bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3637: Delivery of an epigenetic agent using a microparticle drug delivery system
Authors: Do Duc P. , Soluade Keane O. 
Published: August 2015

Abstract
Conventional cancer treatment protocols are either toxic or of minimal therapeutic value, necessitating investigation of new modalities for efficacious treatment and management of cancers. Among the various novel compounds, histone deacetylase inhibitors (HDACIs) target cancer cells over-expressing deacetylases (HDACs). The inhibition of HDACs changes gene expression without altering the DNA sequence. In the present study, an albumin-based microparticulate drug delivery system containing vorinostat was formulated and evaluated for breast cancer therapy. Drug-loaded microparticles were prepared by a microencapsulation method through spray drying. Prepared microparticles containing the active drug were characterized for their physiochemical properties, including size, surface morphology, Zeta potential and surface properties. Dissolution studies were carried out to examine the release profile of the drug from the delivery system. For in vitro characterization and efficacy studies, breast carcinoma HTB-126 wells were used. Histone deacetylase (HDAC) activity was determined from cancer cells, and the efficacy of the free vorinostat and microparticle formulations was compared. Global histone changes in cells were analyzed using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Western blot was also utilized to detect acetylation marks in cells. Uptake studies were carried out in cancer cells to examine the internalization capability of microparticle drug formulations. Data indicated that microparticles were approximately 2-μm in size with Zeta potential measurements of about -30 mV. Release studies in cells showed that the drug released from the microparticulate delivery system at an extended rate over a period of over 24 hours. In vitro data in cancer cell line indicated that there was at least 10% more inhibition of cell viability when vorinostat was used with the microparticles. Similar results were observed from clonogenic studies. Additionally, in vitro data suggested that cell death induced by the drug-loaded microparticles was caused by apoptosis. Drug-loaded microparticle formulations were able to be internalized into cancer cells. Microparticles were shown to be a promising targeting strategy for cancer epigenetic therapy by providing an extended-release of the drug in the body.
Citation Format: Duc P. Do, Keane O. Soluade. Delivery of an epigenetic agent using a microparticle drug delivery system. [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 3637. doi:10.1158/1538-7445.AM2015-3637
Abstract 3640: Discovery of quinazolinones as fibroblast growth factor receptor (FGFR1-4) kinase inhibitors
Authors: Querolle Olivier , Angibaud Patrick , Colombel Hélène , Caron Virginie , Pilatte Isabelle , Poncelet Virginie , Esser Norbert , Gilissen Ron , King Peter , Meerpoel Lieven , Verhulst Tinne , Wroblowski Berthold , Vialard Jorge , Murray Chris W. , Rees David C. , Reningovolo Anita , Saxty Gordon 
Published: August 2015

Abstract
Recent data obtained in several tumor types have identified Fibroblast Growth Factor signaling as a key factor in the molecular pathology of a number of cancers1. This has stimulated the development of a number of agents that block this pathway, including FGFR kinase inhibitors with diverse inhibition and pharmacological profiles that are currently being evaluated in clinical studies.
We recently reported that a quinoxaline moiety can efficiently bind the hinge region of FGFR kinase catalytic sites. In continuation of our efforts to discover additional FGFR1-4 inhibitors, we have identified a quinazolinone scaffold as a novel FGFR kinase hinge binder. Initial hits were optimized into compounds displaying nanomolar affinity for FGFR1-4, potent activity in FGFR driven cells and efficacy in a Ba/F3-FGFR3 xenograft model.
This report represents the first disclosure of the structure-activity relationships as well as the chemical synthesis pathways of these novel quinazolinone-based FGFR1-4 inhibitors.
Turner N. and Grose R. Nature Reviews-Cancer 2010, 10, 116-129
Citation Format: Olivier Querolle, Patrick Angibaud, Hélène Colombel, Virginie Caron, Isabelle Pilatte, Virginie Poncelet, Norbert Esser, Ron Gilissen, Peter King, Lieven Meerpoel, Tinne Verhulst, Berthold Wroblowski, Jorge Vialard, Chris W. Murray, David C. Rees, Anita Reningovolo, Gordon Saxty. Discovery of quinazolinones as fibroblast growth factor receptor (FGFR1-4) kinase inhibitors. [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 3640. doi:10.1158/1538-7445.AM2015-3640
Abstract 3641: Identification of naphthyridines as potent inhibitors of fibroblast growth factor receptor kinase family
Authors: Angibaud Patrick R. , Obringer Michel , Marin Julien , Jeanty Matthieu , Esser Norbert , Gilissen Ron , King Peter , Meerpoel Lieven , Querolle Olivier , Rees David C. , Roux Bruno , Saxty Gordon , Verhulst Tinne , Wroblowski Berthold , Murray Christopher C. , Vialard Jorge 
Published: August 2015

