bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A65: IACS-10759: A novel OXPHOS inhibitor that selectively kills tumors with metabolic vulnerabilities
Authors: Protopopova Marina , Bandi Madhavi , Sun Yuting , Bardenhagen Jennifer , Bristow Christopher , Carroll Christopher , Chang Edward , Feng Ningping , Gay Jason , Do Mary Geck , Greer Jennifer , Konopleva Marina , Matre Polina , Kang Zhijun , Liu Gang , Muller Florian , Lofton Timothy , McAfoos Timothy , Smith Melinda , Theroff Jay , Han Jing , Wu Yuanqing , Chin Lynda , Draetta Giulio , Jones Philip , Toniatti Carlo , Francesco M. Emilia Di , Marszalek Joseph R. 
Published: May 2016

Abstract
Tumor cells normally depend on both glycolysis and oxidative phosphorylation (OXPHOS) to provide the energy and macromolecule building blocks for rapid growth. Metabolic vulnerabilities caused by inactivation of glycolysis render tumor cells highly dependent on OXPHOS, and represent a therapeutic opportunity. Through an extensive medicinal chemistry campaign, we have identified IACS-10759 as a potent inhibitor of complex I of OXPHOS. IACS-10759 effectively inhibits ATP production and oxygen consumption in isolated mitochondria, and inhibits the conversion of NADH to NAD+ in immunoprecipitated complex I in low nM range. The exact subunit that IACS-10759 binds to is under investigation. Importantly, IACS-10759 is orally bioavailable with excellent physicochemical properties in preclinical species, and shows significant efficacy in multiple tumor indications both in vitro and in vivo. Specifically, in a glycolysis-deficient xenograft model, IACS-10759 causes robust tumor regression, but has no effect in the same model when glycolysis is restored. In addition, in AML where tumor cells have been shown to be highly OXPHOS-dependent, IACS-10759 robustly suppresses cell growth and induces apoptosis in both primary AML samples and cell lines in vitro, but not in normal patient-derived bone marrow cells. Significantly, IACS-10759 extends median survival by over 50 days in an AML orthotopic xenograft model. Furthermore, IACS-10759 also shows selective efficacy in other cell line panels including pancreatic cancer, non-small cell lung cancer and colorectal cancer, and has synergism with glycolysis inhibitors. In light of these results, we are currently performing IND enabling studies for IACS-10759, with first-in-human studies targeted for fourth quarter of 2015.
Citation Format: Marina Protopopova, Madhavi Bandi, Yuting Sun, Jennifer Bardenhagen, Christopher Bristow, Christopher Carroll, Edward Chang, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Marina Konopleva, Polina Matre, Zhijun Kang, Gang Liu, Florian Muller, Timothy Lofton, Timothy McAfoos, Melinda Smith, Jay Theroff, Jing Han, Yuanqing Wu, Lynda Chin, Giulio Draetta, Philip Jones, Carlo Toniatti, M. Emilia Di Francesco, Joseph R. Marszalek. IACS-10759: A novel OXPHOS inhibitor that selectively kills tumors with metabolic vulnerabilities. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A65.
