bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 326: Overexpression of the carboxyl-terminus of MUC16 can accelerate the occurrence of phenotypes in p53 heterozygous mouse model.
Authors: Tian Huasong , Zhou Qin , Iasonos Alexia , David Spriggs 
Published: August 2014

Abstract
Ovarian cancer is the fifth leading cause of cancer death in women. Cancer antigen 125 (CA125), also known as MUC16, is a high molecular weight glycoprotein overexpressed in sera of women with epithelial ovarian cancer, but not in normal epithelial ovarian tissue. As a biomarker, CA125 is widely used to screen, diagnose and monitor the epithelial ovarian cancer. To further understand the roles of MUC16 in tumorigenesis, recently, some mouse models related Muc16 and MUC16 were created. There is no phenotype for the Muc16 knockout mice (Cheon et al., PLoS ONE, 2009). We built a MUC16 carboxyl-terminus transgenic mouse (MUC16ΔC354) and found out that the transgenic mice appear to be viable, fertile, and develop normally through the more than two years of life. In order to investigate the relationship of p53 mutation and MUC16 overexpression in tumorigensis, we generated mice in which MUC16ΔC354 can be overxepressed with p53 heterozygote. Like the MUC16ΔC354 transgenic mice, the MUC16ΔC354; p53+/- mice develop normally. Both mouse strains are susceptible to spontaneous tumors, including sarcoma and lymphoma. However, comparing p53+/- mice, overexpression of MUC16ΔC354 significantly accelerates the occurrence of phenotypes in MUC16ΔC354; p53+/- mice. Out of a study population of 94 MUC16ΔC354; p53+/- mice, 22 (23.4%) developed obvious neoplasms by 18 months of age, 13 (11.9%) out of 109 for p53+/- mice (ρ &lt;0.014). Tumor tissues and tumor cells carrying MUC16ΔC354 and p53+/- are transplantable. MAPK/ERK signaling pathway is upregulated in these tumors. Our findings demonstrate our hypothesis that MUC16 may play a role in tumorigensis.
Citation Format: Huasong Tian, Qin Zhou, Alexia Iasonos, Spriggs David. Overexpression of the carboxyl-terminus of MUC16 can accelerate the occurrence of phenotypes in p53 heterozygous mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 326. doi:10.1158/1538-7445.AM2013-326
Abstract 3266: Repurposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints.
Authors: Beeharry Neil , Fink Lauren , Banina Eugenia , Khazak Vladimir , Skobeleva Natalia , Peterson Jeffrey R. , Astsaturov Igor , Yen Timothy J. 
Published: August 2014

Abstract
Many conventional chemotherapies act as DNA damaging agents. Chemotherapy activates cell cycle checkpoint signaling to prevent cells from entering mitosis with either damaged or unreplicated DNA. Based on the observations that interference with the checkpoint mechanism (checkpoint override) results in cell death via mitotic catastrophe, the development of checkpoint inhibitors is actively being pursued as an anti-cancer therapy. In a cell-based screen of clinically relevant kinase inhibitors we identified three compounds that display checkpoint override properties: isomer of bosutinib, a recently FDA-approved Abl and Src inhibitor; BEZ235, a PI3K/mTOR inhibitor; and dovitinib, a multi-receptor tyrosine kinase inhibitor. Most interestingly, all compounds display off-target activity towards DNA damage checkpoint kinases including Chk1, ATR and Wee1. We determined these kinase inhibitors potently sensitized a panel of pancreatic cancer cell lines to S-phase acting (Gemcitabine, cisplatin) or G2-phase arresting (doxorubicin) DNA-damaging agents. Using a combination of live-cell videomicroscopy and immunofluorescence, we demonstrated that the inhibitors forced drug-treated cells to override the DNA damage induced checkpoint activation and aberrantly enter mitosis. The aberrant mitoses had characteristic chromatin fragmentation and that kinetochores and centromeres appeared to be detached from the chromatin mass, in a manner reminiscent of mitosis with unreplicated genomes (MUGs). As a result, cells died either in mitosis or due to mitotic catastrophe. The efficacy of pulsatile (24h and 48h after chemotherapy) administration of these previously unsuspected checkpoint inhibitors was further validated in tumor explants and cells isolated directly from a pancreatic cancer patient who is currently undergoing treatment. Tellingly, xenograft studies showed that gemcitabine and bosutinib isomer had significant activity as single agents but the combination significantly prevented tumor growth, even after drug removal. Our findings suggest that kinase inhibitors targeting cell cycle checkpoints, albeit in an off-target manner, may be fast-tracked into the clinic to enhance the efficacy of standard chemotherapies.
Citation Format: Neil Beeharry, Lauren Fink, Eugenia Banina, Vladimir Khazak, Natalia Skobeleva, Jeffrey R. Peterson, Igor Astsaturov, Timothy J. Yen. Repurposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3266. doi:10.1158/1538-7445.AM2013-3266
Abstract 3285: Synergistic anticancer effects of resveratrol and clofarabine in malignant mesothelioma cells.
Authors: Lee David M. , Lee Yoon-Jin , Im Jae-Hyuk , Won Seong-Youn , Nam Hae-Seon , Lee Sang-Han 
Published: August 2014