Abstract
The fibroblast growth factor receptor (FGFR) tyrosine kinase family members, FGFR1, 2, 3 and 4, have roles in a variety of key cellular processes, including proliferation, migration, survival, and differentiation1. Aberrant activation of FGFRs through mutation, amplification, chromosomal translocation, and ligand up-regulation being strongly implicated in oncogenic signalling in many tumour types, has triggered efforts to identify selective FGFR inhibitors. As a result, several potent FGFR kinase inhibitors are currently being evaluated in clinical studies across many tumor types, including non-small cell lung, breast and bladder cancers.
We have designed novel 1,5 and 1,7-naphthyridine derivatives that are potent kinase inhibitors of all FGFR family members in enzymatic and cellular systems. Initial hits were further optimized to increase potency and ADME properties leading to identification of a novel 1,5-naphthyridine-based chemical series with nanomolar affinity for FGFR1, 2, 3, and 4, activity in cells, and selectivity with respect to VEGFR-2. In vivo screening using an FGFR3-driven xenograft model revealed efficacious compounds that could be explored further as antitumoral agents.
This report represents the first disclosure of the structure-activity relationship and synthesis pathway of novel naphthyridine chemical series displaying nanomolar affinity for FGFRs1, 2, 3 and 4.
1 Dieci M. V., Ardenos M., Andre F., Soria J.C. Cancer Discovery. 2013, 3(3) 264-279.
Citation Format: Patrick R. Angibaud, Michel Obringer, Julien Marin, Matthieu Jeanty, Norbert Esser, Ron Gilissen, Peter King, Lieven Meerpoel, Olivier Querolle, David C. Rees, Bruno Roux, Gordon Saxty, Tinne Verhulst, Berthold Wroblowski, Christopher C. Murray, Jorge Vialard. Identification of naphthyridines as potent inhibitors of fibroblast growth factor receptor kinase family. [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 3641. doi:10.1158/1538-7445.AM2015-3641
Abstract 3645: A non-ATP competitive IKKβ inhibitor for cancer therapy
Authors: Rana Sandeep , Blowers Elizabeth , Natarajan Amarnath 
Published: August 2015

Abstract
Kinases are promising targets in cancer drug discovery. IKKβ is an important kinase in the canonical NF-κB pathway, which promotes survival of cancer cells and is constitutively active in number of cancers including pancreatic cancer. Inflammatory stimulus such as tumor necrosis factor-α (TNFα) is known to activate the canonical IKKβ-NF-κB pathway. Upon TNFα stimulation, serine residues 177 and 181 in the activation loop of IKKβ undergo phosphorylation resulting in activated IKKβ. Immunohistochemistry (IHC) studies showed the presence of the proinflammatory cytokine TNFα in ∼50% of surgically resected tumor specimens but in only ∼10% of corresponding normal tissues. Consistently, IHC studies by us with patient samples obtained from the UNMC rapid autopsy pancreatic cancer program showed elevated levels of phosphorylated S181 IKKβ in the tumor and liver metastases samples when compared to the stroma and ductal cells for normal pancreas.
Several small molecule IKKβ inhibitors were developed by pharmaceutical industry to treat chronic inflammatory diseases. Despite complete preclinical characterization of many candidates, to date none of them has been approved by the FDA for clinical use. Nearly all the small molecule IKKβ inhibitors reported are ATP competitive. These inhibitors completely block IKKβ mediated NF-κB activity as a result chronic administration in mice leads to granulocytosis and increased susceptibility to infection-mediated death. Here we report the discovery a non-ATP competitive IKKβ inhibitor that allows transient activation but blocks the sustained activation of IKKβ mediated NF-κB activity. We present a model that has a novel-binding site, which is accessible upon activation of IKKβ and explains the observed experimental results. Our IKKβ inhibitor does not share the toxicity profile of the ATP competitive IKKβ inhibitors. In an orthotopic pancreatic tumor model mice treated with our inhibitor showed reduced tumor growth and metastasis compared to vehicle controls. We also showed that in a mantle cell lymphoma model the median survival of mice treated with our inhibitor nearly doubled when compared vehicle treated mice. Our results suggest that non-ATP competitive IKKβ inhibitors are viable lead candidates for cancer therapy.
Citation Format: Sandeep Rana, Elizabeth Blowers, Amarnath Natarajan. A non-ATP competitive IKKβ inhibitor for cancer therapy. [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 3645. doi:10.1158/1538-7445.AM2015-3645
Abstract 3652: Development of novel chemical inhibitors targeting the N-terminal domain (NTD) of androgen receptor variants as anti-prostate cancer agents
Authors: Wu Jian Hui 
Published: August 2015

