bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 960: Deregulation of the Hippo pathway in soft tissue sarcoma promotes FOXM1 expression and tumorigenesis
Authors: Eisinger T.S. Karin , Mucaj Vera , Biju Kevin , Nakazawa Michael , Gohil Mercy , Cash Timothy , Yoon Sam , Skuli Nicolas , park Kyung Min , Gerecht Sharon , Simon Celeste 
Published: August 2015

Abstract
The genetic aberrations responsible for soft tissue sarcoma formation in adults are largely unknown, and targeted therapies are sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft tissue sarcomas, resulting in elevated expression of the effector molecule YAP. Based on data gathered from human sarcoma patients, we concluded that more than 40% of human sarcomas have lost one or more copies of upstream HIPPO pathway regulators including SAV1, LATS2, and NF2. Loss of these molecules deactivates the HIPPO pathway, permitting uncontrolled proliferation and growth. Expression of active YAP is the direct result of this copy number loss and we have found YAP to be elevated in primary human fibrosarscomas, liposarcomas, and pleomorphic tumors. Pharmacologic inhibition of YAP significantly impaired primary sarcomagenesis in a murine allograft model. Using a novel autochthonous mouse model and mechanistic analyses in human and murine sarcoma cells, we determined that YAP-dependent expression of the transcription factor, FOXM1, is necessary for sarcoma cell proliferation and tumorigenesis. FOXM1 expression is elevated in multiple human soft tissue sarcoma subtypes. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in co-regulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of sarcomas.
Citation Format: T.S. Karin Eisinger, Vera Mucaj, Kevin Biju, Michael Nakazawa, Mercy Gohil, Timothy Cash, Sam Yoon, Nicolas Skuli, Kyung Min park, Sharon Gerecht, Celeste Simon. Deregulation of the Hippo pathway in soft tissue sarcoma promotes FOXM1 expression and tumorigenesis. [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 960. doi:10.1158/1538-7445.AM2015-960
Abstract 962: PA2G4 predicts poor prognosis in neuroblastoma patients and promotes neuroblastoma progression by enhancing MYCN protein stability
Authors: Koach Jessica , Liu Bing , Bell Jessica L. , Hüttelmaier Stefan , Liu Tao , Carter Daniel R. , Haber Michelle , Norris Murray D. , Fletcher Jamie , Cheung Belamy B. , Marshall Glenn M. 
Published: August 2015

Abstract
MYCN oncogene amplification is found in one third of primary neuroblastoma at diagnosis, and correlates with poor prognosis. We identified Proliferation-associated protein 2G4 (PA2G4) as a binding partner for MYCN using co-immunoprecipitation and mass spectrometry. The long isoform of PA2G4 (p48) has a known oncogenic function, whereas the short isoform (p42) acts as a tumour suppressor. However, the role of PA2G4 in neuroblastoma and its link with MYCN is currently unknown.
Using a panel of 11 human neuroblastoma cell lines and 477 patient tumour samples, we analysed the expression of PA2G4 by real-time PCR and Western blotting. We found that high expression of PA2G4 was a strong independent clinical predicator of poor survival and positively correlated with MYCN expression. Analysis of pre-cancerous ganglia cells from TH-MYCN neuroblastoma mouse model showed that PA2G4 mRNA was expressed 8-fold higher in ganglia from TH-MYCN transgenic homozygote, compared to wild-type mice.
Chromatin immunoprecipitation showed MYCN binds to PA2G4 promoter to activate its transcription. Surprisingly, suppression of PA2G4 in neuroblastoma cell lines markedly reduced MYCN protein level. Cycloheximide-chase assay confirmed that PA2G4 increased MYCN protein stability, thus creating a positive forward feedback loop which we showed resulted from effects on pERK. Suppression of PA2G4 down-regulated pMDM2 and pAKT, leading to an increase in p53 expression. Furthermore, PA2G4 knockdown promoted retinoid induced neurite formation, reduced cell migration and colony formation. Importantly, the expression of MYCN was required for the effect of PA2G4 on colony formation. A small molecule inhibitor of PA2G4, WS6, significantly decreased neuroblastoma cell growth and PA2G4 and MYCN protein levels.
PA2G4 is a novel MYCN-binding protein which increases MYCN protein stability and acts as an oncogenic co-factor in a forward feedback expression loop with MYCN, to drive MYCN protein levels to high thresholds even in the presence of MYCN amplification.
Citation Format: Jessica Koach, Bing Liu, Jessica L. Bell, Stefan Hüttelmaier, Tao Liu, Daniel R. Carter, Michelle Haber, Murray D. Norris, Jamie Fletcher, Belamy B. Cheung, Glenn M. Marshall. PA2G4 predicts poor prognosis in neuroblastoma patients and promotes neuroblastoma progression by enhancing MYCN protein stability. [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 962. doi:10.1158/1538-7445.AM2015-962
Abstract 973: Coordinated regulation of cap-dependent translation and microRNA function by convergent signaling through the PI3K/Akt/mTOR and Jak/Stat/Pim signaling pathways
Authors: Olejniczak Scott H. , La Rocca Gaspare , Radler Megan , Thompson Craig B. 
Published: August 2015

