bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 99: Identification of G9a inhibitors by AlphaLisa™ technology and hit confirmation using MT-Glo™
Authors: Fromond Claudia , Espanel Xavier , Chene Laurent , Masson Philippe , Boubia Benaïssa , Montalbetti Christian , Broqua Pierre 
Published: August 2015

Abstract
Epigenetic processes control gene expression and play a major role in cell proliferation, survival and differentiation. Dysregulation of epigenetic mechanisms may lead to alterations in gene expression, resulting in cellular transformation and malignant outgrowth. Epigenetic enzymes are recognized as promising therapeutic targets for the treatment of cancer. Inventiva has several research programs in epigenetics, with specific focus on histone lysine methyltransferases (HKMTs). Emerging evidence suggests that G9a, a HKMT, able to mono and dimethylate H3K9 leading to the inactivation of tumor suppressor genes, plays a predominant role in lung and ovarian cancers. To identify novel G9a inhibitors, we used an AlphaLisa assay, with a histone H3-derived peptide and a specific antibody against H3K9me2. The assay, in 384-well format, displayed a robust Z-factor (0.84) with a signal to noise ratio around 800. We screened Inventiva's proprietary compound library using this assay. Three hundred thirty-six hits inhibited G9a by more than 60% (Hit rate: 0.14%). Despite the advantages offered by AlphaLisa technology, such as high S/N ratios and straightforward automation, this technology has been reported to generate a high number of false positives. In order to confirm the activity of our hits, we used a different technology, the methyltransferase Glo (MT-Glo) assay, which measures the reaction product SAH by luminescence read-out. Out of the 336 identified compounds, 75 were confirmed by this orthogonal screening (Hit confirmation rate: 22%). Additional compound characterization is ongoing to allow the selection of the best hit series for chemical optimization.
In conclusion, the AlphaLisa assay, coupled with MT-Glo assay allowed the identification and confirmation of potent hits against G9a, as chemical starting points for our hit-to-lead optimization program.
Citation Format: Claudia Fromond, Xavier Espanel, Laurent Chene, Philippe Masson, Benaïssa Boubia, Christian Montalbetti, Pierre Broqua. Identification of G9a inhibitors by AlphaLisa™ technology and hit confirmation using MT-Glo™. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 99. doi:10.1158/1538-7445.AM2015-99
Abstract CT119: Early results from a phase II study of RRx-001, a novel, triple epigenetic inhibitor, showing resensitization to irinotecan in colorectal cancer
Authors: Reid Tony , Fisher George , Carter Corey , Cho-Phan Cheryl , Kunz Pamela , Oronsky Bryan , Fanger Gary R. , Caroen Scott , Parker Christopher , Scicinski Jan 
Published: August 2015

Abstract
Background: Resistance acquisition to standard therapy in advanced colon cancer leads to poor patient survival. Epigenetic therapies can potentially reverse the chemoresistant phenotype. RRx-001, a novel ROS-mediated epigenetic modifier may resensitize to irinotecan-based therapies and increase overall survival compared to standard third-line regorafenib.
Methods: The phase II ROCKET study evaluates a sequential rechallenge to irinotecan-based therapies after RRx-001 or regorafenib. Patients with an ECOG PS 0-1 with irinotecan-refractory metastatic colorectal cancer who progressed on oxaliplatin-, and irinotecan-based regimens with or without bevacizumab, cetuximab or panitumumab are randomized 2:1 to receive RRx-001 16.5 mg/m2 IV 1x/week or regorafenib 160 mg orally 21 of 28 days until progression or unacceptable toxicity followed by treatment with refractory irinotecan-based therapies. The primary end point is overall survival with secondary endpoints to investigate resensitization. The study is planned to accrue approx. 190 patients and recruitment is ongoing.
Study Status and Results: To date, 23 patients have been randomized with 10 patients evaluable for resensitization. Post RRx-001 patients demonstrated marked decreases in CEA in all 6 patients as compared to 4 patients receiving regorafenib who were too systemically unwell to proceed to subsequent treatment.
