bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5046: Exposure-efficacy (OS) analysis of tremelimumab in unresectable malignant mesothelioma
Authors: Baverel Paul , Roskos Lorin , Tatipalli Manasa , Lee Nancy , Stockman Paul , Taboada Maria , Vicini Paolo , Horgan Kevin , Narwal Rajesh 
Published: July 2017

Abstract
Purpose: Tremelimumab is a fully human anti-CTLA-4 IgG2 monoclonal antibody that enhances human T-cell activation. Tremelimumab was evaluated in a Phase IIb (DETERMINE), randomised, double-blind, placebo-controlled study in patients with unresectable pleural or peritoneal malignant mesothelioma, randomised (2:1) to receive either tremelimumab (10 mg/kg, seven doses Q4W followed by Q12W) or placebo. The study demonstrated no clinically meaningful differences in overall survival (OS). The primary objectives of this analysis were to evaluate the relationship of exposure with OS, and the impact of potential confounders.
Methods: A population PK model was developed to estimate and derive PK exposure metrics (area under the curve at steady state [AUCss] or clearance [CL]) for exposure-OS analysis. Impact of potential confounders was evaluated using graphical and exploratory approaches. Factors including body weight, age, gender, race, ECOG status, anatomical site (pleural or peritoneal), line of therapy, EORTC status, tumour histology, baseline tumour size, LDH, and CRP were evaluated. The analyses were performed using NONMEM 7.2 and R software.
Results: The population PK included 376 patients and 1328 post-first dose PK concentrations. PK was consistent with previous knowledge and low incidence of anti-drug antibodies was observed. A 2-compartment linear PK model adequately described the data. Tremelimumab CL and volume of distribution (V1) were 310 mL/day and 3.85 L, with moderate variability of ~38% and ~32%, respectively. There was an apparent exposure-OS relation when stratified by AUCss. However, at least 3 factors (gender, CRP, and baseline tumour size) were statistically significant PK predictors (p&lt;0.05 on CL) indicating multi-dimensional confounding effect. Higher baseline tumor size, higher CRP levels and males were associated with lower PK exposure of tremelimumab.
Conclusions: The observed apparent exposure-OS relationship is the result of imbalance in prognostic factors impacting OS rather than a true association of exposure with efficacy.
Citation Format: Paul Baverel, Lorin Roskos, Manasa Tatipalli, Nancy Lee, Paul Stockman, Maria Taboada, Paolo Vicini, Kevin Horgan, Rajesh Narwal. Exposure-efficacy (OS) analysis of tremelimumab in unresectable malignant mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5046. doi:10.1158/1538-7445.AM2017-5046
Abstract 5055: Multiplatform metabolomics analysis of growth arrest in pancreatic tumor xenografts
Authors: Wainer Irving W. , Dudzik Danuta , Bernier Michel , Barbas Coral 
Published: July 2017