Abstract
Growth and proliferation of tumor cells requires coordinated activation of many cellular processes, including cap-dependent mRNA translation. MicroRNAs oppose cap-dependent translation to set thresholds for expression of target proteins. Emerging data suggest that microRNA function, like cap-dependent translation, is enhanced by activation of cancer-associated signaling due, at least in part, to induction of GW182 protein expression. In the current study, we demonstrate that increased expression of GW182 in normal and transformed hematopoietic cells contributes to enhanced microRNA function by increasing overall capacity for microRNA-mediated target repression. Furthermore, expression of GW182 was found to be regulated post-transcriptionally by the translation initiation complex downstream of convergent signaling through the PI3K/Akt/mTOR and Jak/Stat/Pim signaling pathways, both of which are commonly activated in hematopoietic malignancies. PI3K/Akt/mTOR signaling contributed to GW182 expression primarily by stimulating eIF4E binding to GW182 mRNA, while Jak/Stat/Pim signaling enhanced GW182 expression by additionally increasing eIF4A-dependent unwinding of G-quadraplexes in the 5′ untranslated region (UTR) of GW182 mRNA. Inhibition of either eIF4E-dependent translation initiation by treatment with rapamycin or eIF4A-dependent unwinding of the GW182 5′ UTR by treatment with silvestrol led to decreased GW182 expression and microRNA function. Our data provide a mechanism by which microRNA function is linked to cap-dependent translation, allowing thresholds for expression of microRNA targeted proteins to be maintained despite changes in protein synthesis.
Citation Format: Scott H. Olejniczak, Gaspare La Rocca, Megan Radler, Craig B. Thompson. Coordinated regulation of cap-dependent translation and microRNA function by convergent signaling through the PI3K/Akt/mTOR and Jak/Stat/Pim signaling pathways. [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 973. doi:10.1158/1538-7445.AM2015-973
Abstract 998: Induction of non-protective autophagy by radiation in tumor cells: Implications for autophagy inhibition as a therapeutic strategy
Authors: Chakradeo Shweta , Sharma Khushboo , Alhaddad Aisha , Bakhshwin Duaa , Le Ngoc , Harada Hisashi , Yeudall W. Andrew , Torti Suzy , Torti Frank , Gewirtz David 
Published: August 2015

