bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I First-in-Human Study of CUDC-101, a Multitargeted Inhibitor of HDACs, EGFR, and HER2 in Patients with Advanced Solid Tumors
Authors: Shimizu Toshio , LoRusso Patricia M. , Papadopoulos Kyri P. , Patnaik Amita , Beeram Muralidhar , Smith Lon S. , Rasco Drew W. , Mays Theresa A. , Chambers Glenda , Ma Anna , Wang Jing , Laliberte Robert , Voi Maurizio , Tolcher Anthony W. 
Published: August 2014

Abstract
Purpose: This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-hour intravenous (i.v.) infusion for 5 consecutive days every 2 weeks.
Experimental Design: Twenty-five patients with advanced solid tumors received escalating doses of CUDC-101 (range, 75–300 mg/m2/day) following a standard 3 + 3 dose escalation design.
Results: The MTD was determined to be 275 mg/m2. Common grade 1/2 adverse events included nausea, fatigue, vomiting, dyspnea, pyrexia, and dry skin. DLTs occurred in 1 patient in the 275-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 1) and 3 patients in the 300-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 2; pericarditis, n = 1), all of which were transient and reversible. CUDC-101 exposure increased linearly with the mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vdss), area under curve (AUC), and terminal elimination half-life (t1/2) at the MTD dose of 9.3 mg/L, 51.2 L/h, 39.6 L, 9.95 h·ng/mL and 4.4 hours, respectively. Acetylated histone H3 induction was observed in posttreatment skin samples from 3 patients in the 275-mg/m2 dose cohort, suggesting adequate systemic exposure and target inhibition. One patient with gastric cancer had a partial response and 6 patients had stable disease.
Conclusion: CUDC-101 administered by 1-hour i.v. infusion for 5 consecutive days every 2 weeks was generally well tolerated with preliminary evidence of antitumor activity. A dose of 275 mg/m2 is recommended for further clinical testing. Clin Cancer Res; 20(19); 5032–40. ©2014 AACR.
Phase II Study of Bevacizumab, Temozolomide, and Hypofractionated Stereotactic Radiotherapy for Newly Diagnosed Glioblastoma
Authors: Omuro Antonio , Beal Kathryn , Gutin Philip , Karimi Sasan , Correa Denise D. , Kaley Thomas J. , DeAngelis Lisa M. , Chan Timothy A. , Gavrilovic Igor T. , Nolan Craig , Hormigo Adilia , Lassman Andrew B. , Mellinghoff Ingo , Grommes Christian , Reiner Anne S. , Panageas Katherine S. , Baser Raymond E. , Tabar Viviane , Pentsova Elena , Sanchez Juan , Barradas-Panchal Renata , Zhang Jianan , Faivre Geraldine , Brennan Cameron W. , Abrey Lauren E. , Huse Jason T. 
Published: August 2014

Abstract
Purpose: Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab.
Experimental Design: Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1.
Results: Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84–100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P &lt; 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT.
Conclusions: This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non–IDH-1–mutated glioblastoma. Clin Cancer Res; 20(19); 5023–31. ©2014 AACR.
Abstract A13: Molecular profiling of low grade serous ovarian tumors
Authors: Hunter Sally M. , Gorringe Kylie L. , Anglesio Michael S. , Sharma Raghwa , Chiew Yoke-Eng , Moss Phillip , Stephens Andrew , Gilks C Blake ,   Group Australian Ovarian Cancer Study, Hunstman David , deFazio Anna , Campbell Ian 
Published: August 2014

