tbuckley/cabot-search huggingface dataset:
Abstract 4660: Inhibition of p38 enhances ERK inhibitor efficacy in pancreatic ductal adenocarcinoma
Authors: Meagan B. Ryan, Kirsten L. Bryant, Tikvah K. Hayes, Swapnil Kher, Kris C. Wood, Ahmed A. Samatar, Adrienne D. Cox, Channing J. Der
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States, with a poor prognosis and limited treatment options. Oncogenic mutation of KRAS in greater than 90% of PDAC leads to aberrant activation of multiple effector pathways including the extra cellular related kinase (ERK)/mitogen activated protein kinase (MAPK) cascade. Hyperactivation of the ERK MAPK cascade has been correlated with poorer prognosis in PDAC patients. We recently showed that direct pharmacological inhibition of ERK1/2 kinases with the ERK1/2-selective inhibitor SCH772984 inhibits the growth of PDAC cell lines both in vitro and in vivo. However, much like the response to ERK/MAPK pathway inhibitors acting at upstream nodes RAF or MEK, resistance to direct inhibition at the level of ERK will also inevitably arise. We performed a novel gain-of-function “Cancer Toolkit” (CTK) genetic screen to identify mechanisms of resistance to the ERK inhibitor SCH772984 in a panel of KRAS-mutant PDAC cell lines. Our CTK screen revealed that expression of either MAPK14 (p38α) or its upstream activator MKK6 could cause resistance to this and other ERK inhibitors. Because we identified activation of the p38 pathway as a mechanism of ERK inhibitor resistance, we tested whether inhibition of p38 would enhance sensitivity to SCH772984. We observed a &amp;gt;2 fold shift to a lower GI50 of SCH772984 upon cotreatment of a panel of established and patient-derived xenograft (PDX) PDAC cell lines with SCH772984 and the clinical candidate p38 inhibitor LY2228820. Consistent with this, we found that SCH772984 induced p38 signaling, marked by phosphorylation of the downstream substrate HSP27, and that combination treatment of SCH772984 and LY2228820 both reversed p38 pathway activation and enhanced PARP cleavage. Results of in vivo testing of the combination treatment as well as the mechanistic basis for p38-driven resistance will be reported. We propose that p38 is a mechanism of resistance to ERK inhibition in PDAC and that p38 inhibitors such as LY2228820 can overcome that resistance to enhance ERK inhibitor efficacy. Citation Format: Meagan B. Ryan, Kirsten L. Bryant, Tikvah K. Hayes, Swapnil Kher, Kris C. Wood, Ahmed A. Samatar, Adrienne D. Cox, Channing J. Der. Inhibition of p38 enhances ERK inhibitor efficacy in pancreatic ductal adenocarcinoma. [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 4660.
Premature termination of genitourinary cancer clinical trials.
Authors: Kristian D. Stensland, Russell McBride, Juan P. Wisnivesky, Asma Latif, Ryan Hendricks, Nitin Roper, Paolo Boffetta, Simon J Hall, William K. Oh, Matt D. Galsky
Journal: Journal of Clinical Oncology (2014)