Conclusions: Early results in this study suggest that resensitization to irinotecan-based therapies mediated by RRx-001, a systemically non-toxic novel epigenetic inhibitor, may be a general effect. These early results are intriguing and may predict for increased overall survival, adding an additional regimen after disease progression. The trial is continuing.
Citation Format: Tony Reid, George Fisher, Corey Carter, Cheryl Cho-Phan, Pamela Kunz, Bryan Oronsky, Gary R. Fanger, Scott Caroen, Christopher Parker, Jan Scicinski. Early results from a phase II study of RRx-001, a novel, triple epigenetic inhibitor, showing resensitization to irinotecan in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT119. doi:10.1158/1538-7445.AM2015-CT119
Abstract CT130: Intravenous chemotherapy plus intraperitoneal perfusion chemotherapy for gastric cancer: A systematic review and meta-analysis
Authors: Yang Sheng , Feng Rui , Pan Zhangchi , Jiang Tao , Xu Qian , Chen Qiang 
Published: August 2015

Abstract
Purpose: This a review of randomized controlled trials (RCTs) of intravenous (IV) with or without intraperitoneal (IP) chemotherapy in patients with gastric cancer to determine the impact on effect and safety.
Methods: Databases, including Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Current Controlled Trials, and CINAHL were electronically searched for RCTs up to June 2013, and relevant references of the included articles were also manually searched. Two authors independently searched articles, extracted data, and assessed the quality of included studies. Meta-analyses were performed on the included data, for the outcomes survival rate, metastasis rate and adverse events. The Grading of Recommendations Assessment, Development and Evaluation System was used to rate the level of evidence.
Results: Five RCTs involving 1072 patients were included. Overall, a significant improvement in overall survival rate [relative risk (RR) = 1.21, 95% confidence interval (95% CI) 1.13 to 1.29, P&lt;0.01], one-year survival rate (RR = 1.10, 95% CI 1.04 to1.17, P = 0.005), three-year survival rate (RR = 1.22, 95% CI 1.11 to1.35, P = 0.001), and five-year survival rate (RR = 1.42, 95% CI 1.12 to 1.80, P = 0.004) were associated with IV plus IP chemotherapy. Meta-analysis demonstrated that metastasis rate can be effectively decreased (RR = 0.35, 95% CI 0.25 to 0.50, P&lt;0.01) but incidence of adverse events were increased using IV plus IP chemotherapy.
Conclusion: IV plus IP chemotherapy in patients with gastric cancer is associated with improved overall survival and prevented distant or peritoneal metastasis. However, increased risk of neutropenia, peripheral edema and neuropathy are also demonstrated.
Citation Format: Sheng Yang, Rui Feng, Zhangchi Pan, Tao Jiang, Qian Xu, Qiang Chen. Intravenous chemotherapy plus intraperitoneal perfusion chemotherapy for gastric cancer: A systematic review and meta-analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT130. doi:10.1158/1538-7445.AM2015-CT130
Abstract CT306: Radiolabeled anti-PSMA antibody J591 immunotherapy is associated with favorable circulating tumor cell (CTC) count control in men with castration-resistant prostate cancer
Authors: Date Pravin , Karir Beerinder S. , Batra Jaspreet S. , Jhanwar Yuliya , Beltran Himisha , Nanus David M. , Bander Neil H. , Tagawa Scott T. 
Published: August 2015

Abstract
Background: J591 is a monoclonal antibody that selectively binds to prostate-specific membrane antigen (PSMA). Prospective phase I and II trials with therapeutic radiolabeled 177Lu-J591 have shown favorable PSA decline rates. Additionally, our group has previously reported that non-invasive evaluation of PSMA expression by imaging with planar gamma camera imaging is associated with response and survival. Initial anecdotal experience showed declines in CTC counts which led to prospective study.
