tbuckley/cabot-search huggingface dataset:
Probing the association of smoking status with tumor-infiltrating lymphocytes (TILs) in muscle-invasive bladder cancer (MIBC).
Authors: Jessica Mary Clement, Enrique Ballesteros, Miranda Lynch, Pramod K. Srivastava
Journal: Journal of Clinical Oncology (2015)

e15524 Background: Bladder cancer is strongly associated with smoking, with close to a 50% case attribution. There is ample evidence to support the direct genotoxic effect of cigarette smoke on the urothelium. We propose that smoking-induced immune dysregulation is also an essential contributor to MIBC progression. In that context, this study investigates the impact of smoking status on TILs in MIBC and on patient survival; the first to do so. Methods: Using the UConn tumor registry, patients (n = 53) with MIBC were identified, and chart reviews performed to obtain smoking history and outcomes. De-identified specimens without linked clinical data were analyzed for expression of CD20, CD3, CD57, CD45, CD4, CD8, FOXP1, and CD25 on TILs within the neoplasm (scored semi-quantitatively as 0, 1+, 2+, and 3+). Survival endpoints were probed using Kaplan Meier plots and log-rank tests for comparing smoking groups and TIL status groups. Cox Proportional Hazards regression with smoking variables (current status, duration, and exposure level), TILs status, and combined smoking and TILs as predictor variables were also explored. Results: No statistically significant differences were seen; however, in spite of the small sample size, higher smoking intensity correlated with decreased CD4+ and CD8+ TILs. In addition, regression coefficients and trends in Kaplan Meier analyses were highly suggestive of the positive role of TILs consistent with previous analyses (Liakou et al. 2007), as well as a negative role of smoking in determining survival outcomes. Analysis of survival, when evaluated by TIL status, demonstrated that patients scored as 3+ for the presence of CD4+ and CD8+ TILs, had better survival, with a trend to lower survival with decreasing TIL presence. Conclusions: The results from this exploratory study support the case for immunological contribution to progression of MIBC and a detrimental effect of smoking on TILs. These analyses are timely and significant in view of the emerging evidence for efficacy of checkpoint blockade in treatment of MIBC. These promising results will serve as the basis for future investigations of immune regulation, smoking and patient survival.
Abstract 3896: Novel in vivo pan-Hsp90 family protein inhibitor, Panvotinib-401, showed potent anticancer activities without HSF1 activation
Authors: Byoung Heon Kang
Journal: Cancer Research (2016)

Abstract Hsp90 family proteins are implicated in tumorigenesis and many inhibitors have been developed as cancer therapeutics. The inhibitors showed potent inhibitory activities against purified Hsp90 family proteins, Grp94 and TRAP1, as well as Hsp90 in vitro. The mitochondrial TRAP1, however, is not inactivated in vivo due to insufficient drug accumulation in the mitochondria. Here, we showed that simultaneous inactivation of Hsp90 family proteins in different compartments can augment anticancer activity of the Hsp90 inhibitors. When simultaneously inhibited, cytoplasmic calcium elevation and activation of calcineurin inhibited HSF1 triggering heat shock responses such as cytoprotective Hsp70 induction. To improve anticancer efficacy of Hsp90 inhibitors, we developed a small molecule (∼380 Da) mitochondrial inner membrane-permeable Hsp90 inhibitor, and named it as Panvotinib-401, briefly Pan-401. Pan-401 showed much improved cancer-selective cytotoxic activity compared with Hsp90 inhibitors or mitochondria-targeted (accumulating) inhibitor, gamitrinib. Collectively, with improved subcellular distribution, cancer-specific cytotoxic activity of Hsp90 inhibitors can be further enhanced. Citation Format: Byoung Heon Kang. Novel in vivo pan-Hsp90 family protein inhibitor, Panvotinib-401, showed potent anticancer activities without HSF1 activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3896.
Abstract 2972: Development and characterization of synthetic antibodies with a human framework that directly link metabolism to immune system in cancer cells
Authors: Jelena Tomic, Megan McLaughlin, Ron Geyer, Sachdev Sidhu, Jason Moffat
Journal: Cancer Research (2016)