Abstract
Malignant mesothelioma is highly resistant to apoptosis. Hence, new strategies to enhance the apoptotic signal and overcome resistance to therapeutic drugs are necessary to improve the therapeutic efficacy of malignant mesothelioma. Here, we investigated the effects of the combined treatment of various phytochemicals as a chemo-potentiator in combination with the chemotherapeutic agent clofarabine in malignant mesothelioma MSTO-211H cells and normal mesothelial Met-5A cells. Treatment with resveratrol in combination with clofarabine at a subtoxic concentration produced a synergistic antiproliferative effect and induced apoptotic cell death, as evidenced by increased subG1 peak on flow cytometric analysis, chromatin condensation and nuclear fragmentation on DAPI staining, and DNA laddering on agarose gel electrophoresis, in MSTO-211H cells, but not in Met-5A cells. In MSTO-211H cells, endogenous expression of the transcription factors Nrf2 and Sp1 proteins, several Nrf2 and Sp1-regulated gene products (HO-1, c-Met, and cyclin D1), and Akt phosphorylation, were effectively suppressed by the combined treatment of clofarabine and resveratrol. Furthermore, the nuclear accumulations of Nrf2 and Sp1 were inhibited by the combination treatment. In combination with clofarabine, the ability of resveratrol to increase the contents of the phosphorylated p53 and the apoptotic molecules, PARP and cleaved caspase 3, was also evident in a time- and dose-dependent experiment. Taken together, the data provide evidence that the synergistic antiproliferative effect of resveratrol and clofarabine is linked to simultaneous suppression of multi-target molecules, such as Nrf2, Sp1, and Akt activities, and suggest that this combination may have therapeutic value in treatment of malignant mesothelioma.
Citation Format: David M. Lee, Yoon-Jin Lee, Jae-Hyuk Im, Seong-Youn Won, Hae-Seon Nam, Sang-Han Lee. Synergistic anticancer effects of resveratrol and clofarabine in malignant mesothelioma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3285. doi:10.1158/1538-7445.AM2013-3285
Abstract 3287: Sensitizing cancer cells to chemotherapy.
Authors: Wolak Kathryn E. , Bainer Russell , Skol Andrew , Onel Kenan 
Published: August 2014

Abstract
A wide range of cancers are either initially resistant to chemotherapy or are sensitive, but subsequently relapse through acquired drug resistance. Alterations in the p53 pathway are associated with drug resistance, underscoring its central role in determining response to chemotherapy. Using pediatric B-cell acute lymphoblastic leukemia as a model, we identified a set of p53-regulated transcriptional targets that comprise an apoptotic gene signature significantly associated with response to therapy and independently prognostic for outcome in pediatric ALL. We hypothesize that cells can be primed for an enhanced apoptotic response to chemotherapy by modulating expression levels of the p53-regulated apoptotic signature genes with small molecules before administering chemotherapy. We conducted a high-throughput screen to identify novel compounds that prime ALL cells for apoptosis to convert a chemotherapy-resistant cell into one that is sensitive. This screen was performed using 83,745 compounds in both the wild-type p53 cell line TK6 and the mutant-p53 line, WTK1. Cells were treated with either compound alone or compound plus daunorubicin, a drug used to treat ALL. Compounds were normalized and scored by using both the B-score and the robust Z-score. “Hits” were defined as compounds that do not significantly alter viability of the cells alone, but significantly increase daunorubicin-induced cell death. We confirmed the effects of the compounds in other B-cell ALL cell lines. In an effort in investigate mechanism, we looked at synergism using other chemotherapies with different modes of action. One compound was very synergistic with cisplatin, and we then extended the experiment to other cell types. We found that the synergism with cisplatin holds in all cell types tested, including T-cell ALL, lymphoma, breast, ovarian and colon cancer. In paired cisplatin-sensitive and resistant ovarian cancer cell lines, we find that the non-toxic doses of the compound can sensitize the resistant line and convert it to respond to cisplatin at the same doses as the parental sensitive line. Looking at the pathways induced by these compounds, we find important components in the cellular response to chemotherapy that can be manipulated to convert a chemoresistant cell into one that is sensitive.
Citation Format: Kathryn E. Wolak, Russell Bainer, Andrew Skol, Kenan Onel. Sensitizing cancer cells to chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3287. doi:10.1158/1538-7445.AM2013-3287
Abstract 3305: Sustained production of a soluble IGF-I receptor by gutless adenovirus - transduced host cells protects from tumor growth in the liver .
Authors: Wang Ni , Lu Yifan , Pilotte Amelie , Pinard Maxime , Gilbert Rénald , Massie Bernard , Brodt Pnina 
Published: August 2014