Abstract A72: Novel NAMPT inhibitors for the treatment of Pancreatic cancer
Authors: Chikanna Dinesh , Lakshminarasimhan Anirudha , Khairnar Vinayak , Panigrahi Sunil , Ramanathan Anuradha , Rao Narasimha , Narayanan Kishore , Gopinath Sreevalsam , Ramachandra Raghuveer , Chelur Shekar , Pandit Chetan , Ramachandra Murali 
Published: May 2016

Abstract
Pancreatic cancer is reported to be dependent on NAD salvage pathway for its growth and survival. Nicotinamide phosphoribosyl transferase (NAMPT), an enzyme that catalyzes the rate limiting step of NAD biosynthesis is over expressed in a number of cancers. Inhibition of NAMPT with first generation inhibitors has been demonstrated to result in anti-tumor efficacy in preclinical models. Clinical development of first generation NAMPT inhibitors has been hindered because of their poor pharmacological profile, high cytochrome inhibition and possibly mechanism-based toxicities. Therefore, our objective was to develop NAMPT inhibitors with the “best-in-class” profile with strategies for overcoming mechanism-based toxicities. Utilizing structure-guided drug design including determination of co-crystal structures and SAR-based approaches, we have identified a novel chemical series of inhibitors of NAMPT. Optimization of the series for transient target inhibition as a result of reduced binding strength coupled with desirable pharmacokinetic profile to minimize mechanism based toxicity resulted in identification of AU-4869 as the lead compound. AU-4869 showed potent cross-species activity and reduced strength of binding in comparison with first generation NAMPT inhibitors. Anti-proliferative activity of AU-4869 correlated well with NAD depletion in a pancreatic cancer cell line. The anti-proliferative activities were rescued in NAPRT-proficient cell lines with the addition of nicotinic acid due to the NAMPT independent salvage pathway for biosynthesis of NAD, confirming the mechanism of action through NAD depletion. AU-4869 exhibited desirable drug-like properties including solubility, permeability, metabolic stability, lack of CYP & hERG inhibition and pharmacokinetic exposure upon oral dosing. At well-tolerated doses, AU-4869 exhibited superior efficacy at MTD doses in mice xenograft models as compared to first generation inhibitors. Addition of nicotinic acid improved the tolerability of AU-4869 and reversed the effects of mechanism based toxicity in Rodents. Anti-tumor activities of AU-4869 in the presence of nicotinic acid in NAPRT-deficient pancreatic cancer models are currently being evaluated in preclinical models.
Citation Format: Dinesh Chikanna, Anirudha Lakshminarasimhan, Vinayak Khairnar, Sunil Panigrahi, Anuradha Ramanathan, Narasimha Rao, Kishore Narayanan, Sreevalsam Gopinath, Raghuveer Ramachandra, Shekar Chelur, Chetan Pandit, Murali Ramachandra. Novel NAMPT inhibitors for the treatment of Pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A72.
Abstract B03: Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers
Authors: Wang Zhenghe 
Published: May 2016

Abstract
Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. PIK3CA, which encodes the p110 alpha catalytic subunit of phosphatidylinositol 3-kinase, is the most frequently mutated oncogene in human cancers. However, whether PIK3CA mutations reprogram cancer metabolism is an important unaddressed question. Using isogenic cell lines expressing either wild-type (WT) or oncogenic mutant allele of PIK3CA, we demonstrated that colorectal cancer cells harboring PIK3CA mutations are more dependent on glutamine to grow. In contrast, the isogenic PIK3CA WT and mutant cell lines did not show differential sensitivity to glucose deprivation. Through gene expression analyses, we showed that glutamate pyruvate transaminase 2 (GPT2) is up-regulated in the colorectal cancer cell lines with PIK3CA mutations compared to the isogenic cell lines expressing WT PIK3CA. We demonstrated that induction of GPT2 by mutant p110 alpha is necessary and sufficient to render colorectal cancer cells dependent on glutamine. Moreover, aminooxyacetate, which inhibits enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumor growth of colorectal cancers with PIK3CA mutations, but not colorectal cancers with WT PIK3CA. Thus our data suggest that targeting glutamine metabolism may be an effective approach to treat colorectal cancer patients harboring PIK3CA mutations. Mutant p110 alpha up-regulates GPT2 gene expression through an AKT-independent PDK1-RSK2-ATF4 signaling axis. We showed that ATF4 is a transcription factor that activates GPT2 gene expression. We further demonstrated that mutant p110 alpha activates RSK2 kinase through PDK1. Activated RSK2 then phosphorylates ATF4 at the serine residue 245, which in turn recruits deubiquitinase USP8 and protects ATF4 from ubiquitin-mediated degradation. Lastly, using [13C5-]glutamine isotope-tracing technology, we showed that PIK3CA mutant colorectal cancer cells convert more glutamine to alpha-keto-glutarate to replenish the tricarboxylic acid cycle to generate ATP. Together, our data establish oncogenic PIK3CA mutations as a cause of glutamine addiction in colorectal cancers.
