Abstract 1010: Effect of dietary energy balance modulation on the ability of metformin to inhibit skin tumor promotion

Abstract The prevalence of obesity has drastically increased over the last decade and is associated with increased risk for several cancers. In contrast, calorie restriction (CR) universally inhibits cancer. Plausible mechanisms for the energy balance-cancer link include differential signaling through Akt/mTOR via the IGF-1R as well as other growth factor receptors. Previous data from our lab, using topical administration of rapamycin, support the hypothesis that pharmacological disruption of mTORC1 signaling mimics some of the effects of CR on skin tumor promotion. To further explore the role of mTORC1 signaling in tumor promotion we have conducted studies using metformin. In the present study, metformin was administered in the drinking water at doses of 250 mg/kg and 50 mg/kg body weight per day to female FVB/N mice, to assess its ability to reverse the effects of overweight/obesity on skin tumor promotion during two-stage skin carcinogenesis. Metformin treatment during skin tumor promotion significantly inhibited tumor multiplicity in a dose dependent manner in mice on an overweight control diet (AIN76A). There was a 70% reduction in papillomas per mouse at the 250 mg/kg dose and a 35% reduction at the 50 mg/kg dose. Short term mechanistic experiments with these same doses revealed significant decreases in TPA-induced epidermal hyperproliferation (as measured by epidermal hyperplasia and labeling index) after oral administration of metformin. Metformin also activated AMP Kinase in the epidermis as measured by pAMPKαT172 at both doses used as well as attenuated signaling through mTORC1 at the highest dose as measured by downstream signaling proteins p70S6KT389 and prS6S235/236. Treatment with the higher dose of metformin also prevented TPA-induced mTORC1 mediated degradation of translational repressor PDCD4. Current experiments are assessing the ability of metformin to suppress skin tumor promotion in mice maintained on an obesity inducing diet (60kcal% fat) and these studies will also be presented. Overall, the current data support the hypothesis that selectively targeting mTORC1, either directly (rapamycin) or indirectly via AMPK activation, may be an effective strategy for reversing the effects of overweight and obesity on tumor development during epithelial carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1010. doi:1538-7445.AM2012-1010</jats:p

Abstract 1847: Effect of rapamycin and metformin on skin tumor promotion in mice overweight and obese

Abstract The prevalence of obesity in the US has risen drastically over the past few decades and is an established risk factor for several human cancers. Insights into the mechanisms underlying this link are urgently needed to develop strategies for treatment and prevention. Various studies have shown that calorie restriction (CR) during tumor promotion in the two-stage model of skin carcinogenesis causes a significant reduction in tumorigenesis. In addition, diet induced obesity (DIO) leads to insulin resistance, increased circulating levels of IGF-1 and increased susceptibility to tumor development. Current data indicate that signaling through the IGF-1R and EGFR as well as several downstream signaling pathways plays an important role in dietary energy balance effects on tumor promotion during epithelial carcinogenesis. The current study was designed to evaluate the ability of rapamycin (an established mTORC1 inhibitor) to inhibit or reverse the effects of overweight/obesity on skin tumor promotion in mice. In initial experiments using female FVB mice on an AIN76A diet, rapamycin (5-1000 nmol per mouse) was found to be a potent inhibitor of skin tumor promotion by TPA. In this regard, rapamycin reduced both tumor multiplicity and incidence in a dose dependent manner. A dose of 5 nmol rapamycin given 30 min before each TPA treatment reduced the number of papillomas per mouse by approximately 50%. Rapamycin treatment inhibited TPA-induced mTORC1 activation as well as downstream signaling proteins p70S6KT389, prS6S240/244 and p4EBP1T37/46. Multiple treatment experiments were performed to evaluate the effects of rapamycin (5-200 nmol per mouse) on TPA-induced epidermal hyperproliferation (as assessed by epidermal hyperplasia and epidermal labeling index). Rapamycin significantly inhibited TPA-induced epidermal hyperproliferation in a dose dependent manner. In addition, immunohistochemical analyses of the skin from mice in this multiple treatment experiment revealed that rapamycin significantly decreased the number of infiltrating macrophages, T-cells, neutrophils, and mast cells seen in the dermis following TPA treatment. Moreover, topical application of rapamycin to existing papillomas induced regression and/or inhibited their growth. Two-stage skin carcinogenesis studies are currently underway to further evaluate the impact of rapamycin treatment on mice made overweight (AIN76A) or obese (DIO diet; 60 Kcal % fat) via dietary energy balance manipulation. In addition, groups of mice are also being treated with metformin. These ongoing studies will clarify whether suppression of the mTORC1 signaling pathway is a viable strategy for reversing the effects of obesity on tumor development in this well established model of epithelial carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1847. doi:10.1158/1538-7445.AM2011-1847</jats:p