Abstract
The IGF-I receptor (IGF-IR) plays an important role in malignant disease by increasing cancer cell survival and promoting metastasis. It is presently the target of several drugs in clinical trials. Gene therapy is currently being developed for cancer treatment using different nanoparticle vectors designed to deliver therapeutic genes that could induce cell death, increase sensitivity to chemotherapy, block angiogenesis or enhance the anti-cancer immunological response. Previously, we have shown that the implantation of autologous bone-marrow stromal cells producing a soluble form of IGF-IR (sIGFIR) inhibited experimental liver metastasis of several tumor types in mice. Here we evaluated the utility of adenovirus-based gene delivery for generating therapeutically effective plasma levels of this decoy. A third generation gutless adenovirus was selected to deliver the sIGFIR gene because of its reduced immunogenicity and preferential tropism for the liver, the main source of endocrine IGF-1. We found that HEK-293 cells transduced by this, but not by control adenoviruses, secreted soluble receptor protein that blocked IGF-I-induced tumor cell migration, proliferation and survival in vitro. Following virus injection in vivo, viral DNA was detectable by PCR in several host organs, particularly the liver, and this resulted in the production of measurable sIGFIR plasma levels for up to 21 days post injection. In mice producing virus-encoded sIGFIR, experimental liver metastasis was inhibited, indicating that sIGFIR levels were therapeutically effective. The results show that adenovirus-based delivery of inhibitory soluble proteins can provide an effective strategy for blockade of cancer cell growth.
Citation Format: Ni Wang, Yifan Lu, Amelie Pilotte, Maxime Pinard, Rénald Gilbert, Bernard Massie, Pnina Brodt. Sustained production of a soluble IGF-I receptor by gutless adenovirus - transduced host cells protects from tumor growth in the liver . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3305. doi:10.1158/1538-7445.AM2013-3305
Abstract 3306: Traditional Chinese Medicine (TCM) enhances efficacy and reduces toxicity of tumor-targeting S. typhimurium A1-R in a syngeneic breast cancer metastatic mouse model.
Authors: Zhang Yong , Zhang Nan , Su Shibing , Hoffman Robert M. , Zhao Ming 
Published: August 2014

Abstract
We have previously developed a bacterial cancer therapy strategy using the genetically-engineered strain, Salmonella typhimurium A1-R (A1-R). A1-R has been shown to be effective against metastatic human prostate, breast, and pancreatic cancer cell lines as well as osteosarcoma, fibrosarcoma, and glioma cell lines in nude mouse models. In the current study, we have evaluated Traditional Chinese Medicine (TCM) (Huang Zi, Mai Men Dong, Mu Dan Pi, Sheng Di Huang) in combination with A1-R bacterial therapy in a syngeneic orthotropic model of 4T1 mouse breast cancer. TCM treatment improved the host's ability to clear bacteria from the liver and spleen and prevent body weight loss after bacterial infection. Fur discoloration and reduced activity was also observed in mice treated with A1-R only, but ameliorated when bacterial treatment was combined with TCM. The combination of TCM and A1-R enabled S. typhimurium to be safely administered at a dose of 1×107 CFU once a week i.v. for a long period of time in immunocompetent mice. Efficacy and survival were increased by combination treatment compared to monotherapy with A1-R (1 × 107CFU) . The results of the present study suggest that TCM potentiates A1-R cancer therapy.
Citation Format: Yong Zhang, Nan Zhang, Shibing Su, Robert M. Hoffman, Ming Zhao. Traditional Chinese Medicine (TCM) enhances efficacy and reduces toxicity of tumor-targeting S. typhimurium A1-R in a syngeneic breast cancer metastatic mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3306. doi:10.1158/1538-7445.AM2013-3306
Abstract 331: Head and neck and skin squamous cell carcinoma developed in a BRCA2 knockout mouse model.
Authors: Kamradt Michael , Zou Chaozhong , Liu Lin , Wang Yuexia , Fitchev Philip P. , Worman Howard J. , Crawford Susan E. , Talamonti Mark , Gao Qingshen 
Published: August 2014