Abstract Deregulated cellular energetics and evasion of immune system are two hallmark features of cancer cells. In fact, increased uptake of glucose and glutamine by cancer cells elevates flux of a minor glucose pathway known as the hexosamine biosynthetic pathway (HBP), resulting in alteration of glycosylation. Addition of sugar moieties to proteins plays an important role in sensing cellular metabolism, growth factors, signaling molecules, nutrient flux and stress. Since many of these processes are de-regulated in tumorigenesis, global alterations in glycosylation via HBP flux are likely to play an important role in cancer. We hypothesize that cancer cells can “sense” stress through the HBP pathway, and, consequently, reprogram the cell surface and adapt to tougher conditions. Neo-epitopes on the cell surface that emerge from tuning the HBP pathway activity may be prime candidates as readouts that reliably report the status of metabolic reprogramming. In order to advance the understanding of metabolic reprogramming from the perspective of the cell surface, we combined genetics and advanced protein engineering using phage-displayed synthetic human antibody libraries to generate recombinant antibodies (rAbs) that respond to changes in the activity of the HBP. Our method for discovery of surface and nutrient-associated protein sensors (SNAPS) has allowed us to identify multiple human synthetic rAbs whose activity is potentiated under different metabolic states. More specifically, these rAbs recognize cell surface features that discriminate cancer cells with increased HBP flux and effectively recruit components of the immune system to initiate tumor cell lysis. Our findings suggest that the nutrient-dependent cell surface epitopes may have functional roles in defining cancer cell identity and may link multiple cancer hallmarks. Citation Format: Jelena Tomic, Megan McLaughlin, Ron Geyer, Sachdev Sidhu, Jason Moffat. Development and characterization of synthetic antibodies with a human framework that directly link metabolism to immune system in cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2972.
Abstract 3600: Next generation high capacity DNA damage detection assay for chemotherapy and genotoxic compound screening
Authors: Peter Sykora, Sandra Woodgate, Jay George, Robert W. Sobol
Journal: Cancer Research (2016)

Abstract The mechanism of action of many classes of chemotherapeutic agents involves either the repression of DNA repair or an increase in DNA damage. However the measurement of DNA damage levels within a cell has been notoriously difficult and current methods to asses DNA damage potential of new chemotherapeutics have major technical flaws. The single cell gel electrophoresis (SCGE) assay is a long-standing method for measuring levels of DNA damage within a cell. The principle of SCGE is that DNA damage can cause DNA strand breaks in cells. These breaks cause the relaxation of the compact highly supercoiled DNA. The application of an electric field while the cells are embedded in agarose allows damaged DNA to migrate faster than intact DNA. The more breaks in the DNA, the further it will travel in the agarose resulting in the formation of a “comet” tail, the size and length of which directly correlates to the amount of DNA damage. The SCGE method benefits from both technical simplicity and high sensitivity. The major drawback is the assay is extremely laborious, lacks appropriate controls and has poor reproducibility. We have recently overcome these drawbacks by developing a 96-well plate format of the SCGE, aptly named “CometChip”. The CometChip uses micro-pillar technology to create an agarose 96-well chip where each well has approximately 300 micro-wells used to capture individual cells. Using this technology we can incorporate multiple treatments, controls and time points on a single CometChip which can then be rapidly analyzed using a fluorescence based imaging instrument. The utility of the new technology was tested using 75 different chemical compounds considered either genotoxic, non-genotoxic or unknown. The compounds were tested on two lymphocyte cell lines with different p53 status to compare the accumulation and repair of DNA damage. We report that the CometChip gives highly reproducible and accurate results without loss of sensitivity. In the high throughput screening approach using multiple CometChip apparatus, we estimate the throughput of the assay to be approximately 10,000% greater than doing traditional slide based comet analysis. The massive increase in processivity brings new opportunity for large-scale compound screening. The increased sensitivity coupled with large sample sizes will allow researchers the option to measure minor changes in DNA damage with unparalleled accuracy. Citation Format: Peter Sykora, Sandra Woodgate, Jay George, Robert W. Sobol. Next generation high capacity DNA damage detection assay for chemotherapy and genotoxic compound screening. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3600.
Abstract 3851: Synergy between statins and BCL-2 inhibitors in blood cancers
Authors: Jong-Hoon S. Lee, Thanh-Trang T. Vo, David A. Fruman
Journal: Cancer Research (2016)