Methods: Three clinical trials of 177Lu-J591 in men with metastatic CRPC have included prospective evaluation of CTC counts (CellSearch methodology) prior to and following therapy (single-dose 177Lu-J591, fractionated-dose 177Lu-J591, and fractionated-dose 177Lu-J591 + docetaxel). Based upon prior experience of J591-based therapy without an effector molecule as immunotherapy, and an anecdotal report of CTC count decline following a low (imaging) dose of J591 without an effector molecule, a cohort of patients who received J591 without 177Lu labeling was also retrospectively analyzed.
Results: 44 pts unselected for PSMA expression received 177Lu-J591 therapy had prospectively measured CTC counts. 39 of 44 pts (88.6%) had imaging evidence of PSMA expression. 57% of pts had baseline unfavorable (≥ 5 cells/7.5 mL) CTC counts. Of overall evaluable pts, 72.4% had decline in CTC counts (7.5 to 100% decline), with 50% of those with unfavorable baseline counts converting to favorable counts at 4-6 weeks. 17.1% with undetectable CTC counts remained undetectable at follow up. 7 pts with mCRPC and elevated CTC counts who received low-dose (naked J591) prior to imaging were also identified, and 4 (57%) of these pts demonstrated CTC count decline.
Conclusion: In addition to previously reported PSA declines, treatment with 177Lu-J591 is associated with favorable CTC count decline in men with metastatic CRPC. Infusion with unlabeled J591 may also lead to CTC count clearance. Based on this finding, we are planning a prospective clinical trial with unlabeled (naked) J591 in men with metastatic CRPC and unfavorable CTC counts.
Citation Format: Pravin Date, Beerinder S. Karir, Jaspreet S. Batra, Yuliya Jhanwar, Himisha Beltran, David M. Nanus, Neil H. Bander, Scott T. Tagawa. Radiolabeled anti-PSMA antibody J591 immunotherapy is associated with favorable circulating tumor cell (CTC) count control in men with castration-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT306. doi:10.1158/1538-7445.AM2015-CT306
Abstract CT309: Rapid evaluation of a novel small molecule cMet tyrosine kinase inhibitor in healthy subjects
Authors: Millington A Dawn , Chaplan Sandra R. , Aguilar Zuleima , Fisher Dennis M. , Collier Jo , Mata Marielena , Mannens Geert , Goyvaerts Nico , Peddareddigari Vijay , Takimoto Chris 
Published: August 2015

Abstract
Inhibiting cMet has potential therapeutic value in oncology. The Janssen WAVE Early Development unit, a team focused on efficient proof-of-concept evaluations, sought to rapidly assess the safety, pharmacokinetics, and pharmacodynamics of a novel, highly selective small molecule cMet TK inhibitor with a favorable preclinical safety profile. We conducted a placebo-controlled, randomized, double blind single ascending dose and multiple dose trial in 84 healthy males at Quotient Clinical LTD (UK). The trial design was adaptive in several respects: to expedite determination of an optimal formulation and to maintain sufficient systemic exposure to sustain target inhibition. In the single ascending dose phase, doses ranged from 6-350 mg, with early transition from a solution to capsule formulation at 18 mg. Two multiple dose cohorts received 60 mg twice daily for 7 days (inter-dose intervals of 4.5 and 12 hours). Target engagement biomarkers were plasma hepatocyte growth factor and soluble cMet. Evaluation of renal safety was of particular interest.
Clinical evaluation, including both single ascending and multiple dose phases, was completed in only 6 months. All doses were safe and well tolerated. Pharmacokinetic analysis revealed dose-proportional increases in exposure. Dose escalation was limited by concentrations of a major metabolite that approached the ceiling established in preclinical toxicology studies. Renal toxicity was not identified.