Abstract
Our laboratory has previously described the four functional forms of autophagy, specifically cytoprotective, cytotoxic, cytostatic and nonprotective (Gewirtz DA, Cancer Research 2014). Evidence for the nonprotective form was based on studies where murine 4T1 breast tumor cells failed to be sensitized to ionizing radiation by pharmacological or genetic inhibition of autophagy (Bristol ML, JPET, 2013). To determine whether radiation induces the cytoprotective and nonprotective forms of autophagy in human tumor cells lines of different tissue origin, the influence of autophagy inhibition on radiation sensitivity was studied in human breast, head and neck and non-small cell lung cancer cell lines. In order to examine the potential involvement of p53 in the protective and nonprotective forms of autophagy, the impact of autophagy inhibition on radiation sensitivity was compared in cell lines that were either wild type or mutant/null in p53. While ionizing radiation promoted autophagy in all tumor cell lines studied, autophagy inhibition resulted in radiation sensitivity only in the p53 wild type A549 and H460 NSCLC cells and the HN30 head and neck tumor cells. In contrast, pharmacological inhibition of autophagy and/or genetic silencing of autophagy genes failed to influence sensitivity to radiation in the p53 mutant Hs578t breast tumor cells, the HN6 head and neck tumor cells, and the H358 non-small cell lung cancer cells, indicative of nonprotective autophagy. The apparent requirement for functional p53 in the promotion of cytoprotective autophagy by radiation was confirmed by the observation that radiation induced autophagy was nonprotective in p53 null H1299 cells but was converted to the cytoprotective form with induction of p53. Conversely, whereas p53 wild-type HN30 cells did show sensitization to radiation upon autophagy inhibition HN30 cells in which p53 was knocked down were not sensitized. These observations have implications for efforts to modulate the response of malignancies to radiation (and possibly also to cancer chemotherapeutic drugs) through autophagy inhibition.
Citation Format: Shweta Chakradeo, Khushboo Sharma, Aisha Alhaddad, Duaa Bakhshwin, Ngoc Le, Hisashi Harada, W. Andrew Yeudall, Suzy Torti, Frank Torti, David Gewirtz. Induction of non-protective autophagy by radiation in tumor cells: Implications for autophagy inhibition as a therapeutic strategy. [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 998. doi:10.1158/1538-7445.AM2015-998
Abstract 999: Utilization of catastrophic autophagy in ovarian cancer
Authors: Delaney Joe R. , Patel Chandni , Stupack Dwayne G. 
Published: August 2015

Abstract
In ovarian cancer, the dysfunction of apoptotic effectors such as p53 suggests that therapies which act tangential to ‘apoptotic’ pathways may offer alternative avenues to target recalcitrant disease. These pathways include necroptosis, ER stress, and autophagy. Evaluating combinations of agents which impact these pathways, we found that effects of ‘non-toxic’ drugs that induced ER stress and autophagy were potentiated when used with drugs that prevented autophagy resolution. At the cellular level, LC3-II levels were elevated in response to these agents, and predicted efficacy. GRP78 and SQSTM1/p62 were similarly elevated, indicating induction of the ER stress pathway impaired autophagic flux, respectively. The resulting death, via ‘catastrophic autophagy,’ may be an effective way to target traditional-chemotherapy-resistant ovarian cancer.
Citation Format: Joe R. Delaney, Chandni Patel, Dwayne G. Stupack. Utilization of catastrophic autophagy in ovarian 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 999. doi:10.1158/1538-7445.AM2015-999
Abstract CT207: Phase I dose escalation and pharmokinetic study of 14-O-phosphonooxymethyltriptolide
Authors: Greeno Edward , Borazanci Erkut , Gockerman Jon , Korn Ronald , Saluja Ashok , Von Hoff Daniel 
Published: August 2015

Abstract
Introduction: We are conducting a phase I, first-in-human trial of 14-O-phosphonooxymethyltriptolide (Minnelide,) a water-soluble prodrug of triptolide, a diterpene derived from the thunder god vine (tripterygium wilfordii). Triptolide is a potent inhibitor of heat shock protein 70 (HSP70) and pancreatic ductal adenocarcinoma over-expresses HSP70 as a protective mechanism. We have previously shown Minnelide to be effective and well tolerated in preclinical models of pancreatic carcinoma.
Methods: The study uses a 3+3 dose escalation scheme, enrolling subjects with gastrointestinal malignancies refractory to standard therapies. The drug is administered as a daily, brief IV infusion for 21 days out of a 28 day cycle. The primary endpoint is toxicity, with secondary endpoints of pharmokinetics and response.
Results: To date we have enrolled 27 subjects (17 pancreas, 7 colorectal, 3 other GI) at doses from 0.16 to 0.8 mg/m2, with 24 evaluable for toxicity. The therapy has been generally well tolerated with the only common toxicity being hematologic, but one patient experienced reversible cerebellar dysfunction at the highest dose. Pharmokinetics (n = 21) indicate rapid conversion of Minnelide to triptolide, with all Minnelide cleared within 30 minutes and peak triptolide levels achieved within 5 minutes of completion of infusion. Triptolide was rapidly cleared with a half-life of less than 30 minutes, and complete clearance by 6 hours, except in the patient with cerebellar toxicity who demonstrated delayed clearance of the drug. All subjects, except those in the lowest dose cohort, have had a reduction in HSP70 levels. The 9 patients in the first 3 dose cohorts all progressed by the end of cycle two. Tumor response by PET after cycle 1 (n = 19), shows a partial metabolic response in 36%, and stable metabolic disease in 52%. Response after 2 cycles by RECIST criteria (n = 10) shows a 10% PR (gastric) and 60% SD (5 pancreas, 1 rectal) rate with disease control for up to 6 months. 5 patients remain on study, with ongoing enrollment planned.
Conclusions: We have seen promising evidence of significant clinical activity in this group of heavily pretreated patients with refractory GI malignancies. The toxicity profile and optimal dosing of Minnelide are being defined.
Citation Format: Edward Greeno, Erkut Borazanci, Jon Gockerman, Ronald Korn, Ashok Saluja, Daniel Von Hoff. Phase I dose escalation and pharmokinetic study of 14-O-phosphonooxymethyltriptolide. [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 CT207. doi:10.1158/1538-7445.AM2015-CT207
Abstract CT211: Biomarker search using gene expression databases in a phase III controlled clinical trial of postoperative adjuvant chemotherapy for stage III colon cancer (ACTS-CC): correlation between clinicopathological factors and gene expression level
Authors: Uetake Hiroyuki , Ishikawa Toshiaki , Ishiguro Megimi , Matsui Shigeyuki 
Published: August 2015