Abstract
Borderline ovarian tumors fill an unusual niche between completely benign tumors and frank malignancies. These tumors tend to follow a relatively benign clinical course; however, they can recur as low grade serous carcinoma. Tumor features such as invasive implants and micropapillary growth pattern have been proposed to separate serous borderline tumors (SBTs) with invasive-like behaviour from SBTs with benign behaviour. It is currently unknown whether these features are associated with specific molecular events and whether molecular profiling of borderline tumors could offer a significant improvement of predicting likelihood of recurrence and progression.
This study aimed to perform genome-wide high-resolution molecular analysis of a large cohort of serous borderline ovarian tumors (n=57), employing copy number analysis and mutation screening, and compared these to a cohort of low grade serous carcinomas (n=19).
Clinical features such as tumor stage and laterality were found to correlate with the identity of the underlying oncogenic driver mutation, as were the presence or absence of genomic copy number aberrations and the presence of specific copy number aberrations in the SBT cohort. Comparison of genomic aberrations in SBTs to low grade serous carcinomas (LGSCs) identified loss of heterozygosity events that were very significantly enriched in carcinomas.
In conclusion, we have identified correlations between the specific oncogenic mutation a tumor carries and tumor characteristics such as level of genomic aberration and spread beyond the ovary. These findings are consistent with previous reports that specific oncogenic mutations may have a better prognosis in low grade serous tumors. Identifiable correlations between molecular events and tumor characteristics suggest it will be possible to use patient-specific tumor characteristics to better define a suitable level of treatment and follow-up. This is an important consideration as although patients have a very good short term prognosis, over an extended period recurrence and progression of SBTs to LGSCs is not insignificant and later stage LGSCs are relatively chemoresistant.
Citation Format: Sally M. Hunter, Kylie L. Gorringe, Michael S. Anglesio, Raghwa Sharma, Yoke-Eng Chiew, Phillip Moss, Andrew Stephens, C Blake Gilks, Group Australian Ovarian Cancer Study, David Hunstman, Anna deFazio, Ian Campbell. Molecular profiling of low grade serous ovarian tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A13.
Abstract A46: Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis
Authors: Vigliotti Michele , Lum Elena , Banerjee nilanjana , Cutter Noelle , Wrzeszczynski Kazimierz O. , Khan Sohail , Kamalakaran Sitharthan , Levine Douglas A. , Dimitrova Nevenka , Lucito Robert 
Published: August 2014

Abstract
Ovarian cancers are highly heterogeneous and while chemotherapy is the preferred treatment many patients are intrinsically resistant or quickly develop resistance. Furthermore, all tumors that recur ultimately become resistant. Recent evidence suggests that epigenetic deregulation may be a key factor in the onset and maintenance of chemoresistance. Epigenetic events are reversible and the identification of genes altered by this mechanism may lead to studies on how to reprogram the process leading up to resistance. We set out to identify epigenetically silenced genes that affect chemoresistance. The epigenomes of a total of 45 ovarian samples were analyzed to identify epigenetically altered genes that segregate with platinum response, and further filtered with expression data to identify genes that were suppressed. A tissue culture carboplatin resistance screen was utilized to functionally validate this set of candidate platinum resistance genes. Our screen identified a number of genes that when suppressed altered the chemoresistance of the cells in culture. One of the validated candidate genes identified through the pooled shRNA screen was DOK2, an adapter protein downstream of tyrosine kinase, which has been shown by others to be a lung cancer tumor suppressor. We show that suppression of DOK2 by short hairpin RNAs in ovarian cell lines conferred resistance to platinum treatment. Functional analysis of loss of DOK2 effect on chemoresistance determined that there was no change in growth or influx or efflux of carboplatin. However, we determined that loss of DOK2 increased growth in soft agar and also increased migratory capabilities. Furthermore the loss of DOK2 decreased the level of apoptosis in response to carboplatin. Furthermore, in cells with reduced DOK2, the level of anoikis was decreased. We have developed a screening methodology that analyzes the epigenome and informatically identifies candidate genes followed by in vitro culture screening of the candidate genes. To validate our screening methodology we further characterized one candidate gene, DOK2, and showed that loss of DOK2 induces chemotherapy resistance by decreasing the level of apoptosis in response to treatment.
Citation Format: Michele Vigliotti, Elena Lum, nilanjana Banerjee, Noelle Cutter, Kazimierz O. Wrzeszczynski, Sohail Khan, Sitharthan Kamalakaran, Douglas A. Levine, Nevenka Dimitrova, Robert Lucito. Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A46.
Abstract B11: Expression analysis of 2D versus 3D culture growth in HEY ovarian cancer cells
Authors: Lotito Trillitye , Powell Chase , Menzie Christopher , Aiosa Candice , Cheng Feng , Westerheide Sandy 
Published: August 2014

Abstract
Human tissue culture has many uses in cancer research. For example, this technique allows for a simple method of testing potential anti-cancer drugs. However, standard 2D cell culture seldom yields the same results in clinical testing. This may be due to the cell culture being exposed to a much different environment than what can be found at its site of origin, including the cellular interactions found in a 3D tumor. A cell culture spheroid model can alleviate some of these issues, creating a 3D version of the culture which more closely represents the cellular conditions experienced by a tumor. We were interested in determining which genes are most affected by 3D growth. Here, we have performed expression analysis on 2D versus 3D HEY ovarian cancer cells. Interestingly, we show that expression of many chaperone genes are increased in 3D growth conditions. This may be due to increased proteotoxic stress encountered by cells grown in spheroids. Future work will analyze the significance of chaperones and the heat shock response in 3D growth of ovarian cancer cells.
Note: This abstract was not presented at the conference.
Citation Format: Trillitye Lotito, Chase Powell, Christopher Menzie, Candice Aiosa, Feng Cheng, Sandy Westerheide. Expression analysis of 2D versus 3D culture growth in HEY ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B11.
Abstract B22: Genomic and functional analysis of gene amplification in high-grade serous and endometrioid ovarian cancer
Authors: Davis Sally J. , Simpson Kaylene J. , Campbell Ian G. , Gorringe Kylie L. 
Published: August 2014

