tbuckley/cabot-search huggingface dataset:
Abstract 4954: Decoding tumor microenvironment to enhance NSCLC targeted therapy
Authors: Haichuan Hu, Lecia Sequist, Zosia Piotrowska, David Kodack, Aaron Hata, Matt Niederst, Cyril Benes, Jeffrey Engelman
Journal: Cancer Research (2018)

Abstract Background: Tyrosine kinase inhibitors (TKI) have yielded promising responses in non-small-cell lung cancer (NSCLC) with EGFR mutations and ALK translocations. However, these and other targeted therapies are limited by intrinsic and acquired drug resistance. The previous study from our group investigated tumor autonomous resistance mechanisms by developing patient-derived cancer models (PDCs). In this study, we aimed to decipher the non-autonomous resistance mechanisms via tumor microenvironment by developing patient-derived fibroblast (PDF) models. Method: Cancer-associated fibroblast cell lines are established directly from individual EGFR mutant NSCLC biopsies. These cell lines, as representative of each patient's tumor microenvironment, are further subjected to functional analysis. An imaging-based high-throughput platform is developed to screen for non-autonomous resistance by co-culturing PDC and PDF models in vitro. In the parallel, two independent approaches are performed to further identify mechanisms underlying the non-autonomous resistance. These include a drug screen to determine the pathway maintaining the cancer cells' survival, and a secretomic analysis on the PDFs to identify the plausible cytokine(s) responsible for the resistance. Result: By co-culturing screening, non-autonomous resistance can be found in a wide spectrum of models. The subsequent drug screen reveals both a canonical HGF dependent and novel HGF independent mechanisms contributing to EGFR TKI resistance. Both of these can be explained by the PDF's variable cytokine secretion and can be overcome by specific therapeutic combinations. Moreover, the microenvironment-driven EGFR TKI resistance has also been validated in vivo. And the prevalence of the identified cytokine is further tested in clinical specimens. Conclusion: PDFs provide a new avenue to explore non-autonomous resistance for targeted therapy. Applying this approach, we identified both the canonical HGF dependent and novel HGF independent mechanisms that putatively conferring EGFR TKI resistance. Taking EGFR TKI therapy as a paradigm, these findings will be valuable to optimize targeted therapy and to inform the design of personalized pharmaceutical interventions. Citation Format: Haichuan Hu, Lecia Sequist, Zosia Piotrowska, David Kodack, Aaron Hata, Matt Niederst, Cyril Benes, Jeffrey Engelman. Decoding tumor microenvironment to enhance NSCLC targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4954.
Commentary: does the selective inversion approach demonstrate bias in the results of studies using routinely collected data?
Authors: Jonathan Sterne
Journal: BMJ (2018)

In early 2016, The BMJ published a paper by Hemkens and colleagues entitled “Agreement of treatment effects for mortality from routinely collected data and subsequent randomized trials: meta-epidemiological survey” (doi:10.1136/bmj.i493).1 This study used a novel design: the authors identified observational studies based on routinely collected data (RCD) that were performed before any randomised controlled trial (RCT) on the same clinical question, reported on all cause mortality, and used a propensity score based analysis to control confounding. The authors identified 16 RCD studies for which results from RCTs were subsequently reported. The main result was: “Overall, RCD studies showed significantly more favorable mortality estimates by 31% than subsequent trials (summary relative odds ratio [ROR] 1.31 (95% CI 1.03 to 1.65; I2=0%)).” The authors also reported that “Confidence intervals in nine (56%) RCD studies did not include the RCT effect estimate.” They concluded that “studies using routinely collected health data do not agree with subsequent randomized trials” and that “the emerging pattern was that RCD studies systematically and substantially overestimated the mortality benefits of medical treatments compared with subsequent trials investigating the same question.”