288 Background: The GU oncology literature is inundated with clinical trials that terminated prematurely, particularly in bladder cancer. Such trials require substantial resource expenditure and entail the time, trust, and commitment of patients, yet contribute minimally to the scientific knowledgebase and divert resources from answering critical questions. We sought to determine the scope of this problem within the clinical trials enterprise. Methods: ClinicalTrials.gov was queried to identify all phase II-III interventional adult cancer clinical trials registered between 9/11/05 and 11/11/11. Prematurely terminated trials were “stopped early” as defined by the registry. Kaplan-Meier methods and Cox regression were used to determine risk of premature trial termination. Results: We identified 7,776 trials, including 491 prostate (PCa), 142 kidney, 75 bladder, and 34 testis cancer trials. The risk of premature termination due to any cause for all cancers was 25% (95% CI 19-31%) and the risk due to poor accrual was 10% (95% CI 9-12%). Poor accrual was the most common reason for premature termination (Table). Risk was not significantly different for kidney, bladder or testis cancers compared to other cancer types with the exception of PCa (HR 1.35 [1.03-1.78]). Industry-funded trials were more likely to terminate prematurely (HR 2.26 [1.83-2.80]). Trials with sites outside of the USA (HR 0.63 [0.54-0.74]) or both within and outside of the USA (HR 0.68 [0.54-0.74]) were less likely to terminate prematurely as were trials with multiple sites (HR 0.56 [0.48-0.64]). Conclusions: In this large cohort of clinical trials, ~1 in 4 trials terminated prematurely (1 in 10 due to poor accrual). GU cancer trials were at similar risk of termination compared to other cancer clinical trials with the exception of PCa. Novel approaches are needed to improve the efficiency of the clinical cancer research enterprise. [Table: see text]
Abstract 2331: HDAC6, new role as master regulator of PD-L1 and immune-related pathways
Authors: Tessa Knox, Maritza Lienlaf, Patricio Perez, Mibel Pabon, Calvin Lee, Fengdong Cheng, Eva Sahakian, John Powers, Susan Deng, Smalley Keiran, Alan Kozikowski, Javier Pinilla, Amod Sarnaik, Ed Seto, Jeffrey Weber, Eduardo Sotomayor, Alejandro Villagra
Journal: Cancer Research (2016)

Abstract Histone deacetylases (HDACs), originally described as histone modifiers, have more recently been demonstrated to modify a variety of other proteins involved in diverse cellular processes unrelated to the chromatin environment, including the modulation of proteins related to cell cycle/apoptosis and immune regulation. In contrast to the well-documented effects of HDAC inhibitors (HDACi) in the control of cell cycle and apoptosis, their role in immunobiology is still not completely understood, and the reported immunological outcomes when using HDACi are heterogeneous. Our group recently reported that the pharmacological or genetic abrogation of a single HDAC, HDAC6, modulates the expression of immuno-regulatory proteins, including PD-L1, PD-L2, MHC class I, B7-H4 and TRAIL-R1. We primarily focused in PD-L1, which is an important negative regulator of T-cell function and often over-expressed in cancer cells. In a mechanistic point of view, we have found that the pharmacological inhibition and genetic abrogation of HDAC6 inactivates the STAT3 pathway, impairs the nuclear translocation and the recruitment of STAT3 to the PD-L1 promoter and subsequently down-regulates the expression of PD-L1. Moreover, the in vivo abrogation of HDAC6 reduces tumor growth in melanoma models, effect that is enhanced in the presence of the immune check-point blocking antibodies anti-PD-1 and anti-CTLA4. These results provide a key pre-clinical rationale and justification to further study isotype selective HDAC6 inhibitors as potential immunomodulatory agents in cancer. Citation Format: Tessa Knox, Maritza Lienlaf, Patricio Perez, Mibel Pabon, Calvin Lee, Fengdong Cheng, Eva Sahakian, John Powers, Susan Deng, Smalley Keiran, Alan Kozikowski, Javier Pinilla, Amod Sarnaik, Ed Seto, Jeffrey Weber, Eduardo Sotomayor, Alejandro Villagra. HDAC6, new role as master regulator of PD-L1 and immune-related pathways. [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 2331.
Abstract 4902: A mouse GITRL fusion protein drives T-cell activation and antitumor activity in preclinical mouse models of cancer
Authors: Rebecca Leyland, Amanda Watkins, Kathy A. Mulgrew, Lisa Bamber, Natalie J. Tigue, Emily Dick, Nick Holoweckyj, Lesley Young, Michelle Morrow, Scott A. Hammond, Ching Ching Leow, Robert W. Wilkinson, Ross Stewart
Journal: Cancer Research (2016)