Citation Format: Zhenghe Wang. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B03.
Abstract B29: LRP16 is an essential mediator for DNA double-strand breaks induced NF-kappaB activation
Authors: Wu Zhiqiang , Wang Chunmeng , Bai Miaomiao , Li Xiaolei , Mei Qian , Li Xiang , Wang Yao , Fu Xiaobing , Luo Guangbin , Han Weidong 
Published: May 2016

Abstract
DNA double-strand breaks (DSBs) are an intermediate in several important processes, such as V(D)J recombination, class-switch recombination, and meiosis; and a byproduct of a number of both normal or pathological conditions, such as metabolic respiration and inflammation. Thus, the determination of the proper fates of cells with this specific type of DNA damage, i.e., to repair and survive or to die, constitutes an important element in the homeostasis of individual mammals. The activation of NF-kappaB has emerged as an important mechanism for the modulation of the response to DSBs. The concomitant SUMOylation and phosphorylation of IKKgamma; by the SUMO E3 ligase protein inhibitor of activated STAT (PIASy) and the phosphorylation by ataxia telangiectasia mutated (ATM), respectively, is a key event in this mechanism. However, IKKgamma SUMOylation or phosphorylation can occur separately without activating NF-kappaB. Thus, the mechanism through which mammalian cells are able to accomplish these IKKgamma modifications in a timely and lesion-specific manner remains unclear. In this study, we demonstrate that LRP16 constitutively interacts with PARP1 and IKKgamma. This interaction is essential for efficient interactions among PARP1, IKKgamma, and PIASy, the modifications of IKKgamma, and the activation of NF-kappaB following DSB induction. The regulation of LRP16 in NF-kappaB activation is dependent on its poly (ADP-ribose) binding capability through the unique macro domain. The depletion of the DSB-specific sensor Ku80 resulted in a significant reduction in the physical interactions among LRP16, PARP1 and IKKgamma. Additionally, the knockdown of either endogenous Ku80 or Ku70 by siRNA markedly diminished DSB-induced NF-kappaB reporter gene activity and NF-kappaB target gene expression. These data strongly suggest that LRP16, through its constitutive interactions with PARP1 and IKKgamma, functions to facilitate the lesion-specific recruitment of PARP1 and IKKgamma and, ultimately, the concomitant recruitment of PIASy to IKKgamma in response to DSB damage. Therefore, the study has provided important new mechanistic insights concerning DSB-induced NF-kappaB activation.
Citation Format: Zhiqiang Wu, Chunmeng Wang, Miaomiao Bai, Xiaolei Li, Qian Mei, Xiang Li, Yao Wang, Xiaobing Fu, Guangbin Luo, Weidong Han. LRP16 is an essential mediator for DNA double-strand breaks induced NF-kappaB activation. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B29.
Abstract B36: Serum adiponectin levels association with acute leukemias: A meta-analysis
Authors: Dendi Vijaya SenaReddy , Aloor Sivakanth , Keerty Dinesh , Gryn Jeffrey , Gryn Jeffrey 
Published: May 2016

Abstract
Background: Adiponectin, a novel adipokine, secreted by adipocytes in inverse proportion to body fat mass. It is hypothesized that adiponectin exerts a protective role for several type of carcinogenesis, notably those related to obesity including hematological cancers through its anti-apoptotic, anti-inflammatory and anti-angiogenesis properties.
Purpose: The aim of this study is to conduct a meta-analysis to investigate the association between serum adiponectin levels and presence of acute leukemia's.
Methods: We searched MEDLINE, CIINHAL and COCHRANE databases for studies reporting serum adiponectin levels in the peripheral blood with and without acute leukemia's [Acute lymphoblastic leukemia (ALL)/Acute myleogenous leukemia (AML)]. We included case controls, cohort and cross-sectional studies. We calculated the weighted standardized mean difference (SMD) in serum adiponectin levels between the acute leukemia's patients and control groups.