Initial evaluation of this oncology drug in healthy subjects offered the advantages of rapid trial enrollment and completion, robust placebo comparison data, absence of concomitant illness or laboratory abnormalities, rapid dose escalation in a carefully-monitored, controlled setting, a thorough preliminary safety evaluation, and reduced costs. This approach, enabled by the acceptable preclinical safety profile of the compound, efficiently produced high quality clinical safety and pharmacokinetic data to support compound progression decisions.
Citation Format: A Dawn Millington, Sandra R. Chaplan, Zuleima Aguilar, Dennis M. Fisher, Jo Collier, Marielena Mata, Geert Mannens, Nico Goyvaerts, Vijay Peddareddigari, Chris Takimoto. Rapid evaluation of a novel small molecule cMet tyrosine kinase inhibitor in healthy subjects. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT309. doi:10.1158/1538-7445.AM2015-CT309
Abstract CT313: Phase Ib trial of dodecafluoropentane as a radiation sensitizer during chemoradiation for glioblastoma
Authors: Lickliter Jason , Ruben Jeremy , Longacre Olivia , Wilson David , Unger Evan 
Published: August 2015

Abstract
Purpose: Using post-resected glioblastoma multiforme (GMB) patients to evaluate the pharmacokinetics, safety and potential survival benefit of Dodecafluoropentane emulsion (DDFPe) in combination with the current standard of care; radiation therapy (RT) and temozolomide (TMZ). Glioblastoma multiforme (GBM) is known to be a hypoxic tumor. Tumor hypoxia limits response to RT. DDFPe is an oxygen therapeutic (OT) which transports more than 100x more oxygen as other tested fluorocarbons OT’s. Studies in tumor xenografts show that DDFPe increases tumor pO2 by up to 400% and mitigates radiation resistance.
Methods: Previously untreated GBM patients with post-resected residual tumor visible on MRI post surgery were enrolled. Patients received standard RT (60 Gray in 30 fractions over 6 weeks) with concurrent and adjuvant TMZ. In addition, DDFPe was infused intravenously over 30 minutes immediately prior to each fraction of RT while patients simultaneously breathed carbogen (98%O2:2% CO2). DDFPe was dosed using an accelerated titration design with 1 patient per dose level. Blood samples were drawn to evaluate DDFP pharmacokinetics. Objective tumor responses were assessed with gadolinium-enhanced MRI scans and RANO criteria, and tissue oxygen level dependent (TOLD) MRI was employed as an exploratory biomarker of tumor oxygenation.
Results: Two patients have been enrolled to date. The first patient received DDFPe at 0.05 cc/kg and completed chemoradiation and 2 cycles of adjuvant TMZ with dose reduction or delay. Therapy was well tolerated except for transient grade 3 ALT elevation during recovery from chemoradiation. A post-radiation MRI scan showed stable disease. The second patient has completed a regimen of chemoradiation in combination with DDFPe at 0.1 cc/kg.
Conclusions: DDFPe administration prior to each radiation fraction during standard chemoradiation of GBM is feasible. Further dose escalation od DDFPe is planned to establish a maximum tolerated dose and recommended dose for an envisioned Phase IIb multi-center GBM trial of DDFPe in combination with the accepted standard of care.
Citation Format: Jason Lickliter, Jeremy Ruben, Olivia Longacre, David Wilson, Evan Unger. Phase Ib trial of dodecafluoropentane as a radiation sensitizer during chemoradiation for glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT313. doi:10.1158/1538-7445.AM2015-CT313
Abstract CT318: Evaluation of salivary transcriptome markers for early detection of squamous cell cancer in a prospective blinded trial
Authors: Gottehrer Neil , Martin Jack 
Published: August 2015

Abstract
Oral squamous cell cancer (OSCC) is often diagnosed in late stages. Informative biomarkers could play a key role in early diagnosis. Prior case-control studies identified discriminatory salivary mRNA markers for OSCC. The National Cancer Institute (NCI) recommends prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) design study for rigorous biomarker identification and validation.