Abstract
R,S-4-Methoxy-1-naphthylfenoterol, MNF, inhibits the G protein-coupled receptor GPR55. In this study, we determine the effect of MNF on human PANC-1 pancreatic tumor growth in mice and apply multiplatform metabolomics analysis to identify pathways associated with growth arrest.
Methods: Female Balb/c nude mice, 6-8 weeks old, 18-20g, were inoculated subcutaneously with 5 x 106 PANC-1 cells. On Day 8, mice were placed in groups of 10 using random block design based upon tumor volume. Mice received daily ip injections of vehicle or 40mgxkg-1 MNF 5 days/week for 3 treatment cycles. Mice were monitored daily and tumor volumes measured at beginning and end of each dosing cycle. On Day 33, mice were euthanized, and plasma samples and tumors collected. Tumor tissue was homogenized, extracted and analyzed using liquid chromatography-QTOF-MS, capillary electrophoresis-TOF-MS and gas chromatography-EI-Q-MS. Differences between groups were evaluated by unpaired t-test or Mann−Whitney test with post hoc Benjamini-Hochberg correction. Statistical significance was set at P≤0.05. Compound identification was accomplished using online databases and in-house standards
Results Tumor volume increased in vehicle-treated mice by ~700%, 142 ± 8 mm3 to 957 ± 79 mm3 and only ~250% in MNF-treated mice, 143 ± 8 mm3 to 259 ± 27 mm3. On Day 33, MNF was not detected in plasma but accumulated in tumor tissues, 43.9 ± 32.7 ng/g. Plasma L-lactate levels were reduced from 3.29 ± 0.66 mmol/L το 2.81 ± 0.60 mmol/L, P≤0.001. Differences in tumor tissue metabolome were observed with MNF compared to vehicle, which was reflected by significant, P≤0.05, changes in relative metabolite signals. MNF treatment was accompanied by the disruption of pyrimidine nucleotide biosynthesis at uridine 5'-monophosphate, UMP, and increased UMP degradation. Moreover, the +237% increase in ophthalmic acid and +95% increase in its precursor 2-aminobutyrate indicate higher oxidative stress and the +51% increase in 2-hydroxyproline suggest greater HFI-1α proteolysis upon MNF treatment.
Conclusions These results are consistent with our previous observations in PANC-1 cells showing that GPR55 inhibition attenuates activation of the EGFR-MEK-ERK, Wnt-β-catenin and PI3K/AKT pathways resulting in lower cyclin D1 expression and halting the cell cycle in G1. The reduction in HIF-1α expression and glycolytic flux in MNF-treated PANC-1 cells is in line with the decline in L-lactate plasma levels in MNF-treated mice. The data from this study indicate that MNF may be useful in the treatment of pancreatic cancer.
Citation Format: Irving W. Wainer, Danuta Dudzik, Michel Bernier, Coral Barbas. Multiplatform metabolomics analysis of growth arrest in pancreatic tumor xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5055. doi:10.1158/1538-7445.AM2017-5055
Abstract 5062: Development of a first in class inhibitor of BET bromodomains and dopamine receptor 2
Authors: Yoshioka Makoto , Chauhan Jay , Fletcher Steven , Strovel Jeffrey W. 
Published: July 2017

Abstract
ConverGene has developed a first-in-class dual-active small molecule inhibitor that i) inhibits BET family of bromodomain-containing proteins, and ii) antagonizes dopamine receptor D2 (DRD2). BET protein family includes BRD4, an epigenetic reader protein that mediates expression of MYC oncogene. Thus, BRD4 is considered as a cancer therapeutic target to indirectly suppress MYC expression. In addition to being a therapeutic target for psychiatric diseases, DRD2 is emerging as a potential therapeutic target in neuroendocrine tumors, subsets of pancreatic ductal adenocarcinoma and small cell lung cancer. Our lead compound showed high activity in a binding test against BRD4 (Ki = 34 nM); exhibited high bioavailability upon oral administration; profoundly suppressed MYC expression both in vitro and in vivo; inhibited growth of AML and solid tumor cells in xenograft models; potently inhibited both isoforms of DRD2 (IC50 0.1 µM); and interfered with DRD2/β-arrestin/Akt pathway in vitro. Therefore, our BRD4/DRD2 dual-active compounds may hold promise as a novel class of therapeutics that interferes with both cancer growth and maintenance by simultaneously interfering with MYC and DRD2 pathways. We currently are investigating these dual-active compounds in multiple in vitro and in vivo models and expect to report the outcomes at the AACR Annual Meeting in 2017.
Citation Format: Makoto Yoshioka, Jay Chauhan, Steven Fletcher, Jeffrey W. Strovel. Development of a first in class inhibitor of BET bromodomains and dopamine receptor 2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5062. doi:10.1158/1538-7445.AM2017-5062
Abstract 5066: Combination treatment with SAHA and 5-Azacytidine (Decitabine) induces apoptosis and suppresses tumor growth in preclinical models of chondrosarcoma
Authors: Sheikh Tahir , Patwardhan Parag , Schwartz Gary K. 
Published: July 2017

