tbuckley/cabot-search huggingface dataset:
Abstract 3767: Highly effective inhibitory agent identified by high-throughput screening of genetically characterized anaplastic thyroid cancer cell lines
Authors: Nicole C. Pinto, Morgan Black, Kara Ruicci, John Yoo, Danielle MacNeil, Kevin Fung, Alessandro Datti, Stephenie Prokopec, Paul Boutros, John Barrett, Anthony Nichols
Journal: Cancer Research (2016)

Abstract Introduction While most types of thyroid cancer are treatable, anaplastic thyroid cancer (ATC) is the most lethal human malignancy. Current treatment strategies are largely ineffective with only 10% of patients surviving longer than one year. As such, new treatments are desperately needed to improve patient survival in this aggressive cancer. Objective Identify highly effective drugs using high-throughput screening methods with a large panel of kinase inhibitors that can be used in the treatment of ATC. Methods High-throughput screening (HTS) of 13 genetically characterized ATC cell lines was carried out over a 6-dose range using 320 kinase inhibitors. Dose-response curves were generated and drugs with high potency were identified. Drugs with the highest activity were selected for further evaluation including investigating mechanism of action and cell death, and assays for migration and invasion. Results Based on HTS studies, Lestaurtinib was identified as a highly effective agent with submicromolar mean inhibitory concentrations in all 13 ATC cell lines. Lestaurtinib was found to inhibit STAT5 phosphorylation, as well as cell line migration and invasion. The anti-proliferative effect of Lestaurtinib did not cause apoptosis, autophagy or cell senescence. Conclusions With the use of HTS, we have identified many (&amp;gt;20) kinase inhibitors as highly effective agents in the control of ATC. The kinase inhibitor Lestaurtinib was effective at controlling ATC cell proliferation, invasion and migration. Future in vivo analysis of Lestaurtinib with patient-derived xenografts are planned to continue preclinical development of this drug with the ultimate goal of improving outcomes for patients suffering with ATC. Citation Format: Nicole C. Pinto, Morgan Black, Kara Ruicci, John Yoo, Danielle MacNeil, Kevin Fung, Alessandro Datti, Stephenie Prokopec, Paul Boutros, John Barrett, Anthony Nichols. Highly effective inhibitory agent identified by high-throughput screening of genetically characterized anaplastic thyroid cancer cell lines. [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 3767.
Abstract 4766: Establishment of drug sensitivity and resistance testing using focused drug libraries to develop targeted therapies for patients with leukemia
Authors: Apurvi Patel, Justin J. Montoya, Daniel H. Wai, Robert J. Arceci, David O. Azorsa
Journal: Cancer Research (2016)

Abstract Despite major advancements in pediatric leukemia therapy, toxicities and morbidity from chemotherapy regimens have been detrimental. Advances in genomic research as well as precision medicine have helped identify specific mutations that may be susceptible to targeted therapy in leukemic patients. Overall, the use of targeted drug therapy is rising in the pediatric oncology field. To complement genomic analysis of leukemia patients, our laboratory is working on the development of a drug sensitivity and resistance screening library, that would provide functionally relevant drug response data of the patient's leukemia cells. Development of this assay included the preparation of pre-dosed library plates allowing for rapid initiation of the assay. Cells were treated for 72 hours and cell viability was determined. Preliminary work in our laboratory used a library of 56 anti-cancer and targeted agents, which were tested on 16 AML cell lines and 10 ALL cell lines. Biological replicates were preformed for each cell line and drug response data in the form of IC50s and Area Under the Curve (AUC) were calculated. Hierarchical clustering was performed to determine similar responses between cell lines. Our results identified several cell lines that showed hypersensitivity to specific drugs. Among them, the AML cell line KG-1a showed sensitivity to three FGFR inhibitors including Ponatinib, which was previously reported. Validation of the screening results was done using a 10-concentration drug dose response assay. Further testing will include expansion of our drug library and application to ex vivo patient samples. The results from these studies can lead to the establishment of a drug sensitivity and resistance assay that could provide specifically engineered therapies for each patient. This form of personalized therapy would lead to diminished toxicities from systemic therapies as well as allow increased cure rates. Citation Format: Apurvi Patel, Justin J. Montoya, Daniel H. Wai, Robert J. Arceci, David O. Azorsa. Establishment of drug sensitivity and resistance testing using focused drug libraries to develop targeted therapies for patients with leukemia. [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 4766.
Abstract 1919: Nitric oxide stimulates expression of miRNA-155 through the BRCA1-dependent pathway
Authors: Justin Hawley, Vasily A. Yakovlev
Journal: Cancer Research (2016)