Abstract BCL-2 is a key pro-survival protein that is highly expressed in many leukemias and lymphomas. ABT-199 (venetoclax) is a small molecule inhibitor of BCL-2 that has demonstrated promising clinical potential in chronic lymphocytic leukemia (CLL). However, other hematologic malignancies are less responsive to ABT-199 as a single agent, suggesting that combinations of targeted therapies may be required to elicit more promising responses. We have investigated the potential of combining ABT-199 with HMG-CoA reductase (HMGCR) inhibitors (statins), which have known anti-cancer potential in hematologic malignancies. Using multiple chemically distinct statin compounds, we observed profound synergistic induction of apoptosis when combined with ABT-199 in both human diffuse large B cell lymphoma (DLBCL) as well as acute myeloid leukemia (AML) cell lines. This synergy was also seen in primary murine B lymphoma cells over-expressing MYC and BCL-2. Importantly, addition of exogenous mevalonate completely rescued cells from the combination, confirming on-target efficacy of HMGCR inhibition. Using BH3 profiling, we found that simvastatin significantly primed lymphoma cells for undergoing apoptosis (termed mitochondrial priming). Notably, the degree of priming correlated with its ability to synergize with ABT-199, suggesting that this method may be used to predict patient responses. Strikingly, the combination did not synergize to kill normal human peripheral blood mononuclear cells from healthy donors, suggesting that statins may selectively prime cancer cells for apoptosis. Mechanistic studies support the hypothesis that statins synergize with ABT-199 by suppressing protein prenylation, particularly protein geranylgeranylation. In support, the addition of exogenous geranylgeranyl pyrophosphate (GGPP) completely rescued cells from the effects of simvastatin. Furthermore, selective inhibition of protein geranylgeranyl transferase (GGT) was sufficient to recapitulate the effects of simvastatin in combination with ABT-199. Lastly, we have identified Rap1A de-prenylation as a marker of pharmacodynamic response to statins in vivo. Thus, this project highlights a novel combination for use in aggressive lymphomas, establishes its efficacy and tolerability using preclinical models, and provides proof-of-concept to warrant investigation of its clinical potential. Citation Format: Jong-Hoon S. Lee, Thanh-Trang T. Vo, David A. Fruman. Synergy between statins and BCL-2 inhibitors in blood cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3851.
P19 Predictors of COPD Mortality, 2 year Follow-up Data from the ARCADE study: Abstract P19 Table 1
Authors: NS Gale, A Albarrati, MM Munnery, R Tal-Singer, JR Cockcroft, DJ Shale
Journal: Thorax (2015)

<h3>Background</h3> COPD is a systemic disease with associated comorbidities including cardiovascular disease which have significant impact on morbidity and mortality.<sup>1</sup> However, the progression of the disease is not well understood as there are few longitudinal studies of sufficient duration which include outcome data. The aim of this analysis was to evaluate predictors of mortality from the Assessment of Risk in Chronic Airways Disease Evaluation Study (ARCADE), Clinical Trials registration: NCT01656421.<sup>2</sup> <h3>Methods</h3> The ARCADE study is a longitudinal observational study of cardiovascular risk and other comorbidities in patients with COPD. Patients were assessed at recruitment and after 2 years including the following outcomes: Spirometry, BMI, St Georges Respiratory Questionnaire (SGRQ), mMRC breathlessness, number of exacerbations and 6 min walk distance (6MWD). A sample of blood was analysed for the inflammatory mediator fibrinogen. <h3>Results</h3> At baseline 524 patients with COPD, confirmed with spirometry, were recruited to the study. Thus far, at the 2 year follow up there have been 47 deaths. According to hospital records, causes of death were: respiratory n = 22 (including acute exacerbations/respiratory infections (n = 12) and pneumonia (n = 10)), cardiovascular n = 9, cancer n = 10, septicaemia n = 3 and unknown n = 4. At baseline the subjects who did not survive were similar to survivors in age, gender and BMI, but had greater airflow limitation, worse SGRQ, more breathlessness, more exacerbations and lower 6MWD, fibrinogen was also higher (Table 1). Using logistic regression of the objective markers which differed between the groups; FEV1% predicted, number of exacerbations, 6MWD and fibrinogen were entered into the model. Of these Fibrinogen (p = 0.013) and 6MWD (p = 0.024) were significant predictors of mortality (X2 (4) = 18.678, p = 0.001). <h3>Conclusions</h3> The follow up mortality rate was 9%, with the majority of deaths due to respiratory causes, followed by cancer and cardiovascular events. The non-survivors had poorer objective and patient reported outcomes. Further follow-up of this cohort will provide greater power to predict outcomes. <i>Thanks to all our volunteers and GlaxoSmithKline who funded the study.</i> <h3>References</h3> 1 Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD.<i> Eur Respir J</i>. 2008;<b>32</b>:962–69 2 Gale NS, Albarrati AM, Munnery MM, <i>et al</i>. Assessment of Risk in Chronic Airways Disease Evaluation (ARCADE): Protocol and preliminary data. <i>Chron Respir Dis</i>. 2014;<b>11</b>(4):199–207
miR-206 Inhibits Stemness and Metastasis of Breast Cancer by Targeting MKL1/IL11 Pathway
Authors: Ravand Samaeekia, Valery Adorno-Cruz, Jessica Bockhorn, Ya-Fang Chang, Simo Huang, Aleix Prat, Nahun Ha, Golam Kibria, Dezheng Huo, Hui Zheng, Rachel Dalton, Yuhao Wang, Grigoriy Y. Moskalenko, Huiping Liu
Journal: Clinical Cancer Research (2016)