Abstract
Chondrosarcomas are the second most frequently occurring type of bone malignancy, and account for approximately 25% of all bone sarcomas. They are often highly aggressive neoplasms that rapidly progress and eventually recur and give distant metastases. They are largely considered to be resistant to conventional chemotherapy and radiotherapy. Several studies have reported that targeting epigenetic mechanisms including DNA methylation or histone acetylation are novel approaches for the treatment of some human cancers. Previous reports have shown that the interaction of DNA methylation and histone modification regulates gene expression. In the present study, we hypothesized that concurrent inhibition of histone acetylation and DNA methylation could result in decreased viability of chondrosarcoma cells both in vitro and in vivo. To test this, we used a panel of chondrosarcoma cell lines including IDH wild type (CH2879), IDH1 mutant (JJ012) and IDH2 mutant (CS1) cell line. Results from our in vitro proliferation assay showed that combination of sub-IC50 concentrations of the DNA methyltransferase (DNMT) inhibitor Decitabine (5-AZA-dC) and histone deacetylase (HDAC) inhibitor (SAHA) resulted in decreased cell viability of all the three chondrosarcoma cell lines tested when compared to either drug alone. Western blot analysis showed induction of cleaved Poly-ADP Ribose Polymerase (PARP), a known marker of apoptosis. Consistent with augmented DNA damage, combination of Decitabine and SAHA markedly increased the levels of phospho-H2AX, a DNA damage marker, and pro-apoptotic BH3-only proteins such as Bim. Combination treatment also resulted in increased induction of histone acetylation (AcH3) and increased expression of E-Cadherin. Previous reports have shown that E-cadherin is critical for apoptosis and depletion and inhibition of E-Cadherin impairs apoptosis induction via DR4 and DR5 death receptors. To this end, we showed that induction of cleaved PARP by Apo2L/TRAIL stimulation decreased over time when E-Cadherin was knocked down by siRNA. Xenograft studies using IDH2 mutant (CS1) tumor model showed a significant suppression of tumor volume when animals were treated in combination with SAHA and Decitabine compared to single agent treatments. Taken together, our data strongly suggests that combination treatment with SAHA and Decitabine is a novel treatment approach and merits evaluation in the treatment of chondrosarcoma.
Citation Format: Tahir Sheikh, Parag Patwardhan, Gary K. Schwartz. Combination treatment with SAHA and 5-Azacytidine (Decitabine) induces apoptosis and suppresses tumor growth in preclinical models of chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5066. doi:10.1158/1538-7445.AM2017-5066
Abstract 5068: A novel dual action inhibitor of histone deacetylase and demethylase in melanoma
Authors: WU Muzhou , Kalin Jay , Ryu Byungwoo , Cole Philip , Alani Rhoda 
Published: July 2017

Abstract
Epigenetic agents have drawn great attention as anti-cancer therapies, with several HDAC inhibitors approved for a subset of hematologic malignancies. One of the biggest challenges in targeting epigenetic mechanisms of tumorigenesis is the wide spectrum of effects which restrict the therapeutic window for these compounds. We have developed a series of potent small molecule inhibitors with specificity towards the CoREST epigenetic corepressor complex through a dual-action mechanism targeting LSD1 and HDAC1. These compounds show a unique profile of pharmacologic action with an improved therapeutic window in a variety of cell types. Screening of tumor cell lines for growth inhibitory effects revealed variable efficacy in a broad spectrum of cancers with the most consistent and potent effects seen in human melanomas. The growth of a number of melanoma cell lines was found to be potently inhibited by one of these compounds, Corin 2; however, primary human melanocytes were relatively resistant to this agent. Transcriptomic analysis revealed that Corin2 was a more potent inducer of tumor suppressor genes compared to the parent HDAC and LSD1 compounds. Genetic knockdown of CoREST or LSD1 in cancer cell lines abolished the differences in potency of Corin2 vs. the parent HDAC inhibitor, Entinostat, suggesting that Corin2's favorable pharmacologic effects rely on an intact CoREST complex. Corin2 was also effective in slowing tumor growth in a melanoma mouse xenograft model. These dual action inhibitors demonstrate a novel, potent, and specific therapeutic approach to targeting epigenetic pathways in human melanomas which may lead to improved therapeutic benefits in patients with advanced disease.
Note: This abstract was not presented at the meeting.
Citation Format: Muzhou WU, Jay Kalin, Byungwoo Ryu, Philip Cole, Rhoda Alani. A novel dual action inhibitor of histone deacetylase and demethylase in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5068. doi:10.1158/1538-7445.AM2017-5068
Abstract 5073: Determination of sensitivity to BET and HDAC inhibitors in lung cancer cell lines
Authors: Verdura Sara , Torres-Diz Manuel , Sanchez-Cespedes Montserrat 
Published: July 2017