Abstract
The androgen receptor (AR) signaling is a driver of prostate cancer. Current therapeutic strategy for advanced prostate cancer is to suppress the AR signaling by androgen deprivation therapy (ADT) via castration and by antiandrogens to stop androgens from working. However, prostate cancer cells are very versatile in circumventing the ADT and reactivate the AR via multiple mechanisms, resulting in lethal castration-resistant prostate cancer (CRPC). An alarming problem is the emergence of AR variants that lack the ligand-binding domain (such as AR-V7) in CRPC patients, which are constitutively active without the need for androgens. Studies revealed that AR-v7 expression level was correlated with the risk of tumor recurrence after radical prostatectomy and was associated with short patient survival. In addition, mutations in full-length AR is another important mechanism of aberrant AR activation in CRPC cells. Recently, it was found that the F876L mutation is sufficient to confer enzalutamide resistance in cell lines and xenograft model. The AR F876L mutant is detected in CRPC patients treated with an enzalutamide analogue (ARN-509). The AR W741C mutant was detected in CRPC patient treated with bicalutamide and was found to be paradoxically activated by bicalutamide. In this project, we propose to develop novel AR inhibitors that target the AR N-terminal domain (NTD). The rationale for this has at least three fold: i) All of the FDA-approved antiandrogens are targeting the AR-LBD and thereby all of them are inactive against AR-v7; ii) All of the known mechanisms that could account for AR reactivation in CRPC cells are critically depending on the AR-NTD to reactivate AR; and iii) Among the NTD, DNA-binding domain (DBD) and LBD domains, the NTD is the most different domain between the AR and other members of steroid receptors. By a panel of in vitro assays, we have discovered a series of compounds that target the AR-NTD and potently inhibit all forms of the AR variants in our assays, including AR-V7, the wild-type and multiple clinically-relevant mutants of full-length ARs. Our inhibitors showed selectivity towards AR as they are inactive against the close homology proteins within the same steroid family (such as GR and PR). This project could lead to novel AR-NTD inhibitors as drug candidates for treating CRPC patients who have acquired resistance to AR-LBD-directed therapies, such as enzalutamide and abiraterone.
Citation Format: Jian Hui Wu. Development of novel chemical inhibitors targeting the N-terminal domain (NTD) of androgen receptor variants as anti-prostate cancer agents. [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 3652. doi:10.1158/1538-7445.AM2015-3652
Abstract 3680: Albumin-chitosan hybrid onconase nanocarriers for mesothelioma therapy
Authors: Tekade Rakesh K. , Youngren-Ortiz Susanne R. , Yang Haining , Haware Rahul , Chougule Mahavir B. 
Published: August 2015