Purpose: Effective targeting of cancer stem cells is necessary and important for eradicating cancer and reducing metastasis-related mortality. Understanding of cancer stemness-related signaling pathways at the molecular level will help control cancer and stop metastasis in the clinic.Experimental Design: By analyzing miRNA profiles and functions in cancer development, we aimed to identify regulators of breast tumor stemness and metastasis in human xenograft models in vivo and examined their effects on self-renewal and invasion of breast cancer cells in vitro To discover the direct targets and essential signaling pathways responsible for miRNA functions in breast cancer progression, we performed microarray analysis and target gene prediction in combination with functional studies on candidate genes (overexpression rescues and pheno-copying knockdowns).Results: In this study, we report that hsa-miR-206 suppresses breast tumor stemness and metastasis by inhibiting both self-renewal and invasion. We identified that among the candidate targets, twinfilin (TWF1) rescues the miR-206 phenotype in invasion by enhancing the actin cytoskeleton dynamics and the activity of the mesenchymal lineage transcription factors, megakaryoblastic leukemia (translocation) 1 (MKL1), and serum response factor (SRF). MKL1 and SRF were further demonstrated to promote the expression of IL11, which is essential for miR-206's function in inhibiting both invasion and stemness of breast cancer.Conclusions: The identification of the miR-206/TWF1/MKL1-SRF/IL11 signaling pathway sheds lights on the understanding of breast cancer initiation and progression, unveils new therapeutic targets, and facilitates innovative drug development to control cancer and block metastasis. Clin Cancer Res; 23(4); 1091-103. ©2016 AACR.
Safety and efficacy of PD-1 blockade using pembrolizumab in patients with advanced soft tissue (STS) and bone sarcomas (BS): Results of SARC028—A multicenter phase II study.
Authors: Hussein Abdul-Hassan Tawbi, Melissa Amber Burgess, John Crowley, Brian Andrew Van Tine, James Hu, Scott Schuetze, Sandra P. D'Angelo, Steven Attia, Dennis A. Priebat, Scott H. Okuno, Richard F. Riedel, Lara Emily Davis, Sujana Movva, Damon R. Reed, Laurence H. Baker, Denise K. Reinke, Robert G. Maki, Shreyaskumar Patel
Journal: Journal of Clinical Oncology (2016)