Abstract
BRCA1 and BRCA2 were originally identified as breast cancer tumor suppressor genes. Germline mutations of BRCA1 have been found to predispose the carrier mainly to breast and ovarian cancers. However, germline mutations of BRCA2 can cause a much wider spectrum of cancers, including breast, ovarian, pancreatic and prostate cancers. There are conflicting reports on whether BRCA2 mutations also contribute to the tumorigenesis of head and neck squamous cell carcinoma (HNSCC). Previously, it had been reported that K14-cre; BRCA2f/f mice do not develop any cancer of epithelial origin even at 600 days of age in a 129/C57 background. Here, we generated a K14-cre mediated BRCA2 knockout mouse model in a different mouse strain background than previously reported. To our surprise, we found that K14-cre; BRCA2 f/f mice started to develop tumors at seven months of age. Most of the tumors were in the head and neck region, while others were skin tumors in other locations. The head and neck tumors showed no skin involvement or ulceration. Tumor growth in many mice eventually affected their food intake and they had to be euthanized for humane reason. At around 11 months of age, we sacrificed the remaining mice and subjected them to necroscopy. All the visually suspicious tissues were processed for pathologic examination. In total, we found 8 out of 31 K14-cre; BRCA2 f/f mice (26%) with pathologically confirmed head and neck cancer and 4 out 31 K14-cre; BRCA2 f/f mice (13%) with skin cancer. None of the 28 control BRCA2 f/f mice developed any cancer at this age. The head and neck cancers are squamous cell carcinomas arising from the mucosa surface and form large, palpable masses. In some areas, the tumors are well-differentiated with evidence of abundant keratin production, while in other areas they are less differentiated and exhibit high nuclear to cytoplasmic ratios, nuclear aytpia, mitoses and central necrosis. These histological features are highly reminiscent of the pathological characteristics of human HNSCC. This finding strongly indicates that mutations of BRCA2 play an important role in the tumorigenesis of HNSCC in a specific genetic background.
Citation Format: Michael Kamradt, Chaozhong Zou, Lin Liu, Yuexia Wang, Philip P. Fitchev, Howard J. Worman, Susan E. Crawford, Mark Talamonti, Qingshen Gao. Head and neck and skin squamous cell carcinoma developed in a BRCA2 knockout mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 331. doi:10.1158/1538-7445.AM2013-331
Abstract 335: A genetic mouse model of head-and-neck squamous cell carcinoma using targeted deletion of E-cadherin and TGFβ receptor II.
Authors: Andl Thomas , Le Bras Gregoire F. , Richards Nicole F. , Allison Gillian L. , Washington M. Kay , Lee R. Katie , Andl Claudia D. 
Published: August 2014