In August 2016, Franklin and colleagues submitted to The BMJ a paper that criticised the methods used by the Hemkens article. After The BMJ invited these authors to submit their comments as a rapid response rather than a separate paper, the work was published in Epidemiologic Methods .2 In their article, Hemkens and colleagues had “inverted the RCD effect estimates where necessary so that each RCD study indicated an odds ratio less than 1”.1 Their aim was to overcome the problem that some of the pairs compared two active interventions, so that the choice of direction of comparison was arbitrary. Franklin and colleagues showed that, under reasonable assumptions, the selective inversion …
Abstract 2369: AMPK regulation of apoptosis through OSBP
Authors: Kai Li Ong, Trever Thurgood, Michael Christensen, Jonny Malmrose, Denise Ng, Julianne Grose
Journal: Cancer Research (2018)

Abstract Alterations in lipid metabolism have been frequently reported in tumor progression, with impaired PI(4,5)P2 homeostasis in the plasma membrane implicated in various cancers and metabolic disorders. Oxysterol binding protein (OSBP) and its related proteins (ORPs) constitute a large family of ubiquitously expressed, evolutionarily conserved lipid binding proteins that play critical roles in intracellular lipid trafficking. OSBP and ORPs associate with a wide range of cellular activities, however their functions and regulations are largely unclear. Emerging evidence has supported an essential role of OSBP in cell signaling pathways and cancer development. We recently identified yeast oxysterol binding protein Osh7 as a true substrate of yeast AMPK (Snf1). AMPK's involvement in cancer has been extensively studied in the past decade, and is an important mediator of cellular energy homeostasis. Despite many downstream targets identified, AMPK is not known to regulate oxysterol binding protein activities. We found that Snf1 may be responsible for the degradation of Osh7 and cells deficient in Osh7 and its homolog Osh6 display higher rates of apoptosis. Understanding the regulation of OSBP by AMPK may aid in better targeting AMPK for cancer treatment and prevention, at the same time provide a better understanding to the roles of OSBP in cancer development. Citation Format: Kai Li Ong, Trever Thurgood, Michael Christensen, Jonny Malmrose, Denise Ng, Julianne Grose. AMPK regulation of apoptosis through OSBP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2369.
Abstract 334: Detection of BRCAness by a functional biomarker
Authors: Chih-Ying Lee, Min-Yu Ko, Kai-Hang Lei, Peter Chi
Journal: Cancer Research (2018)

Abstract Homologous recombination (HR) is an error-free repair pathway to eliminate DNA double-strand breaks and cells with deficiency of HR repair are highly sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Thus, targeting HR-defective cells becomes a new therapeutic approach for cancer patients. HR deficiency can be identified as BRCAness which may be due to mutations or epigenetic silencing in genes involved in HR, such as BRCA1 and BRCA2. Recent studies have developed several approaches to analyze HR status of cancer cells including RAD51 focus formation assay, large-scale mutational signatures analysis, and genome-wide transcriptome profiling. However, these assays provide an indirect estimation of HR status. We wish to directly measure HR rate in cancer cells. We have successfully developed two approaches, plasmid-based and virus-based functional assays, to directly quantify HR activity in cells and serve as a functional biomarker. Our results show that the signal of the functional biomarker specifically depends on the presence of the key enzyme, RAD51 recombinase, in HR. Finally, these functional assays can be utilized in different cancer cell types to determine the HR activity and can be a functional biomarker to evaluate the “BRCAness” status for the treatment of PARP inhibitors. Citation Format: Chih-Ying Lee, Min-Yu Ko, Kai-Hang Lei, Peter Chi. Detection of BRCAness by a functional biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 334.
Abstract LB-017: HER2 overexpression induces sensitivity to moringa isothiocyanates in breast cancer cells
Authors: JULIA B. OLAYANJU, Bing Xia
Journal: Cancer Research (2018)