Abstract
Copy number amplification is a hallmark of oncogene-associated tumor development and progression. The targeted increase in copy number of such chromosomal regions has a significant impact upon gene expression that imparts selective advantages on cancer cells. These genes are attractive therapeutic targets.
To identify amplicon targets we adopted a methodology that combines genomic copy number with RNAi to identify amplified genes that are functionally relevant in ovarian cancer. Analysis of SNP array data for a cohort of ~400 tumors identified ~300 genes amplified at a high level in 10% or more of cases. We utilized SNP array data from a panel of 39 ovarian tumor cell lines to identify 18 cell lines that recapitulate the gene amplifications observed in the clinical specimens. The set of candidate genes has been functionally assessed in these cell lines using a boutique siRNA library to interrogate phenotypic alterations in cellular viability.
Data collected from the screen identified a number of genes and pathways with potential therapeutic value including URI1, GAB2, PAK4 and DYRK1B. We have assessed the therapeutic utility of PAK4 and DYRK1B using targeted small molecule inhibitors using gene amplification as a marker for response. Our preliminary in vitro data indicates that amplification of PAK4 can lead to a marked response to PF-3758309, an ATP-competitive, pyrrolopyrazole inhibitor of PAK4.
The results from this study provide strong evidence for the value of focused functional genomic screening. It has been demonstrated that combining high-throughput technologies has the potential to rapidly identify candidate driver genes that may then be streamlined to a translational phase.
Citation Format: Sally J. Davis, Kaylene J. Simpson, Ian G. Campbell, Kylie L. Gorringe. Genomic and functional analysis of gene amplification in high-grade serous and endometrioid ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B22.
Abstract B26: Non-catalytic effects of PARP inhibitors in the context of cell cycle and homology-directed DNA damage repair
Authors: Jelinic Petar , Levine Douglas A. 
Published: August 2014

Abstract
Background: Poly (ADP)-ribose polymerase inhibitors (PARPis) target PARPs, the stress sensing proteins that respond to DNA single-strand breaks. PARP inhibition has been extensively explored in pre-clinical and clinical studies with successes demonstrated in homology-directed DNA damage repair (HDR) pathway-deficient ovarian cancer patients. The inhibitory potential of PARPis is well established; however non-catalytic effects that may add to their therapeutic properties are not fully understood. Our objective was to comparatively evaluate non-catalytic inhibitory properties, particularly in the context of cell cycle and HDR, of the most widely tested PARPis in pre-clinical and clinical studies, olaparib and veliparib.
Methods: To measure DNA damage repair activity upon PARPi treatment, we used a well-established DR-GFP reporter assay in two model cell lines, U2OSDR-GFP and H1299DR-GFP. Cell cycle progression was assessed by staining with propidium iodide and monitored by flow cytometry. Depletion of p53 in U2OSDR-GFP cells was performed by standard siRNA knock-down technique using electroporation for transfection. Immunoblotting was used to confirm cell cycle results and demonstrate replicative stress on the protein expression levels.
Results: We found a dramatic decrease in DNA damage repair activity in olaparib versus veliparib-treated U2OSDR-GFP cells, regardless of their inhibitory potency. This decrease in HDR activity was a result of olaparib triggering a cell cycle arrest-like state as a response to strong replicative stress. Lack of the same effect in p53-null H1299DR-GFP cells suggests that olaparib's effect is p53-dependent, which was confirmed in U2OSDR-GFP cells depleted of p53. Our data also suggest that cells treated with veliparib are more ambivalent towards p53 status, a difference in comparison to olaparib-treated cells.
Conclusion: These data demonstrate that olaparib and veliparib differ in their non-catalytic inhibitory effects, with olaparib but not veliparib mitigating DNA damage repair activity via cell cycle arrest-like effects in a p53-WT background. This new insight into olaparib's and veliparib's mechanism of action should be considered when developing inclusion criteria for treatment of ovarian cancer patients with these PARP inhibitors or others.
Citation Format: Petar Jelinic, Douglas A. Levine. Non-catalytic effects of PARP inhibitors in the context of cell cycle and homology-directed DNA damage repair. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B26.
Abstract B49: The role of oxidative stress in the development of cisplatin resistance in epithelial ovarian cancer
Authors: Belotte Jimmy , Fletcher Nicole , Awonuga Awoniyi , Alexis Mitchell , Abu-soud Husam , Diamond Michael , Saed Mohammed , Saed Ghassan 
Published: August 2014