Abstract
Onconase (ONC) is a member of a ribonuclease superfamily that has potent cytostatic activity against malignant mesothelioma (MM). However, the recent clinical trials have failed due to unfavorable biopharmaceutical characteristics. The objective of this investigation was to develop BSA-chitosan based hybrid nanoformulations for the efficient delivery of ONC to MM while minimizing the exposure to normal tissues. Taguchi Orthogonal Array L9 type design was used to formulate ONC loaded albumin nanocarriers (ONC-ANC). The ONC-ANC surface was hybridized using varying chitosan concentrations ranging between 0.100-0.175%w/v to form various ONC loaded hybrid nanocarriers (ONC-HNC). The obtained data set was analyzed by principal component analysis (PCA) and principal component regressions (PCR) to decode the effects of investigated design variables. ONC-ANC were found to have a mean particle size of 15.78 ± 0.24 nm (ζ = -21.89 ± 0.11 mV). PCA showed positive correlations between investigated design variables like the bovine serum albumin (BSA) concentration, ethanol dilution, and total ethanol with formulated nanocarrier particle size and entrapment efficiency (EE). PCR showed that the particle size depends on BSA, ethanol dilution, and total ethanol content, while EE was only influenced by BSA content. Further analysis of chitosan and TPP effects used for coating of ONC-ANC by PCR confirmed their positive impacts on the particle size, zeta potential, and prolongation of ONC release compared to uncoated ONC-ANC. PCR analysis of preliminary stability studies showed increase in the particle size and zeta potential at lower pH. However, particle size, zeta potential, and EE of developed HNC were below 63 nm, 31 mV, and 96%, respectively, indicating their stability under subjected buffer conditions. Out of the developed formulations, HNC showed enhanced inhibition of cell viability with lower IC50 against human MM-REN cells compared to ONC and ONC-ANC. This might be attributed to the better cell uptake of HNC, which was confirmed in the cell uptake fluorescence studies. These studies indicated that a developed nanotherapeutic approach might prove beneficial in reducing the therapeutic dose of ONC, minimizing adverse side effects by limiting the exposure of ONC to normal tissues, and help in the development of new therapeutic formulations and routes of administration.
Citation Format: Rakesh K. Tekade, Susanne R. Youngren-Ortiz, Haining Yang, Rahul Haware, Mahavir B. Chougule. Albumin-chitosan hybrid onconase nanocarriers for mesothelioma therapy. [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 3680. doi:10.1158/1538-7445.AM2015-3680
Abstract 3691: A chemical therapeutic screen identifies new targets for wt/wt melanoma
Authors: Verduzco Daniel , Smalley Keiran 
Published: August 2015

Abstract
Once advanced, melanoma is one of the deadliest forms of cancer. Metastatic melanoma has a 5-year survival rate of about 15%. Treatment of melanoma is based by driver mutation - BRAF-mutant, NRAS-mutant, and melanomas wild-type for BRAF and NRAS, termed “wt/wt melanomas”. While targeted therapies are available for BRAF or NRAS mutant melanomas, no effective targeted therapeutic options are available for wt/wt melanomas. Furthermore, chemotherapy rapidly fails for this third subtype prioritizing the need for novel therapies. We seek to overcome this problem by identifying compounds to target wt/wt melanoma. To this end, we have performed a chemical screen of clinically relevant compounds against 8 wt/wt melanoma cell lines. In our screen, we have identified compounds that specifically target critical proteins, such as ALK, PLK1, and PI3K. Exome sequencing of each wt/wt melanoma line is being performed to uncover specific genetic signatures that would allow for specific susceptibility to each hit from the screen. This work will allow us to develop personalized therapies for the treatment of patients with wt/wt melanoma.
Citation Format: Daniel Verduzco, Keiran Smalley. A chemical therapeutic screen identifies new targets for wt/wt melanoma. [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 3691. doi:10.1158/1538-7445.AM2015-3691
Abstract 370: Expansion of CTCs from early stage lung cancer patients using a microfluidic co-culture model
Authors: Zhang Zhuo , Shiratsuchi Hiroe , Lin Jules , Chen Guoan , Reddy Rishindra M. , Azizi Ebrahim , Fouladdel Shamileh , Chang Andrew C. , Lin Lin , Jiang Hui , Waghray Meghna , Simeone Diane M. , Wicha Max S. , Beer David G. , Luker Gary , Ramnath Nithya , Nagrath Sunitha 
Published: August 2015