Abstract Isothiocyanates (ITCs) are a class of natural products with promising anti-cancer activities and chemopreventive prospects. Moringa oleifera is a plant widely cultivated in the tropics and has been popularly used for centuries by locals to treat different diseases. Moringa leaves contain four unique sugar-modified aromatic glucosinolates, which can be converted to moringa isothiocyanates (MICs) by myrosinase also present in the leaves. In this study, we tested the efficacy of MIC-1 on 9 different breast cancer cell lines and found it to be a potent anti-cancer agent against them. Interestingly, the two cells lines most sensitive to MIC-1, BT474 and HCC1954, were both positive for HER2, which is amplified in up to 30% of breast cancer and correlates with poor prognosis. The correlation between HER2 overexpression and hypersensitivity to MIC was further confirmed using pairs of MCF-7 and MDA-MB-231 cells with and without HER2 overexpression. In studies to understand why the HER2+ breast cancer cells were more sensitive to MIC than HER2- lines, we observed higher basal intracellular ROS levels in HER2+ breast cancer cell lines compared to HER2- cells. Moreover, we observed that MIC regulates the abundance of KEAP1 and NRF2 across the different cell lines used in this study. In some cases, MIC-1 upregulated both KEAP1 and NRF2 at the same time, suggesting that it may directly or indirectly inactivate KEAP1 thereby stabilizing NRF2. More efforts are underway to elucidate the precise mechanisms of action. Our work shows that MICs may open new frontiers in breast cancer prevention and therapy, particularly for those with HER2 amplification. Citation Format: JULIA B. OLAYANJU, Bing Xia. HER2 overexpression induces sensitivity to moringa isothiocyanates in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-017.
KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice
Authors: Euan S. Polson, Verena B. Kuchler, Christopher Abbosh, Edith M. Ross, Ryan K. Mathew, Hester A. Beard, Bárbara da Silva, Andrew N. Holding, Stephane Ballereau, Eulashini Chuntharpursat-Bon, Jennifer Williams, Hollie B.S. Griffiths, Hao Shao, Anjana Patel, Adam J. Davies, Alastair Droop, Paul Chumas, Susan C. Short, Mihaela Lorger, Jason E. Gestwicki, Lee D. Roberts, Robin S. Bon, Simon J. Allison, Shoutian Zhu, Florian Markowetz, Heiko Wurdak
Journal: Science Translational Medicine (2018)

Modulation of energy metabolism with the small-molecule KHS101 promoted tumor-selective death of human glioblastoma cells and reduced tumor growth in mice.
Abstract 15726: Characteristics of Patients With <15% Reduction in Low-Density Lipoprotein Cholesterol With Alirocumab
Authors: Harold E Bays, Robert S Rosenson, Marie T Baccara-Dinet, Michael J Louie, Desmond E Thompson, G. Kees Hovingh
Journal: Circulation (2017)

Introduction: Clinical trials of lipid-lowering therapies (LLTs), including statins, often report variable individual effects on LDL-C, but consistent mean LDL-C reductions. Possible explanations i...
Upregulation of β3-Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium
Authors: StéphaneMoniotte, LesterKobzik, OlivierFeron, Jean-NoëlTrochu, ChantalGauthier, Jean-LucBalligand
Journal: Circulation (2001)

Background—Contrary to β1- and β2-adrenoceptors, β3-adrenoceptors mediate a negative inotropic effect in human ventricular muscle. To assess their functional role in heart failure, our purpose was to compare the expression and contractile effect of β3-adrenoceptors in nonfailing and failing human hearts. Methods and Results—We analyzed left ventricular samples from 29 failing (16 ischemic and 13 dilated cardiomyopathic) hearts (ejection fraction 18.6±2%) and 25 nonfailing (including 12 innervated) explanted hearts (ejection fraction 64.2±3%). β3-Adrenoceptor proteins were identified by immunohistochemistry in ventricular cardiomyocytes from nonfailing and failing hearts. Contrary to β1-adrenoceptor mRNA, Western blot analysis of β3-adrenoceptor proteins showed a 2- to 3-fold increase in failing compared with nonfailing hearts. A similar increase was observed for Gαi-2 proteins that couple β3-adrenoceptors to their negative inotropic effect. Contractile tension was measured in electrically stimulated myoca...
Abstract 5784: A novel ERK inhibitor in the treatment of uveal melanoma
Authors: Elgilda Musi, Grazia Ambrosini, Joanne Munck, Gary K. Schwartz
Journal: Cancer Research (2018)