Abstract
Objective: To investigate the role of oxidative stress in the development of cisplatin resistance in epithelial ovarian cancer (EOC).
Methods: Two parent EOC cell lines (MDAH-2774 and SKOV-3) and their chemoresistant counterparts were used. Total RNA was extracted and subjected to real-time RT-PCR to evaluate the expression of inducible nitric oxide synthase (iNOS) and glutathione reductase (GSR) in all cells. Nitrate/nitrite levels and GSR activity were also measured using colorimetric and ELISA assays respectively. Cell proliferation was assessed using Ki-67 immunostaining in all cells. Unpaired t-tests were used for statistical analysis at p-value &lt;0.05 for significance.
Results: Both EOC cisplatin sensitive cells manifested significant increase in the expression and activity of GSR as compared to their resistant counterparts (p&lt;0.05). On the other hand, EOC sensitive cells manifested a decrease in iNOS expression as compared to their resistant counterparts (p&lt;0.05). Nitrate/nitrite levels were significantly decreased in EOC sensitive cells as compared to their resistant counterparts (p&lt;0.05). Ki-67 immunofluorescence staining revealed increased proliferation in cisplatin resistant cells compared to controls for the MDAH-277a and SKOV-3 cell lines.
Conclusion: Our data suggests that the development of cisplatin resistance heighten the prooxidant state in EOC leading to a further increase in cell proliferation.
Citation Format: Jimmy Belotte, Nicole Fletcher, Awoniyi Awonuga, Mitchell Alexis, Husam Abu-soud, Michael Diamond, Mohammed Saed, Ghassan Saed. The role of oxidative stress in the development of cisplatin resistance in epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B49.
Abstract B51: Management of ascites via the alfa-pump closed system in platinum-resistant-ovarian-cancer (PROC): A model of sequential non-invasive tumor-cell sampling through the urinary bladder
Authors: Fotopoulou Christina , Spiers Laura , Adjogatse Delali , Pickford Emily , Dina Roberto , Blagden Sara , Habib Nagy , Gabra Hani 
Published: August 2014

Abstract
Background: Malignant ascites in PROC is a therapeutic dilemma. The Sequana-Medical alfapump-System (AP), a remotely controlled device connecting the patients'peritoneal cavity to their urinary bladder, has been evaluated for ascites in liver cirrhosis, but not as yet for malignant ascites.
Methods: We implanted the AP in the peritoneal cavity of two heavily pretreated PROC-patients (67y and 70y) who required repetitive ascites drainages monthly. We cross correlated the electronic download of recorded volume pumped (intraperitoneally→bladder) with weekly ultrasound, monthly cystoscopies and QoL-evaluation. Early morning urine for evaluation of cytology and tumor-cell molecular analysis was collected weekly.
Results: The implantation was under general anesthesia in a 60- and 35-minute procedure. The pump, draining 350ml – 500ml ascites/day successfully drained the ascites to dryness after 3 days (1stpatient) and 8 days (2ndpatient). The patients did not report pollakiuria or dysuria, merely an increased micturition volume. The 1st patient died of disease progression 2 months later; the 2nd patient we noticed a gradual amelioration of peripheral edemas and overall performance-status within 3 weeks after insertion and was able to commence weekly chemotherapy with paclitaxel. Histopathological analysis of the urine revealed rich malignant cell content; this was used to create FFPE-cell-blocks for molecular- pathological profiling with sequential Caris-Target-Now-analysis and full exome-sequencing. QoL as measured by the EORTC QlQ-C30 and EORTC QLQ-OV28 showed high interindividual differences and only minimal influence by the pump.
Conclusion: This innovative approach addresses an area of unmet need for the control of malignant ascites and provides a non-invasive method of collecting tumor tissue for continuous molecular tumor characterization. A EUTROC-multicenter randomized-trial (AMAZE) is planned for evaluation of clinical and translational implications in PROC.
Citation Format: Christina Fotopoulou, Laura Spiers, Delali Adjogatse, Emily Pickford, Roberto Dina, Sara Blagden, Nagy Habib, Hani Gabra. Management of ascites via the alfa-pump closed system in platinum-resistant-ovarian-cancer (PROC): A model of sequential non-invasive tumor-cell sampling through the urinary bladder. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B51.