Abstract GITR is a member of the TNFR superfamily of proteins and is expressed on resting regulatory T-cells and on other T-cells following activation. Signals through GITR have been shown to drive increased T-cell activity and reduced regulatory T-cell function. In order to explore the potential of therapeutically targeting GITR in a cancer setting, we generated a mouse GITRL fusion protein (mGITRL FP) consisting of the extracellular domain of mGITRL linked to a structural domain and an IgG Fc domain. The antitumor activity and pharmacodynamic effects of this molecule were then explored in the colorectal syngeneic model of cancer (CT26). Treatment of mice with mGITRL FP mediated anti-tumor activity that was dependent on isotype and exposure. The anti-tumor activity could be attributed at least in part to the increased activation and proliferation status of CD8+ and CD4+ T-cells, as evidenced by increases in Ki67 expression and ICOS upregulation. Intratumourally we observed a significant decrease in the frequency of CD4+ T-cells (including T regs), but a corresponding increase in cytotoxic CD8+ T-cells. OX40 is another member of the TNFR superfamily, that has similar expression and functions to GITR. In order to better understand the potential differences between targeting of these two pathways, the activity and pharmacodynamic effects of the mGITRL FP were additionally compared and contrasted to those of a mOX40L FP and the observed differences will be discussed. Citation Format: Rebecca Leyland, Amanda Watkins, Kathy A. Mulgrew, Lisa Bamber, Natalie J. Tigue, Emily Dick, Nick Holoweckyj, Lesley Young, Michelle Morrow, Scott A. Hammond, Ching Ching Leow, Robert W. Wilkinson, Ross Stewart. A mouse GITRL fusion protein drives T-cell activation and antitumor activity in preclinical mouse models of 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 4902.
Glucagon-like Peptide 1 Drugs as Second-line Therapy for Type 2 Diabetes
Authors: Peter C. Butler
Journal: JAMA Internal Medicine (2016)

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Abstract 2230: Evaluation of PD-L1 expression in ovarian carcinosarcoma by immunohistochemistry and RNAscope in-situ hybridization
Authors: Li Liang, Jun-Song Chen, Yi Jiang, Na Niu, Connie Zhang, Emily Park, Xiao-Jun Ma, Jinsong Liu
Journal: Cancer Research (2016)

Abstract Ovarian carcinosarcoma, also called malignant Müllerian mixed tumor, is a rare, but very aggressive biphasic tumor with both malignant epithelial and stromal components. PD-L1 is one of the ligands of immune inhibitory receptor PD-1. PD-L1/PD-1 pathway suppresses T cell immune response, increases programmed cell death of activated T cells and plays an important role in tumor immune escape. Anti-PD-L1 immunotherapy has shown promising results in certain malignancies, such as melanoma and lung cancer. Therefore, we performed PD-L1 immunohistochemical staining on 30 specimens of ovarian carcinosarcoma collected from patients that underwent surgeries at our institution between 2002 and 2015. In addition, we performed RNAscope in-situ hybridization to examine PD-L1 mRNA expression in 16 specimens that were collected within past 5 years (2010-2015). Our result demonstrated focally membranous expression of PD-L1 protein in 23 of 30 cases (77%). PD-L1 mRNA expression correlated with membranous, but not cytoplasmic expression of PD-L1 protein. In conclusion, PD-L1 protein and mRNA are frequently expressed in ovarian carcinosarcoma, suggesting anti-PD-L1 immunotherapy may be helpful in these patients. Citation Format: Li Liang, Jun-Song Chen, Yi Jiang, Na Niu, Connie Zhang, Emily Park, Xiao-Jun Ma, Jinsong Liu. Evaluation of PD-L1 expression in ovarian carcinosarcoma by immunohistochemistry and RNAscope in-situ hybridization. [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 2230.
Abstract 4514: Transcription down-regulation of c-Myc through nucleic acid clamp-mediated stabilization of the promoter G-quadruplex
Authors: Taisen Hao, Tracy Brooks
Journal: Cancer Research (2016)

