived luminal and basal cells is unavailable, Zen-Bio, Inc. will address this need by providing a well characterized system to the research community. Phase I of this project focused on generating an optimized primary human mammary-derived basal/luminal cell system from non-diseased tissue. Isolation and propagation of normal human basal and luminal mammary epithelial cells was achieved. Based on the successful completion of Phase I, we are eager to extend our research in Phase II by focusing on making this cell system commercially available. Additionally, we will expand the cell system to include basal and luminal mammary epithelial cells from breast tumor tissue. Aim 1 of this project is to continue detailed characterization of normal basal and luminal cells focusing on quality control and release criteria for commercialization. Aim 2 is to establish isolation and propagation procedures and detailed characterization of human breast cancer tumor derived cells building on our existing capabilities. Aim 3 is to perform comparative analyses between normal and malignant human cells to establish quality control criteria for commercialization and additional contract assay services at Zen-Bio. Multiple product offerings are expected from this proposal: matched, primary human mammary cell systems from non- diseased and malignant tissue, support media and reagents, contract assay services, and kits for breast cancer research. PUBLIC HEALTH RELEVANCE: At the completion of this project, a fully characterized human primary mammary-derived basal/luminal cell system from normal and malignant breast tissue will be commercially available to researchers. These systems will provide a currently unavailable opportunity to investigate the etiology of breast cancer and to identify potential cures.

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