Abstract
Establishing the role of circulating tumor cells (CTCs) in tumor progression and metastasis depends both on enumeration and on obtaining sufficient numbers of cells for downstream assays. The numbers of CTCs are few in early stages of cancer, limiting detailed molecular characterization. One approach to overcome this limitation is to expand CTCs, i.e. increase their numbers as a result of cell division. Herein, we have developed a novel in-situ capture and culture methodology for ex-vivo expansion of CTCs using a three dimensional co-culture model, simulating a tumor microenvironment to support tumor development. We have successfully identified CTCs isolated from 14 of 19 early stage lung cancer patients. Expanded lung CTCs expressed tumor specific markers and formed spheroids in culture. CTCs derived xenograft demonstrated tumorigenic capability of these cells. Furthermore, CTCs carried mutations of the TP53 gene identical to those observed in the matched primary tumors. Next-generation sequencing further revealed additional matched mutations between primary tumor and CTCs of cancer-related genes. This strategy sets the stage to further characterize the biology of CTCs derived from patients with early lung cancers, thereby leading to a better understanding of these putative drivers of metastasis.
Citation Format: Zhuo Zhang, Hiroe Shiratsuchi, Jules Lin, Guoan Chen, Rishindra M. Reddy, Ebrahim Azizi, Shamileh Fouladdel, Andrew C. Chang, Lin Lin, Hui Jiang, Meghna Waghray, Diane M. Simeone, Max S. Wicha, David G. Beer, Gary Luker, Nithya Ramnath, Sunitha Nagrath. Expansion of CTCs from early stage lung cancer patients using a microfluidic co-culture model. [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 370. doi:10.1158/1538-7445.AM2015-370
Abstract 3715: Survival of patients with mucinous ovarian carcinoma and ovarian metastases: A population-based cancer registry study
Authors: Simons Michiel , Ezendam Nicole , Bulten Johan , Nagtegaal Iris , Massuger Leon 
Published: August 2015

Abstract
Objectives: Patients with mucinous ovarian carcinoma (MOC) generally have a favorable prognosis, although in advanced stage, prognosis is significantly worse compared to patients with serous ovarian carcinomas (SOC). This might be due to the difficulties in the distinction of MOC from metastatic tumors. In the current study we investigate prognosis of MOC compared to other types of ovarian cancer and to synchronous metastases to the ovary (sMO).
Materials and methods: Age, laterality, FIGO stage, tumor grade, treatment and survival were extracted from the Eindhoven Cancer registry for all patients diagnosed with ovarian carcinomas or sMO between 1990 and 2012. 5-year survival analysis and Cox proportional hazard analysis were conducted.
Results: 3,556 patients with primary ovarian carcinoma (of which 474 mucinous) and 289 with sMO were identified. In advanced stage, 5-year survival of patients with MOC was comparable to survival of patients with sMO (11% vs. 11%, p = 0.32) and decreased compared to patients with SOC (26%, p&lt;0.01). For MOC there was no clinically significant effect on 5-year survival of either debulking (12% vs. 8%, p&lt;0.01) or chemotherapy (12% vs. 10%, p = 0.02) as compared to patients with SOC (28 vs. 13% after chemotherapy, p&lt;0.01 and 29% vs. 5% after debulking, p&lt;0.01). Multivariate regression analysis for age, tumor grade and subtype including sMO was carried out, showing a significantly better overall survival for SOC compared to MOC (HR 0.51, p&lt;0.01), whereas there was no difference for sMO compared with MOC (HR 1.16, p = 0.19).
Conclusion: Patients with advanced stage MOC have a worse prognosis than advanced stage SOC. Survival is almost identical to that of patients with sMO, which might indicate that (a large part of) advanced stage MOC are in fact metastases. This may partly explain the limited effects of chemotherapy and debulking in patients with MOC. Methods to differentiate between primary MOC and metastatic disease are needed to provide optimal treatment and insight in prognosis.
Citation Format: Michiel Simons, Nicole Ezendam, Johan Bulten, Iris Nagtegaal, Leon Massuger. Survival of patients with mucinous ovarian carcinoma and ovarian metastases: A population-based cancer registry study. [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 3715. doi:10.1158/1538-7445.AM2015-3715