Catheter Care Bundle and Low Catheter Infection Rates in a Home Parenteral Nutrition Population: A 4 Year Observational Study

Abstract Background Home Parenteral Nutrition (HPN) is often a life-saving therapy for patients. One of the most common complications for HPN is catheter-related blood stream infections (CRBSI). In the home setting there is no single defined “care bundle” for the on-going maintenance of central venous catheters (CVC) for the prevention of CRBSI. We evaluated the impact of a standardized catheter care bundle in patients receiving HPN on the incidence of CRBSI. Methods Data collection included use of standardized tools and processes to capture patient demographics, catheter complications including CRBSI and some associated risk factors. Reported data was collected and analyzed annually and compared year-to-year from the years 2014–2017 from one national home infusion company. CRBSI reported as number of infections/1000 catheter days Results The CRBSI rate/1000 days was reported as 0.43, 0.31, 0.30 and 0.23 (2014, 2015, 2016, 2017 respectively). The type of catheter, number of catheter lumens and type of nursing care provided had importance. In general, single lumen central venous catheters had numerically less CRBSI than double lumen central venous catheters; peripherally-inserted central venous catheters were the most common catheter used but also had the highest percentage of CRBSI. Conclusion The use of a catheter care bundle in an HPN population resulted in a 4- year reported outcomes of low and continuously declining CRBSI in a large, diverse United States-based HPN population.</jats:p

Catheter Care Bundle and Low Catheter Related Bloodstream Infection Rates in a Home Parenteral Nutrition Population; a&amp;nbsp;&amp;nbsp;4 Year Observational Study

Abstract Home Parenteral Nutrition (HPN) is often a life-saving therapy for patients. One of the most common complications for HPN is catheter-related blood stream infections (CRBSI). In the home setting there is no single defined “care bundle” for the on-going maintenance of central venous catheters (CVC) for the prevention of CRBSI. We evaluated the impact of a standardized catheter care bundle in patients receiving HPN on the incidence of CRBSI. Methods: Data collection included use of standardized tools and processes to capture patient demographics, catheter complications including CRBSI and some associated risk factors. Reported data was collected and analyzed annually and compared year-to-year from the years 2014-2017 from one national home infusion company. CRBSI reported as number of infections/1000 catheter days Results: The CRBSI rate/1000 days was reported as 0.43, 0.31, 0.30 and 0.23 (2014, 2015, 2016, 2017 respectively) statistically significant difference (p &lt; .05) between the years 2014 and 2017. CRBSI. Conclusion: The use of a catheter care bundle in an HPN population may have contributed to a 4- year reported outcomes of low and continuously declining CRBSI in a large, diverse United States-based HPN population.</jats:p

Perspective on This Article from Rapamycin Is a Potent Inhibitor of Skin Tumor Promotion by 12-<i>O</i>-Tetradecanoylphorbol-13-Acetate

Perspective on This Article from Rapamycin Is a Potent Inhibitor of Skin Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetat

Supplementary Figure 1 from Metformin Inhibits Skin Tumor Promotion in Overweight and Obese Mice

PDF file - 1781K, Effect of metformin on epidermal phospho-ULK1 in the absence or presence of TPA treatment.</p