Abstract Previously we demonstrated that nitric oxide (NO), generated in macrophages or released from the NO-donors, inhibits expression of the breast cancer type 1 susceptibility protein (BRCA1) in the different cell lines (Yakovlev, Cancer Res., 2013). BRCA1 protein contributes to cell viability in multiple ways, including homologous recombination repair (HRR) of DNA double-stand breaks (DSBs), cell-cycle checkpoint control, mitotic spindle assembly, and regulation of chromosome segregation. In addition BRCA1 protein (in association with histone deacetylase 2) epigenetically suppresses oncogenic microRNA-155 (miR-155) expression (Chang, Nature Med., 2011). miR-155 is an established multifunctional oncomiR, which regulates many pro-oncogenic pathways. miR-155 gene was found to be over expressed in several solid tumors, such as thyroid carcinoma, breast cancer, colon cancer, cervical cancer, pancreatic ductal adenocarcinoma, and lung cancer, where it is considered to be a marker of poor prognosis. We hypothesized that overproduction of NO can stimulate expression of miR-155 through the BRCA1-dependent pathway. A-549 (lung cancer) and MCF-10A (normal breast epithelial) cell lines were incubated with different concentrations of NO-donor DETA NONOate (0 - 300μM). After 24 or 48 hours of incubation cells were analyzed for the BRCA1 and miR-155 expression. Both cell lines demonstrated significant dose- and time-dependent downregulation of BRCA1 expression along with significant stimulation of miR-155 expression. Cell lines infected with adenovirus vector expressing the wild type BRCA1 abolished stimulation of miR-155 in response to NO-donor treatment, compared with the cell lines infected with an empty adenovirus vector. To analyze the effect of NO-dependent stimulation of miR-155 expression, we measured the protein levels of miR-155 targets: DNA mismatch repair (MMR) proteins - MSH2, MSH6, MLH1; SH-2 containing inositol 5’-polyphosphatase 1 (SHIP1); and suppressor of cytokine signaling 1 (SOCS1). Western blot demonstrated time- and dose-dependent amount decrease for all targeted proteins with the one exception: expression level of SHIP1 protein in A-549 cell line was undetectable even in the non-treated control. In future studies we will investigate the role of NO-BRCA1-miR-155 pathway on the MMR capacity and stimulation of microsatellite instability. Citation Format: Justin Hawley, Vasily A. Yakovlev. Nitric oxide stimulates expression of miRNA-155 through the BRCA1-dependent pathway. [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 1919.
A randomized phase III trial of active symptom control (ASC) with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma: First results of the Medical Research Council (MRC) / British Thoracic Society (BTS) MS01 trial
Authors: M. Muers, P. Fisher, M. Snee, E. Lowry, M. O'Brien, M. Peake, R. Rudd, M. Nankivell, C. Pugh, R. J. Stephens
Journal: Journal of Clinical Oncology (2007)