Abstract Uveal melanoma is one of most common intraocular malignancies of the adult eye. GNAQ/ GNA11 genetic alterations are present in 85% of diagnosed cases resulting in activation of MAPK pathway. Recently, MEK inhibitors, such as selumetinib have been used to treat GNAQ/GNA11-mutant uveal melanoma patients. However, selumetinib has shown modest effect compared to chemotherapy. As ERK is the primary downstream effector of the MAPK pathway, it is hypothesized that ERK inhibitors have the potential to improve clinical activity in these patient populations. We examined the effects of a selective and potent ERK inhibitor (Compound A), on several uveal melanoma cell lines including 4 GNAQ cell lines (92.1, Mel202, Omm1.3, MP46), 2 GNA11 cell lines (MP41, Omm1), 2 BRAF cell lines (OCM1A, OCM1) and a Wild Type (Mel290) cell line. The uveal melanoma cell lines were sensitive to ERK inhibition by Compound A, with IC50s concentrations determined to be between 50 to 250 nM. Compound A was more effective at inhibiting growth than the MEK inhibitor selumetinib at nanomolar concentrations. Compound A at 250 nM inhibited pERK1/2 within at least 2 hours of drug exposure. By 24 hours inhibition of pRB and suppression of cyclin D1 was detected in all the cell lines tested except the Wild type cell line Mel290. Cell cycle analysis of Compound A dosed at 250 nM for 24 hours showed significant G1 arrest (85-90% G1). These in vitro results support further evaluation of ERK inhibition in the treatment of uveal melanoma. Citation Format: Elgilda Musi, Grazia Ambrosini, Joanne Munck, Gary K. Schwartz. A novel ERK inhibitor in the treatment of uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5784.
Exercise Response Variations in Skeletal Muscle PCr Recovery Rate and Insulin Sensitivity Relate to Muscle Epigenomic Profiles in Individuals With Type 2 Diabetes
Authors: Natalie A. Stephens, Bram Brouwers, Alexey M. Eroshkin, Fanchao Yi, Heather H. Cornnell, Christian Meyer, Bret H. Goodpaster, Richard E. Pratley, Steven R. Smith, Lauren M. Sparks
Journal: Diabetes Care (2018)

Some individuals with type 2 diabetes do not reap metabolic benefits from exercise training, yet the underlying mechanisms of training response variation are largely unexplored. We classified individuals with type 2 diabetes (n = 17) as nonresponders (n = 6) or responders (n = 11) based on changes in phosphocreatine (PCr) recovery rate after 10 weeks of aerobic training. We aimed to determine whether the training response variation in PCr recovery rate was marked by distinct epigenomic profiles in muscle prior to training.PCr recovery rate as an indicator of in vivo muscle mitochondrial function in vastus lateralis (31P-magnetic resonance spectroscopy), insulin sensitivity (M-value; hyperinsulinemic-euglycemic clamp), aerobic capacity (Vo2peak), and blood profiles were determined pretraining and post-training. Muscle biopsies were performed pretraining in vastus lateralis for the isolation of primary skeletal muscle cells (HSkMCs) and assessments of global DNA methylation and RNA sequencing in muscle tissue and HSkMCs.By design, nonresponders decreased and responders increased PCr recovery rate with training. In nonresponders, insulin sensitivity did not improve and glycemic control (HbA1c) worsened. In responders, insulin sensitivity improved. Vo2peak improved by ∼12% in both groups. Nonresponders and responders were distinguished by distinct pretraining molecular (DNA methylation, RNA expression) patterns in muscle tissue, as well as in HSkMCs. Enrichment analyses identified elevations in glutathione regulation, insulin signaling, and mitochondrial metabolism in nonresponders pretraining, which was reflected in vivo by higher pretraining PCr recovery rate and insulin sensitivity in these same individuals.A training response variation for clinical risk factors in individuals with type 2 diabetes is reflected by distinct basal myocellular epigenomic profiles in muscle tissue, some of which are maintained in HSkMCs, suggesting a cell-autonomous underpinning. Our data provide new evidence to potentially shift the diabetes treatment paradigm for individuals who do not benefit from training, such that supplemental treatment can be designed.
Abstract 3520: Targeting lipid metabolism eradicates peritoneal metastases of ovarian cancer
Authors: Run Chen, David Chan
Journal: Cancer Research (2018)