11006 Background: Inhibition of the programmed death-1 (PD-1)-PD-ligand 1 (PD-L1) axis has shown durable clinical benefit in melanoma, lung, renal, and bladder carcinomas. Herein, we report results of the first phase II evaluation of PD-1 blockade with the anti-PD-1 antibody pembrolizumab (P) in patients (pts) with advanced STS and BS. Methods: SARC028 is an open-label multicenter phase II study of single-agent P in pts with STS (Arm A) or BS (Arm B). All pts receive P 200mg IV q21 days. The primary endpoint for each arm is objective response rate (ORR) by RECIST 1.1 (target ORR = 25%, 82% power vs 10% ORR, α = 0.042). Secondary endpoints include safety, progression free survival (PFS), overall survival, and correlative studies. Tumor biopsies were collected at 0 and 8 weeks (mandatory), and at progression (optional). Arm A enrolled 4 subtypes in balanced cohorts: leiomyosarcoma (LMS), liposarcoma (LPS), undifferentiated pleomorphic sarcoma (UPS) and synovial sarcoma (SS). Arm B enrolled osteosarcoma (OS), Ewing sarcoma (ES) and high-grade/dedifferentiated chondrosarcoma (CS). Results: Of 80 patients enrolled at 12 SARC centers, 76 were evaluable for response by RECIST. In the STS cohort (Arm A), no objective responses were observed for LMS (0/10), LPS (0/9) or SS (0/10) from imaging performed after 8 weeks of therapy. An ORR of 22% was observed, however, for UPS (2/9). In the BS cohort (Arm B), 1 partial response (PR) was seen at 8 weeks in OS (1/19). No objective responses were observed in ES (0/13) or CS (0/6). In 24 pts that have completed evaluations at 20 weeks, 3 additional pts went on to experience PRs including 1 CS, 1 LPS and 1 UPS. PFS rate at 8 weeks was 50% in LMS, 63% in LPS, 30% in SS, 67% in UPS, 24% in OS, 9% in ES and 67% in CS. P was well tolerated and toxicities were consistent with published data. Conclusions: Single agent P has limited activity in unselected sarcoma pts. Early responses are infrequent but noted in UPS, OS, LPS and CS, warranting further investigation. Longer clinical follow-up data are critical to evaluate the therapeutic impact of single agent P in STS and BS and will be presented along with immune monitoring in peripheral blood and tumor tissues. Clinical trial information: NCT02301039.
Abstract 5239: Preventive effects of pentoxifylline on hepatic tumorigenesis in a novel mouse model of NASH-related liver cancer
Authors: Yohei Shirakami, Akinori Maruta, Koki Obara, Takayasu Ideta, Tsuneyuki Miyazaki, Hiroyasu Sakai, Takahiro Kochi, Masaya Kubota, Takuji Tanaka, Masahito Shimizu, Mitsuru Seishima
Journal: Cancer Research (2016)

Abstract Overweight and obesity are becoming more prevalent worldwide. As the hepatic manifestation of the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have received attention as major causes of liver disorder. In addition, hepatocellular carcinoma (HCC) associated with NASH becomes an important issue. Although no standard medicinal treatment for NASH is established, pentoxifylline (PTX), a medicine used to improve circulation, is reported to ameliorate histopathological appearance of NASH and is thought to be a candidate therapeutic agent for NASH. In the present study, we investigated effects of PTX on NAFLD/NASH and the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in monosodium glutamate (MSG)-treated mice, a novel mouse model of NASH-related hepatocarcinogenesis, and db/db obese and diabetic mice. Male MSG and db/db mice were administered DEN, and then they received drinking water containing PTX (100 mg/kg/day) throughout the experiment. At sacrifice, drinking water with PTX significantly inhibited the development of hepatic pre-neoplastic lesions compared with respective control groups. MSG mice were thought to be susceptible to liver tumorigenesis. Hepatic triglyceride contents in db/db mice were decreased by PTX administration. The serum levels of total cholesterol, triglyceride, free fatty acid, and alanine aminotransferase were all decreased by PTX treatment, as was the mRNA expression of pro-inflammatory cytokines (TNF-alpha and IL-1beta) the macrophage-inducing chemokine CCL2/MCP-1, and several lipogenic genes (FASN and SREBP1c) in the liver. In vitro studies also revealed that PTX treatment decreased the expression of several genes associated with de novo lipogenesis and CCL2/MCP-1 in hepatoma and hepatic stellate cell lines, respectively. These findings suggest that PTX prevents NAFLD/NASH-related liver tumorigenesis by attenuating chronic hepatic inflammation and decreasing lipogenic gene expression in the liver. PTX might be a promising and efficient agent for treatment of NAFLD/NASH patients, who have a higher risk for developing liver cancer. Citation Format: Yohei Shirakami, Akinori Maruta, Koki Obara, Takayasu Ideta, Tsuneyuki Miyazaki, Hiroyasu Sakai, Takahiro Kochi, Masaya Kubota, Takuji Tanaka, Masahito Shimizu, Mitsuru Seishima. Preventive effects of pentoxifylline on hepatic tumorigenesis in a novel mouse model of NASH-related liver cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5239.