LBA7525 Background: Although chemotherapy is widely used in the treatment of mesothelioma it has never been compared in a randomized trial with ASC alone. Two chemotherapy regimens that had shown good symptom palliation in phase II studies were chosen for investigation. Methods: Patients with malignant pleural mesothelioma were randomized to ASC alone (regular follow-up in a specialist clinic, and treatment could include steroids, analgesics, bronchodilators, palliative radiotherapy, etc), ASC+MVP (4 × 3-weekly cycles of mitomycin 6g/m 2 , vinblastine 6mg/m 2 , and cisplatin 50mg/m 2 ), or ASC+N (12 weekly injections of vinorelbine 30mg/m 2 ). 420 patients were required to detect a 3-month improvement in median survival with ASC+CT (both chemotherapy arms combined). Quality of Life (QL) was assessed using the EORTC QLQ-C30. Results: 409 patients were accrued (136 ASC, 137 ASC+MVP, 136 ASC+N). Median age: 65 years, male: 91%, Performance status 0: 23%, Epithelial histology: 73%, Stage III: 33%, Stage IV: 48%. In the ASC+MVP group 61% received all 4 cycles, and in the ASC+N group 49% received at least 10 weekly cycles. Good symptom palliation (defined as prevention, control or improvement) was achieved in all 3 groups, and no between-group differences were observed in 4 pre-defined QL subscales (physical functioning, dyspnoea, pain and global QL). A small (not conventionally significant) survival benefit was seen for ASC+CT (349 deaths, HR 0.89, 95%CI 0.72, 1.12, p=0.32). Median survival: ASC: 7.6 months, ASC+CT: 8.5 months. Exploratory analyses suggested a survival advantage for vinorelbine compared to ASC alone (HR 0.81, 95%CI 0.63, 1.05, p=0.11), with a median survival of 9.4 months, but no evidence of a benefit with MVP (HR 0.98, 95%CI 0.76, 1.28), p=0.91). Conclusions: This is the 2nd largest ever randomized trial in mesothelioma and the first to compare ASC with or without chemotherapy. Although the addition of chemotherapy to ASC did not result in a conventionally significant survival benefit, there was an indication that vinorelbine should be investigated further, and that MVP probably has no role in this disease. [Table: see text]
Glucosylsphingosine is a key biomarker of Gaucher disease
Authors: Vagishwari Murugesan, Wei‐Lien Chuang, Jun Liu, Andrew Lischuk, Katherine Kacena, Haiqun Lin, Gregory M. Pastores, Ruhua Yang, Joan Keutzer, Kate Zhang, Pramod K. Mistry
Journal: American Journal of Hematology (2016)

Gaucher disease (GD) involves the accumulation of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) which is implicated in mediating immune dysregulation and skeletal disease. The aim of our study was to assess plasma Lyso-GL1 as a biomarker of GD and its response to therapy. Plasma lyso-GL1 in 169 patients with GD type 1 (GD1) was measured by LC-MS/MS. Significant predictors of plasma LGL1 were assessed by Pearson's correlation coefficient, Wilcoxon Mann Whitney test and multiple linear regression. Propensity scores were used to match patients on treatment mode: Enzyme Replacement Therapy (ERT) vs. Eliglustat Tartrate SRT (ELI-SRT). Plasma Lyso-GL1 levels in healthy controls averaged 1.5 ng/ml (1.3-1.7; 95% CI). In untreated GD patients, the levels were massively elevated (180.9 ng/ml: 95% CI, 145.4-216.5) and imiglucerase ERT resulted in marked reduction (89 ng/ml: 95% CI, 69.2-129.4) (P < 0.001). Lyso-GL1 correlated with chitotriosidase (r = 0.59 P < 0.001), CCL18 (r = 0.62 P <0.001), hepatomegaly (r = 0.28 P < 0.001), splenomegaly (r = 0.27 P = 0.003), splenectomy (P = 0.01) and treatment mode (P < 0.001). By multiple linear regression, the strongest predictors of lyso-GL1 were age (P < 0.001), splenectomy (P = 0.02), Chitotriosidase (P < 0.001) and CCL18 levels (P = 0.001). After propensity score matching to obtain comparable groups of patients on ERT vs ELI-SRT, lyso-GL1 levels were lower among patients receiving ELI-SRT by 113 ng/ml (95% CI: 136-90.3 ng/ml P < 0.001). Plasma lyso-GL1 is a key biomarker of GD. ERT reduced lyso-GL1 levels. By propensity scoring, ELI-SRT resulted in greater reduction of lyso-GL1 than ERT. Am. J. Hematol. 91:1082-1089, 2016. © 2016 Wiley Periodicals, Inc.
Abstract LB-350: In vivo kinome screen reveals potential drivers of brain metastasis
Authors: Frank J. Lowery, Sunil Acharya, Yong Xia, Chenyu Zhang, Jodi M. Saunus, Dihua Yu
Journal: Cancer Research (2016)