Abstract
Purpose: To determine the sensitivity of lung cancer cell lines to different combinations of BET and HDAC inhibitors and to inquire possible associations with the genetic and molecular profiles.
Methods: A panel of lung cancer cell lines were treated in vitro with BET and HDAC inhibitors. The capability of each compound, administered individually or in combination (IC50), to inhibit cell proliferation was assessed by MTT assays. Drug interaction analysis was performed using Compusyn software. The protein and gene expression levels were determined using western blot and real time PCR, respectively.
Results: We found that about 70% of the cell lines tested were sensitive to BET inhibitors and about 60% responded to HDAC inhibitors. In both cases, increased sensitivity was accompanied by changes in cell morphology, a reduction of the MYC protein levels and an increase in the levels of apoptotic-related markers. We also determined the effects of the combination of these epigenetic treatments in cell growth. Our results showed a synergic effect in about 75% of the cell lines which was also correlated with dramatic changes in cell morphology, in apoptosis and in decreasing the levels of the MYC protein. Finally, we determined the possible correlation of the sensitivity to these epigenetic drugs and the expression levels of some genes implicated in lung carcinogenesis.
Conclusions: Our data showed that lung cancer cells responded to BET and HDAC inhibitors and that the combination of both drugs has a synergistic effect in cell growth inhibition, suggesting that this could be an effective treatment in lung cancer. Our data also point out to certain genes as potential biomarkers to determine sensitivity to these compounds.
Citation Format: Sara Verdura, Manuel Torres-Diz, Montserrat Sanchez-Cespedes. Determination of sensitivity to BET and HDAC inhibitors in lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5073. doi:10.1158/1538-7445.AM2017-5073
Abstract 5075: Phenotypic human tumor cell line profiling and predictive biomarker analysis for epigenetic inhibitors
Authors: Warrior Usha , Parry Jesse J. , Burkart Samantha C. , Cavedine Lee R. , Cracchiolo Alyssa M. , Epkins Brogan A. , Garner Steven M. , Sindelar Timothy J. , Wageman Charles R. , King Alastair J. 
Published: July 2017

Abstract
In recent years, epigenetic target inhibitors have emerged as viable therapeutics for treating various types of cancers. Testing of the epigenetic inhibitors in cell proliferation assays revealed that inhibition of many epigenetic targets resulted in a significantly delayed drug response that is not revealed by conventional, 72-hour cell growth assays. OncoPanel LT™ from Eurofins Pharma Discovery Services is developed specifically for evaluation of compounds with a protracted mechanism of action, and consists of a large collection of cell lines with broad cancer type and subtype representation, and extensive genomic characterization. We have tested decitabine, a DNA methyltransferase inhibitor, panobinostat, a histone deacteylase inhibitor, GSK-343, an EZH2 inhibitor, GSK-J4, a JMJD3/UTX inhibitor, and JQ1, a BRD2/3/4 inhibitor in OncoPanel LT™. These epigenetic inhibitors were incubated for 10 days with more than 200 human tumor cell lines and the inhibition data were analyzed to determine IC50, EC50, and GI50 values. These inhibition data, as well as the genomic features of the cell lines, were utilized to perform univariate genomic analysis to identify predictive biomarkers of response. We will discuss the activity of compounds against this cell line panel, as well as statistically significant biomarkers of response, based on the univariate genomic analysis.
Citation Format: Usha Warrior, Jesse J. Parry, Samantha C. Burkart, Lee R. Cavedine, Alyssa M. Cracchiolo, Brogan A. Epkins, Steven M. Garner, Timothy J. Sindelar, Charles R. Wageman, Alastair J. King. Phenotypic human tumor cell line profiling and predictive biomarker analysis for epigenetic inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5075. doi:10.1158/1538-7445.AM2017-5075
Abstract 5083: A novel and highly efficacious small-molecule degrader of BET-BRD proteins for the treatment of acute leukemia
Authors: Fernandez-Salas Ester , Chen Zhuo , Lin Mei , Zhou Bing , McEachern Donna , Przybranowski Sally , Kump Karson , Peterson Luke F. , Kandarpa Malathi , Hu Jiantao , Xu Fuming , Liu Liu , Bai Longchuan , Wen Bo , Sun Duxin , Talpaz Moshe , Wang Shaomeng 
Published: July 2017