Abstract MYC overexpression occurs in up to 80% of all cancers. Down-regulating MYC's expression is an effective therapeutic strategy for the treatment of many of these cancers, and particularly for non-Hodgkin's lymphoma (NHL). NHL is the fifth most common cancer type, accounting for 5% of all cancers and 4% of all cancer deaths. Developing MYC-targeting therapeutics will be very impactful to NHL patients. In the current study, we have developed a nucleic acid clamp to transcriptionally down-regulate MYC expression by stabilizing the G-quadruplex (G4) formed in the nuclease hypersensitivity element III1 promoter region. The clamps complement nucleotides on the 5’- and 3’- regions flanking the G4-forming sequence, linked together with an 18 angstrom abasic moiety. To date, the binding affinity and specificity, G4 structure stabilizing ability, MYC down-regulation capability, and the selective cytotoxicity on cancerous vs non-cancerous cell lines of these clamps have been confirmed by EMSA and electronic circular dichroism, DMS footprinting, luciferase reporter assay, and MTS viability assay respectively. Recently, various replacements have been explored to replace the abasic moiety with non-complementary nucleic acids and to optimize the phosphate backbone with peptide nucleic acids. In addition, complexation with block co-polymers is under investigation to develop a functionalizable nanotherapeutic for NHL. The highly selective G4 stabilizing ability of the clamps used in the current approach offers an advantage over traditional G4 stabilizing small molecules. This novel approach is a promising therapeutic for the treatment of MYC related malignancies, and provides a framework for future G4-therapeutic development for other high-value genes, such as kRAS, VEGF, c-KIT and many more. Citation Format: Taisen Hao, Tracy Brooks. Transcription down-regulation of c-Myc through nucleic acid clamp-mediated stabilization of the promoter G-quadruplex. [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 4514.
Comparative DNA methylation and gene expression analysis identifies novel genes for structural congenital heart diseases
Authors: Marcel Grunert, Cornelia Dorn, Huanhuan Cui, Ilona Dunkel, Kerstin Schulz, Sophia Schoenhals, Wei Sun, Felix Berger, Wei Chen, Silke R. Sperling
Journal: Cardiovascular Research (2016)

For the majority of congenital heart diseases (CHDs), the full complexity of the causative molecular network, which is driven by genetic, epigenetic, and environmental factors, is yet to be elucidated. Epigenetic alterations are suggested to play a pivotal role in modulating the phenotypic expression of CHDs and their clinical course during life. Candidate approaches implied that DNA methylation might have a developmental role in CHD and contributes to the long-term progress of non-structural cardiac diseases. The aim of the present study is to define the postnatal epigenome of two common cardiac malformations, representing epigenetic memory, and adaption to hemodynamic alterations, which are jointly relevant for the disease course.We present the first analysis of genome-wide DNA methylation data obtained from myocardial biopsies of Tetralogy of Fallot (TOF) and ventricular septal defect patients. We defined stringent sets of differentially methylated regions between patients and controls, which are significantly enriched for genomic features like promoters, exons, and cardiac enhancers. For TOF, we linked DNA methylation with genome-wide expression data and found a significant overlap for hypermethylated promoters and down-regulated genes, and vice versa. We validated and replicated the methylation of selected CpGs and performed functional assays. We identified a hypermethylated novel developmental CpG island in the promoter of SCO2 and demonstrate its functional impact. Moreover, we discovered methylation changes co-localized with novel, differential splicing events among sarcomeric genes as well as transcription factor binding sites. Finally, we demonstrated the interaction of differentially methylated and expressed genes in TOF with mutated CHD genes in a molecular network.By interrogating DNA methylation and gene expression data, we identify two novel mechanism contributing to the phenotypic expression of CHDs: aberrant methylation of promoter CpG islands and methylation alterations leading to differential splicing.
Adenomyoma of the common bile duct: a rare lesion diagnosed and treated by ERCP
Authors: Marco D’Assuncao, Saverio Armellini, Daniel Moribe, Lucas Nova da Costa, Gisele Leite, Larissa Vendrame, Andre Montagnini
Journal: Endoscopy (2016)