Abstract Brain metastasis remains an unmet medical need, as its incidence continues to rise while treatment options remain palliative. Advances in targeted therapy for breast cancer have prolonged patient survival through better control of the systemic disease, but an ever-increasing number of patients later recur with brain metastasis. As no effective therapies exist for brain metastasis, the median survival of patients is less than one year. To tackle this growing clinical challenge, we sought to better understand the biological mechanism of brain metastasis and to identify novel targets for intervention. We chose to focus on kinases, as they both occupy the central nodes of cancer cell signaling pathways and structurally lend themselves to targeting by small molecules. To identify novel therapeutic targets, we performed an unbiased kinome screen in vivo for determination of brain metastasis driver kinases. We injected MDA-MB-231 human breast cancer cells overexpressing pools of 16-20 kinase ORFs into the carotid artery of nude mice to form experimental brain metastasis. Several of the kinase pools led to decreased brain metastasis-specific survival, decreasing survival time by as much as 50% relative to controls. We then performed targeted next-generation sequencing (NGS) of the pre-and post-injection tumor cells to determine those kinases most enriched in vivo, revealing 31 ORFs that were significantly increased in vivo in multiple animals. To validate the clinical relevance of these potential targets, we examined their expression in a collection of 32 human brain metastases by RNA-seq, and observed that the majority of the ORFs (29/31) were indeed expressed. One of the kinases with the highest in vivo enrichment and expression in human brain metastases was hexokinase 2 (HK2), an important glycolysis regulator that has been previously implicated in brain metastasis and served to validate our findings. Several other candidate kinases were also related to glycolysis and other metabolic pathways, suggesting that these kinases enable metastatic cancer cells to survive in the nutrient-restricted brain environment. Functional validation of these newly identified kinases as true drivers of brain metastasis will reveal whether they have potential to serve as the first targets of brain metastasis-targeted therapy. Citation Format: Frank J. Lowery, Sunil Acharya, Yong Xia, Chenyu Zhang, Jodi M. Saunus, Dihua Yu. In vivo kinome screen reveals potential drivers of brain metastasis. [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 LB-350.
Abstract 2696: Four new brain tumor entities emerge from molecular classification of CNS-PNETs
Authors: Dominik Sturm, Brent Orr, Umut H. Toprak, Volker Hovestadt, David T.W. Jones, David Capper, Peter Lichter, Andrey Korshunov, Stefan M. Pfister, David W. Ellison, Marcel Kool
Journal: Cancer Research (2016)

Abstract CNS-primitive neuroectodermal tumors (CNS PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Histological diagnosis is complicated by morphological heterogeneity and divergent differentiation. Recent studies suggest the existence of molecular subgroups of CNS-PNETs sharing biological characteristics with other CNS tumors. To investigate this we have analyzed 323 fresh-frozen or paraffin-embedded institutionally diagnosed CNS-PNETs using DNA methylation and expression arrays. Data were compared to 211 reference cases of other pediatric and adult brain tumors representing more than 20 well-known entities. DNA methylation and gene expression patterns showed that a significant proportion of CNS PNETs display molecular profiles indistinguishable from those of various other well defined CNS tumor entities. Hallmark genetic alterations for each of these well-defined entities, such as amplification of 19q13.42, mutations in IDH1 or H3F3A, mutations/deletions of the SMARCB1 locus, or RELA fusions, were frequently detected among the reclassified cases. From the remaining fraction of CNS PNETs we have identified four new CNS tumor entities, each associated with a unique recurrent genetic alteration and distinct histopathological and clinical features. Based on these findings we designated these four new entities as “CNS neuroblastoma with FOXR2 activation (CNS NB FOXR2)”, “CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT CIC)”, “CNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET MN1)”, and “CNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET BCOR)”. Our findings reinforce the importance of incorporating molecular information into the next revision of the WHO classification of CNS tumors, and warrant a replacement of the term “CNS PNET” with biologically specific designations. Our study provides an innovative framework for improving diagnostic accuracy and prognostication in malignant CNS tumors. The approach is amenable to retrospective analyses of patients treated with current regimens and will facilitate the design of more meaningful clinical trials for patients with malignant brain tumors. Citation Format: Dominik Sturm, Brent Orr, Umut H. Toprak, Volker Hovestadt, David T.W. Jones, David Capper, Peter Lichter, Andrey Korshunov, Stefan M. Pfister, David W. Ellison, Marcel Kool. Four new brain tumor entities emerge from molecular classification of CNS-PNETs. [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 2696.
ASCENDE-RT*: A multicenter, randomized trial of dose-escalated external beam radiation therapy (EBRT-B) versus low-dose-rate brachytherapy (LDR-B) for men with unfavorable-risk localized prostate cancer.
Authors: W. James Morris, Scott Tyldesley, Howard H Pai, Ross Halperin, Michael R. McKenzie, Graeme Duncan, Gerard Morton, Nevin Murray, Jeremy Hamm
Journal: Journal of Clinical Oncology (2015)