Abstract
The bromodomain and extra-terminal domain (BET-BRD) family of lysine acetylation readers comprises BRD2, BRD3, BRD4, and BRDT that contain two conserved N-terminal bromodomains (BD1 and BD2) and a long C-terminal region containing the extraterminal (ET) protein-protein interaction domain. These proteins have key roles in the assembly of transcriptional regulatory complexes containing RNA polymerase II. BET-BRDs are new therapeutic targets for cancer treatment and several small-molecule BET-BRD inhibitors are currently in clinical development for a diverse set of cancers including leukemia. Based on the proteolysis targeting chimera (PROTAC) concept, we have developed novel and highly potent BET degraders, ZBC246 and ZBC260, with exceptional selectivity based upon a new class of BET inhibitor, ZBC11. ZBC260 effectively degrades all BET-BRD proteins at concentrations as low as 30 pM within a few hours of treatment in the RS4;11 leukemia cell line and achieves IC50 values of 50 pM in inhibition of RS4;11 cell growth. ZBC260 was tested in a panel of 10 acute leukemia cell lines generating IC50s ranging from 20 pM to 1 nM in 4-days cell growth inhibition assays. In contrast to the cytostatic effect observed with BET-BRD inhibition, degradation of BET-BRDs by ZBC246 and ZBC260 induced robust apoptosis demonstrating a differential biology between BET-BRD inhibitors and BET-BRD degraders. Significantly, ZBC260 induces rapid regression of RS4;11 xenograft tumors without overt signs of toxicity in mice. More importantly, treatment of leukemia cells obtained from 10 patients with ZBC260 demonstrated efficient degradation of BET-BRDs within 5 h at 0.3 nM, while treatment with the inhibitor (300 nM) induced up-regulation of BET-BRDs. Treatment of patients’ peripheral blasts with ZBC260 at 1 to 10 nM induced remarkable levels of apoptosis within 24 h, even in relapsed and refractory patient samples. In conclusion, ZBC260 represents a highly potent and efficacious BET-BRD degrader undergoing extensive preclinical evaluation for the treatment of acute leukemias.
Citation Format: Ester Fernandez-Salas, Zhuo Chen, Mei Lin, Bing Zhou, Donna McEachern, Sally Przybranowski, Karson Kump, Luke F. Peterson, Malathi Kandarpa, Jiantao Hu, Fuming Xu, Liu Liu, Longchuan Bai, Bo Wen, Duxin Sun, Moshe Talpaz, Shaomeng Wang. A novel and highly efficacious small-molecule degrader of BET-BRD proteins for the treatment of acute leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5083. doi:10.1158/1538-7445.AM2017-5083
Abstract 5086: Chronic radiation induced uPA expression mediates neuroblastoma cells survival
Authors: Gnanamony Manu , Fernández Karen , Libes Jaime , Lin Julian , Joseph Pushpa A. , Gondi Christopher S. 
Published: July 2017

Abstract
Neuroblastoma accounts for more than 15% of cancer-related deaths of children in the United States. Despite aggressive treatment regimens, the long-term survival for these children remains less than 40%. The urokinase plasminogen activator (uPA) system plays a role in several critically important biology processes, such as cell adhesion, migration, proliferation and survival. This system includes uPA, a serine protease which converts a zymogen plasminogen into the active serine protease plasmin, its surface receptor uPAR/CD57, which binds uPA with high affinity, facilitates proteolytic activation/conversion of uPA precursor (single-chain uPA, scuPA) into the active two-chain uPA protease (tcuPA) and mediates uPA-induced activation of several intracellular signaling cascades, and protects against several inhibitors, e.g. PAI-1, among others. Recent findings demonstrate that dividing/proliferating cells translocate intact scuPA to the nucleus via the nucleocytoplasmic shuttle protein nucleolin. In this study we demonstrate that both SKNBE(2) and NB1691 neuroblastoma cells when exposed to chronic radiation suppresses nMYC gene copy number and induces the overexpression of cMYC and uPA expression levels without observable change in uPA gene copy number. Increased uPA expression was accompanied with increase in the mitochondrial mass (4 fold in both NB1691 and SKNBE (2) cells). Knockdown of uPA expression in chronic radiation cells using siRNA resulted in reduced cell survival. RT-PCR analysis shows that uPA knockdown resulted in reduced expression of cMYC and its target genes cyclin A and cyclin D1. Overexpression of uPA in both SKNBE(2) and NB1691 wildtype cells resulted in increased cMYC and cyclin D1 expression but not nMYC expression suggesting that cMYC may be specifically regulated by uPA. In conclusion, our study shows that uPA plays a vital role in survival of neuroblastoma cells treated with chronic radiation by associating with cMYC to compensate for loss of nMYC expression. Our study also implies that targeting uPA might be a viable option as a combination therapy in the treatment of high-risk neuroblastoma.
Citation Format: Manu Gnanamony, Karen Fernández, Jaime Libes, Julian Lin, Pushpa A. Joseph, Christopher S. Gondi. Chronic radiation induced uPA expression mediates neuroblastoma cells survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5086. doi:10.1158/1538-7445.AM2017-5086