Abstract
We previously observed that 70% of esophageal tumors demonstrated coordinated loss of E-cadherin and TGFβRII. When grown in three-dimensional organotypic reconstruct cultures, cells lacking E-cadherin and TGFβRII demonstrate fibroblast-dependent invasion into the underlying matrix. Therefore, we hypothesized that coordinated loss of CDH1 (E-cadherin) and TGFBR2 (TGFβRII) will induce tumorigenesis in vivo. We developed a mouse model targeting CDH1 and TGFBR2 loss in the oral-esophageal epithelium using the Epstein-Barr virus L2 promoter, ED-L2. For spatio-temporal control of CDH1- and TGFBR2 gene expression, we also generated an inducible mouse model using Cre-ERT(tam) under the control of the keratin 14 promoter. Few mouse models focusing on genetic alterations of oral and head-and-neck cancer exist. We show that the loss of E-cadherin and TGFβ receptor II without carcinogen treatment is sufficient to induce invasive HNSCC and forestomach tumors. Double knock-out animals succumb to the disease between 1 and 1.5 years of age and show invasive tumors in the oral cavity and tongue, as well as the forestomach. Advanced tumors metastasize to the lung. The tumors are characterized by Ki67-positive and p63-positive staining and show disruption of adherens junctions with loss of β-catenin and mislocalisation of p120 to the cytoplasm. Additional genetic modifications frequently described for HNSCC are the upregulation of c-myc and cyclin D1. We could show that the oral mouse tumors are positive for these markers allowing us to conclude that this animal model recapitulates HNSCC at the pathologic and molecular levels. Furthermore, the forestomach is an extension of the squamous epithelium of the esophagus in the mouse. Known genetic alterations causing esophageal squamous cancer are amplification of EGFR, cyclin D1 and mutations in p53 in addition to the loss of E-cadherin and TGFβRII. The analysis of the forestomach tumors recapitulates these events in the mouse model as a result of CDH1 and TGFBR2 loss. This tumor model will provide us with a unique tool for testing therapeutic approaches.
Citation Format: Thomas Andl, Gregoire F. Le Bras, Nicole F. Richards, Gillian L. Allison, M. Kay Washington, R. Katie Lee, Claudia D. Andl. A genetic mouse model of head-and-neck squamous cell carcinoma using targeted deletion of E-cadherin and TGFβ receptor II. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 335. doi:10.1158/1538-7445.AM2013-335
Abstract 3367: Massbalance, excretion and metabolism of [14C]-Pralatrexate (PDX) incancer patients in a phase I trial.
Authors: Odore Elodie , Rezaï Keyvan , Madar Olivier , Weill Sophie , Awada Ahmad , Pronk Bert , Cvitkovic Esteban , Lokiec Francois 
Published: August 2014

Abstract
Background: PDX is a novel 10-deaza-aminopterin analogue of methotrex[[Unsupported Character - Codename &shy;]]ate consisting of a mixture of R- and S-diastereomeric folate derivatives. PDX inhibits folate metabolism by binding to and inhibiting the enzyme dihydrofolate reductase (DHFR). PDX is the first drug approved by the US Food and Drug Admin[[Unsupported Character - Codename &shy;]]istration (FDA) specifically for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Mass balance studies in animals and humans with radiolabeled compounds represent a standard part of the development process for new drugs. Isotopically labeled analogs of a drug or its metabolites play an important role in understanding the absorption, distribution, metabolism and excretion profiles of a compound. The objectives of this study were to determine the pharmacokinetics (PK), metabolism and routes of excretion of [14C]-PDX and to characterize its metabolites in human plasma and urine.
Methods: Four patients were administered intravenously with a mixture of 50 μCi of [14C]-PDX (0.5 mg) and 224.5 mg of non radioactive PDX over a 3-5 minute infusion. Serial blood and plasma samples were drawn at: 0 (before PDX infusion), and up to 144 h after the start of infusion. Urine and fecal samples were collected for up to 168 h after the start of infusion. Expired air samples were collected up to 24 hours after administration. The radioactivity measurement in biological fluids was performed using liquid scintillation counting.
Results: Mass balance was achieved with a mean recovery radioactivity in excreta= 82.9 % ± 20.0 % for the four patients. The mean recovery of radioactivity in urine, feces, and expired air were 34.1%, 38.7% and 10.1%, respectively, indicating renal and fecal excretions were the major route of elimination of [14C]-PDX. A three-compartment open model adequately described [14C]-PDX time radioactivity-concentration courses. The AUC0-∞, and clearance values for total radioactivity in plasma were 18.1 nCi.h/mL, and 3.95 L/h, respectively. Metabolite profiling will be performed using HPLC with beta radiation detector.
Conclusions:
This study quantified the mass balance of PDX and defined its substantial excretion in both urine and feces after IV administration. The PK of [14C]-PDX was best described by a three compartment open model. The metabolite profiling of PDX is ongoing.
Citation Format: Elodie Odore, Keyvan Rezaï, Olivier Madar, Sophie Weill, Ahmad Awada, Bert Pronk, Esteban Cvitkovic, Francois Lokiec. Massbalance, excretion and metabolism of [14C]-Pralatrexate (PDX) incancer patients in a phase I trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3367. doi:10.1158/1538-7445.AM2013-3367