3 Background: This trial compared the efficacy of DE-EBRT and LDR-B for National Comprehensive Cancer Network (NCCN) high and intermediate-risk disease. Methods: A planned sample size of 400 patients were randomized to one of two treatment arms and stratified by risk group. Both arms received 12 months of androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonist plus a non-steroidal anti-androgen for at least 1 month. After 8 months of neo-adjuvant ADT, both arms received whole pelvis EBRT (46Gy/23#). Patients assigned to DE-EBRT (standard arm) then received a conformal EBRT boost (32Gy/16#). Patients assigned to LDR-B (experimental arm) received an Iodine-125 LDR boost prescribed to a minimum peripheral dose of 115Gy. The primary endpoint was relapse free survival (RFS) defined by biochemical criteria using the nadir+2 ng/mL threshold. Time zero was the date of the first LHRH injection. Results: Between Dec 2002 and Sep 2011, 276 high-risk and 122 intermediate-risk patients were accrued at 6 cancer treatment centers. 200 men were assigned to DE-EBRT and 198 to LDR-B. The treatment arms were well balanced in terms of age and known prognostic factors. Median follow up (FU) is 6.5 years; 65 men have &gt;9 years FU. There were 12 major protocol violations in each arm. By intent-to-treat analysis, the 3-, 5-, 7-, and 9-year Kaplan-Meier RFS estimates are 94% vs 94%, 77% vs 89%, 71% vs 86%, and 63% vs 83% for DE-EBRT and LDR-B respectively (hazard ratio = 0.473; 95% CI 0.292 – 0.765; P = 0.0022). Randomization (p&lt;0.001), percent positive cores (p=0.005), initial PSA (p=0.006) and clinical T-stage (p=0.013) were predictive of RFS in a multivariable Cox model. The median PSA at latest FU for non-relapsing patients assigned to LDR-B is 0.02 vs 0.24 ng/mL for DE-EBRT. Conclusions: In a randomized trial, an Iodine-125 LDR boost was much more effective than an EBRT boost in rendering unfavorable-risk prostate cancer patients biochemically disease free. *ASCENDE-RT- Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy is an NCI registered trial (NCT00175396). Clinical trial information: NCT00175396.
Liver kinase B1 regulates hepatocellular tight junction distribution and function in vivo
Authors: Natalie Porat‐Shliom, Amber J. Tietgens, Christina M. Van Itallie, Lynn Vitale‐Cross, Michal Jarnik, Olivia J. Harding, James M. Anderson, J. Silvio Gutkind, Roberto Weigert, Irwin M. Arias
Journal: Hepatology (2016)

Liver kinase B1 (LKB1) and its downstream effector AMP‐activated protein kinase (AMPK) play critical roles in polarity establishment by regulating membrane trafficking and energy metabolism. In collagen sandwich‐cultured hepatocytes, loss of LKB1 or AMPK impaired apical ABCB11 (Bsep) trafficking and bile canalicular formation. In the present study, we used liver‐specific (albumin‐Cre) LKB1 knockout mice (LKB1 −/− ) to investigate the role of LKB1 in the maintenance of functional tight junction (TJ) in vivo . Transmission electron microscopy examination revealed that hepatocyte apical membrane with microvilli substantially extended into the basolateral domain of LKB1 −/− livers. Immunofluorescence studies revealed that loss of LKB1 led to longer and wider canalicular structures correlating with mislocalization of the junctional protein, cingulin. To test junctional function, we used intravital microscopy to quantify the transport kinetics of 6‐carboxyfluorescein diacetate (6‐CFDA), which is processed in hepatocytes into its fluorescent derivative 6‐carboxyfluorescein (6‐CF) and secreted into the canaliculi. In LKB1 −/− mice, 6‐CF remained largely in hepatocytes, canalicular secretion was delayed, and 6‐CF appeared in the blood. To test whether 6‐CF was transported through permeable TJ, we intravenously injected low molecular weight (3 kDa) dextran in combination with 6‐CFDA. In wild‐type mice, 3 kDa dextran remained in the vasculature, whereas it rapidly appeared in the abnormal bile canaliculi in LKB1 −/− mice, confirming that junctional disruption resulted in paracellular exchange between the blood stream and the bile canaliculus. Conclusion : LKB1 plays a critical role in regulating the maintenance of TJ and paracellular permeability, which may explain how various drugs, chemicals, and metabolic states that inhibit the LKB1/AMPK pathway result in cholestasis. (H epatology 2016;64:1317‐1329)