Results: Our search strategy yielded 14 articles and we included 4 studies enrolling 783 participants with 322 patients and 461 controls of matched age, sex and BMI (body mass index). We included 255 ALL patients compared with 240 controls and 67 AML patients compared with 221 controls. The median age of the ALL and AML group compared to controls was 7.39 yrs. (IQR 4.83 – 18.04) and 27 yrs. (IQR 16.03 – 38.08). The median percentage of females of ALL and AML compared to controls was 44.5 (IQR 39.3 – 46.8) and 46.5 (IQR 42.3 – 50.8). The unweighted median serum leptin levels in the ALL and AML groups were 12.65 µg/ml (11.96 – 14.2) and 9.65 µg/ml (6.58 – 12.73) compared to 19.1 µg/ml (17.1 – 20.4) and 27.1 ng/ml (16.03 – 38.08) in the control groups.
The SMD of having abnormal serum adiponectin levels of acute leukemia patients compared to controls was -2.77 (95% CI -4.25 - -1.3) P &lt; 0.001.
Conclusion: Decreased serum adiponectin levels in acute leukemia's i.e. in both ALL and AML are significantly associated with acute leukemia's. Further investigation into the molecular role of serum adiponectin in carcinogenesis is warranted and would perhaps allow for the use of these biomarkers in early diagnosis of acute leukemia.
Citation Format: Vijaya SenaReddy Dendi, Sivakanth Aloor, Dinesh Keerty, Jeffrey Gryn, Jeffrey Gryn. Serum adiponectin levels association with acute leukemias: A meta-analysis. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B36.
Abstract B40: AKT-ACLY signaling preferentially maintains histone acetylation over lipid synthesis during nutrient limitation
Authors: Lee Joyce V. , Yuan Zuo-Fei , Liu Shichong , Garcia Benjamin A. , Wellen Kathryn E. 
Published: May 2016

Abstract
Metabolic reprogramming by oncogenes is a mechanism to support biosynthesis and growth in cancer cells. Activation of the PI3K/AKT pathway increases glucose consumption and glycolysis, leading to higher acetyl-CoA production. Extra-mitochondrial acetyl-CoA is utilized in lipid synthesis and protein acetylation. We previously showed that tumor cell histone acetylation is regulated in a glucose-dependent manner, through ATP-citrate-lyase (ACLY) conversion of glucose-derived citrate into acetyl-CoA. In low glucose conditions, acetyl-CoA and histone acetylation levels decrease. However, AKT-dependent phosphorylation of ACLY at serine 455 promotes acetyl-CoA production to allow maintenance of global levels of histone acetylation under glucose limitation. It is unclear whether partitioning of acetyl-CoA between lipid synthesis and histone acetylation in the setting of nutrient limitation impacts cell growth or survival. In this study, we examined whether acetyl-CoA utilization for lipid synthesis is impacted by AKT-ACLY signaling during nutrient limitation. Using 13C-glucose labeling and mass spectrometry, we determined that de novo lipid synthesis is suppressed to a much greater extent than histone acetylation in low glucose conditions. Moreover, phosphorylation of ACLY does not sustain fatty acid synthesis under glucose limitation, in contrast to its effects on histone acetylation. These data indicate that the PI3K-AKT-ACLY axis preferentially maintains histone acetylation over lipid synthesis during nutrient limitation. This regulation is likely due to AMPK-dependent phosphorylation of acetyl-CoA carboxylase (p-ACC), blocking acetyl-CoA commitment to fatty acid synthesis. This study reveals that cancer cells employ robust mechanisms to maintain histone acetylation in nutrient limited environments.
Citation Format: Joyce V. Lee, Zuo-Fei Yuan, Shichong Liu, Benjamin A. Garcia, Kathryn E. Wellen. AKT-ACLY signaling preferentially maintains histone acetylation over lipid synthesis during nutrient limitation. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B40.