A PRoBE design study enrolled 170 patients with lesions suspicious for OSCC. Saliva was collected before performing oral biopsy. Six mRNAs (IL1β, IL8, OAZ1, SAT1, S100P, and DUSP1) were measured by quantitative polymerase chain reaction (PCR) without knowledge of tissue diagnosis. A pre-specified multi-marker panel from prior NCI - Early Detection Research Network (EDRN) studies was evaluated in this new PRoBE dataset. Individual marker cycle thresholds (Ct) from PCR were also compared in cancer versus control and new discriminatory models were generated.
The EDRN model was validated based on pre-specified statistical analysis plan. Ct values of individual mRNAs reflect an approximately two to nearly fourfold increase in concentration in invasive OSCC (p&lt;0.01 for all). A new model from this intended use population demonstrates a maximal sum of sensitivity and specificity of 153.5% with an area under the receiver operating characteristic (ROC) curve of 0.81.
The validation of six pre-specified individual salivary transcriptome markers of OSCC and a pre-specified multi-marker model in a new prospective population, support the robustness of these markers and the multi-marker methodology. New models generated in this intended use population have the potential to further enhance the decision process for early biopsy.
Trial ID: NCT01587573
Citation Format: Neil Gottehrer, Jack Martin. Evaluation of salivary transcriptome markers for early detection of squamous cell cancer in a prospective blinded trial. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT318. doi:10.1158/1538-7445.AM2015-CT318
Abstract LB-001: Development and evaluation of a fluorescent antibody-drug conjugate for molecular imaging and targeted therapy of pancreatic cancer
Authors: Knutson Steve , Raja Erum , Bomgarden Ryan , Nlend Marie , Chen Aoshuang , Kalyanasundaram Ramaswamy , Desai Surbhi 
Published: August 2015

Abstract
Developing new strategies to effectively diagnose and treat various types of cancer is paramount to increasing patient survival rates. Although chemotherapeutic small molecules are effective for some cancer types, they often have harmful side effects, resulting in significant damage to healthy tissue. Targeted therapy, where anti-cancer drugs are more precisely delivered to specific cells, has the potential to revolutionize chemotherapy, through increased localized effective doses with minimized systemic toxicity. Antibody-drug conjugates (ADCs) are one such class of targeted therapy biopharmaceuticals, employing the inherent specificity of antibodies as a targeting mechanism to yield a potent drug delivery system. In addition to being used as ADCs, antibody-conjugates are also commonly used as a highly effective tool for cancer typing and longitudinal treatment monitoring by immunohistochemistry staining or diagnostic imaging. However, antibody-conjugates used for tumor diagnosis and treatment are different molecules. Fluorescent dye labeling of therapeutic antibodies has been previously demonstrated for cancer imaging. However, therapeutic antibodies dual-labeled with both chemotherapeutic small molecules and fluorescent dyes has not been reported. Here, we demonstrate the development of a directly-labeled, fluorescent antibody-drug conjugate for simultaneous targeted drug delivery and in vivo molecular imaging of cancer. Our novel biopharmaceutical entity is a monoclonal antibody specific for a carcinoembryonic antigen (CEA) biomarker conjugated to an average of one molecule of paclitaxel and two molecules of a near-infrared fluorophore (DyLight 680-4xPEG). Preliminary data show that this fluorescent ADC selectively binds CEA positive cells and is cytotoxic using in vitro model systems. Ongoing studies using an in vivo mouse xenograft cancer model will demonstrate the utility of this fluorescent ADC as a new concurrent pancreatic cancer detection, monitoring and treatment technology.
Citation Format: Steve Knutson, Erum Raja, Ryan Bomgarden, Marie Nlend, Aoshuang Chen, Ramaswamy Kalyanasundaram, Surbhi Desai. Development and evaluation of a fluorescent antibody-drug conjugate for molecular imaging and targeted therapy of pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-001. doi:10.1158/1538-7445.AM2015-LB-001