Benign biliary tumors are extremely rare, with an incidence ranging from 0.02 % to 0.10 % based on pathological examination of resected ducts [1]. Adenomyomas are defined as duct-like structures with hyperplasia of smooth muscle cells. To our knowledge, only 11 cases originating from the common bile duct have been reported to date [2]. Most of the cases have been diagnosed after extensive surgical resections. This report describes a case of an adenomyoma diagnosed and treated by an endoscopic approach.
Clinical Results of Gemox-R in Mantle CELL Lymphoma: The Role of Oxaliplatin
Authors: Marta García-Recio, Antonio Gutierrez, Antonia Obrador-Hervia, Lucia García Mañó, Leyre Bento, Juan Besalduch, Jose Rodriguez, Antonia Sampol, Priam Villalonga, Silvia Fernandez
Journal: Blood (2015)
p21 mediates macrophage reprogramming through regulation of p50-p50 NF-κB and IFN-β
Authors: Gorjana Rackov, Enrique Hernández-Jiménez, Rahman Shokri, Lorena Carmona-Rodríguez, Santos Mañes, Melchor Álvarez-Mon, Eduardo López-Collazo, Carlos Martínez-A, Dimitrios Balomenos
Journal: Journal of Clinical Investigation (2016)

M1 and M2 macrophage phenotypes, which mediate proinflammatory and antiinflammatory functions, respectively, represent the extremes of immunoregulatory plasticity in the macrophage population. This plasticity can also result in intermediate macrophage states that support a balance between these opposing functions. In sepsis, M1 macrophages can compensate for hyperinflammation by acquiring an M2-like immunosuppressed status that increases the risk of secondary infection and death. The M1 to M2 macrophage reprogramming that develops during LPS tolerance resembles the pathological antiinflammatory response to sepsis. Here, we determined that p21 regulates macrophage reprogramming by shifting the balance between active p65-p50 and inhibitory p50-p50 NF-κB pathways. p21 deficiency reduced the DNA-binding affinity of the p50-p50 homodimer in LPS-primed and -rechallenged macrophages, impairing their ability to attenuate IFN-β production and acquire an M2-like hyporesponsive status. High p21 levels in sepsis patients correlated with low IFN-β expression, and p21 knockdown in human monocytes corroborated its role in IFN-β regulation. The data demonstrate that p21 adjusts the equilibrium between p65-p50 and p50-p50 NF-κB pathways to mediate macrophage plasticity in LPS tolerance. Identifying p21-related pathways involved in monocyte reprogramming may lead to potential targets for sepsis treatment.
Comorbidities predict overall survival (OS) in men with metastatic castrate-resistant prostate cancer (CRPC).
Authors: S. Halabi, W. K. Kelly, D. J. George, M. J. Morris, E. B. Kaplan, E. J. Small
Journal: Journal of Clinical Oncology (2011)

189 Background: Management of prostate cancer in senior adults represents an important challenge as the median age at diagnosis is 68 and comorbidities in patients increase with advancing age. The objective of this analysis was to determine if baseline comorbidities number (CON) prior to initiating frontline chemotherapy impacts OS in men with CRPC. Methods: Data from a randomized phase III trial of 1,050 men who received docetaxel, prednisone with or without bevacizumab were used in this analysis. Eligible patients had metastatic CRPC with evidence of progressive disease despite castration and anti-androgen withdrawal, ECOG performance status ≤ 2, and adequate bone marrow, hepatic and renal function. Comorbidities on 14 conditions including cardiovascular, hypertension, diabetes, arthritis, thrombosis, AIDS, renal disease, liver disease and peptic ulcer were prospectively collected at baseline from men enrolled on this trial. The proportional hazards model was used to test if CON predicted OS adjusting for treatment arm, age, race, body mass index and predicted survival probability at 24 months using the CALGB nomogram. Results: In 1,048 men with comorbidity data, the mean CON was 1.5 (s.d.= 1.47, range=0-9) and 73% of men had at least one comorbidity. There was a statistically significant association between CON and risk of death. In multivariable analysis, the hazard ratio (HR) for death for one unit increase in CON was 1.09 (95% CI= 1.04- 1.14, p-value=0.0008). Conclusions: To our knowledge, this is the first analysis to show that CON is a statistically significant predictor of OS in men with CRPC. These results require prospective validation in phase III trials of men with CRPC. [Table: see text]