Abstract B81: Effects of black raspberry diet on the metabolomic profile of C57BL/6J mouse tissues
Authors: Skaer Chad W. , Pan Pan , Young Matthew R. , Wang Hsin Tzu , Oshima Kiyoko , Huang Yi-Wen , Stoner Gary D. , Lechner John , Wang Li-Shu 
Published: May 2016

Abstract
In our previous work, a diet containing 5% freeze-dried black raspberries (BRB) was shown to significantly inhibit colorectal cancer in ApcMin mice. Studies in recent years have shown that metabolomics may help to elucidate the anti-cancer effects of dietary factors. Initially, therefore, we evaluated the effects of black raspberries on the metabolomic profiles of C57BL/6J mice, the mouse strain from which ApcMin mice were derived. In this study, we report the effects of the BRB diet on the metabolomic profiles from C57BL/6J mice. After 8 weeks on a 5% BRB or control AIN-76A diet, feces, liver, and colon mucosa tissues from 9 BRB-fed mice and 7 control-diet fed mice were collected and profiled using mass spectrometry. A total of 424 named metabolites were observed in the liver, feces, and colon mucosa, with 115 metabolites whose levels were significantly different between BRB and control-diet mice (P&lt;0.05). Of these 115 differentiated metabolites, 41 were altered in the colon mucosa, and 38 and 44 metabolites were different in the feces and liver, respectively. Almost all of the changed metabolites in the colon mucosa (36 of 41) were downregulated by the BRB diet, whereas in the feces and liver the majority were upregulated (58 of 82). Included in the upregulated metabolites were lipids and amino acids in the feces and liver tissue. Benzoate derivatives, the product of gut bacteria metabolism of BRB polyphenols, were also up in all tissues. Among the downregulated metabolites were lipids in the colon mucosa and lysolipids in the liver. The decreased levels of lipid metabolites, particularly fatty acids, in the colon mucosa of mice indicates that antagonizing fatty acid synthesis is a potential mechanism by which the BRB diet is altering energy utilization in the colon mucosa of mice.
Citation Format: Chad W. Skaer, Pan Pan, Matthew R. Young, Hsin Tzu Wang, Kiyoko Oshima, Yi-Wen Huang, Gary D. Stoner, John Lechner, Li-Shu Wang. Effects of black raspberry diet on the metabolomic profile of C57BL/6J mouse tissues. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B81.
Abstract IA24: Acetyl-CoA metabolism, gene regulation, and stress management
Authors: Wellen Kathryn E. 
Published: May 2016

Abstract
Acetyl-CoA plays crucial roles at the interface of cellular metabolism, signaling, and epigenetics. This central metabolite is required for de novo biosynthesis of macromolecules such as fatty acids and cholesterol, and it is produced from catabolism of glucose, amino acids, and fatty acids. In addition to its direct metabolic functions, acetyl-CoA serves as the acetyl group donor for both lysine and N-terminal acetylation. Acetyl-CoA availability directly impacts overall histone acetylation levels and participates in gene regulation. In particular, high acetyl-CoA promotes a pro-proliferative gene expression pattern in cancer cells. Diverse signaling and microenvironmental cues impact acetyl-CoA production and utilization, which may influence the ability of cancer cells both to survive in stressful conditions and to grow and proliferate.
In human prostate cancer, both fatty acid synthesis and oxidation have been implicated in tumor growth and proposed as therapeutic targets. Moreover, histone acetylation levels are highly correlated with activation of the PI3K-AKT pathway in human prostate tumors and are predictive of patient outcome. We hypothesized that proper coordination of acetyl-CoA production and utilization is central to the ability of prostate cancer cells to survive and proliferate. In this presentation, I will discuss new data on the role of ATP-citrate lyase in coordinating metabolism, gene expression, and oncogenic signaling to balance stress responses and promote growth and proliferation of prostate cancer cells. The findings point towards novel strategies for therapeutic intervention.
Citation Format: Kathryn E. Wellen. Acetyl-CoA metabolism, gene regulation, and stress management. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA24.