Abstract Ovarian cancer is one of the deadliest women malignancies in the world. The chemoresistance accompanied with metastasis lead to high mortality of this disease. Different from other solid tumors, the advanced ovarian cancers prefer transcoelomic route in metastasis. Clinical observation indicates ovarian cancer patients with intraperitoneal metastases are closely association with poor prognosis. Emerging evidence has indicated that ascites fluids which acts as a reservoir providing plenty of growth factors, chemokines and importantly, free fatty acids etc. However, the significance of ascites microenvironment in governing ovarian cancer metastatic progression remain unclear. Herein, we report that the ascites microenvironment alters metabolism that in turn, enhances ovarian cancer cell aggressiveness. By mimicking the ascites microenvironment, we established omental conditioned medium (OCM). Ovarian cancer cells co-cultured in OCM showed enhanced ovarian cancer oncogenic capacities as observed in ascites. By RNA-Seq and proteomics analyses, we found the activities of lipid metabolism were elevated in ovarian cancer cells cultured in OCM. Depletion of Glut-1/-3/-4 by shRNAi approach or treatment of STF31, a glycolysis inhibitor, showed no or slight effect on ATP production and cell growth of ovarian cancer cells. In contrast, knockdown of Acetyl-CoA Carboxylase-α or -β (ACC1/2) or treatment of FASN inhibitor, Orlistat, significantly inhibited the ATP production and cell growth, suggesting ovarian cancer cells undergone a metabolic shift from aerobic glycolysis to β-oxidation when co-cultured in fatty acid enriched OCM. On the other hand, AMP-activated protein kinase (AMPK) is a key energy sensor and affects oncogenic capacities of many cancer cells. We found that its activity was induced initially for triggering fatty acid oxidation in ATP production. But the AMPK activity was gradually reduced due to the negative feedback loop of high ATP content. The lowered AMPK activity led to mTOR and TAK1/NF-κB signaling activation that result in the increased oncogenic capacities of ovarian cancer cells. Notably, inhibition of the above signaling pathways by a combined cocktails of AMPK activator, TAK1 and FASN inhibitors could remarkably impair OCM-mediated oncogenic properties of ovarian cancer cells in vitro and in vivo. Taken together, these findings suggest that the ascites microenvironment induces metabolic reprogramming for ovarian cancer cells in production of energy supporting their aggressiveness, while targeting the lipid metabolism and associated signalings could impede peritoneal metastases of ovarian cancer. Citation Format: Run Chen, David Chan. Targeting lipid metabolism eradicates peritoneal metastases of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3520.
Treatment With Dimethylthiourea Prevents Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction in Mice
Authors: ShintaroKinugawa, HiroyukiTsutsui, ShunjiHayashidani, TomomiIde, NobuhiroSuematsu, ShinjiSatoh, HideoUtsumi, AkiraTakeshita
Journal: Circulation Research (2000)

Abstract—Oxidative stress might play an important role in the progression of left ventricular (LV) remodeling and failure that occur after myocardial infarction (MI). We determined whether reactive oxygen species (ROS) are increased in the LV remodeling and failure in experimental MI with the use of electron spin resonance spectroscopy and whether the long-term administration of dimethylthiourea (DMTU), hydroxyl radical (·OH) scavenger, could attenuate these changes. We studied 3 groups of mice: sham-operated (sham), MI, and MI animals that received DMTU (MI+DMTU). Drugs were administered to the animals daily via intraperitoneal injection for 4 weeks. ·OH was increased in the noninfarcted myocardium from MI animals, which was abolished in MI+DMTU. Fractional shortening was depressed by 65%, LV chamber diameter was increased by 53%, and the thickness of noninfarcted myocardium was increased by 37% in MI. MI+DMTU animals had significantly better LV contractile function and smaller increases in LV chamber si...