Abstract
Background: The ACTS-CC trial is a randomized, controlled phase III study designed to validate the noninferiority of S-1 to UFT/leucovorin as adjuvant chemotherapy for stage III colon cancer and rectosigmoid cancer. A prospective biomarker search was performed as an auxiliary study of the ACTS-CC trial, using formalin-fixed, paraffin-embedded (FFPE) specimens obtained from 892 patients. The gene expression levels of 5-FU metabolizing enzymes and folate metabolizing enzymes and alterations of genome-wide copy numbers in tumor have been reported (2012, 2013 and 2014 Annual Meetings of AACR). In the present study, we performed correlation analyses of clinicopathological feature and gene expression level.
Methods: Blocks of resected tumor specimens for this biomarker study were obtained after receiving informed consent from 892 of 1535 patients enrolled between April 2009 and January 2010. Macro-dissections were manually performed to extract total RNA and genomic DNA from 10-μm-thick FFPE specimens of colon cancer. Gene expression levels of 11 enzymes (TS, DPD, TP, OPRT, FPGS, GGH, DHFR, MTHFR, MTHFD, FOLRA, GART) related to 5-FU and folic acid metabolism were studied according to the Danenberg Tumor ProfileTM method (Shirota, Y. JCO 2001).
Results: Gene expression levels were successfully estimated in 521-808 samples (84.0-90.0%, median 89.4%). Among 11 genes, GGH most strongly correlated with tumor locations: expression level of GGH in the distal colon was 1.8 times higher than those in the proximal colon. Gene expressions of DPD and GGH were significantly influenced by differentiation of tumor. DPD and GGH mRNA levels in poorly differentiated tumors were 2.0 or 2.5 times higher than those in well differentiated tumors, respectively. Likewise, TS most strongly correlated with tumor depth: expression level in T1 or T2 tumor was 1.3 times higher than those in T4 tumor.
Conclusions: Location, differentiation and depth of the tumor correlated with each gene expressions. Our findings will facilitate understanding the characteristics of colon cancer. Further investigation on gene expressions including genome-wide copy number analysis may contribute to the exploration of valid biomarkers.
Citation Format: Hiroyuki Uetake, Toshiaki Ishikawa, Megimi Ishiguro, Shigeyuki Matsui. Biomarker search using gene expression databases in a phase III controlled clinical trial of postoperative adjuvant chemotherapy for stage III colon cancer (ACTS-CC): correlation between clinicopathological factors and gene expression level. [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 CT211. doi:10.1158/1538-7445.AM2015-CT211
Abstract LB-035: Hepatitis C virus NS3/4A hijacks the host B-cell receptor signaling pathway
Authors: Dai Bojie , Landon Ari , Houng Simone , Gartenhaus Ronald B. 
Published: August 2015

Abstract
B-cell receptor (BCR) signaling is critical for the development of normal B-cells and B-cell lymphoma. Increasing epidemiological evidence indicates an association between chronic hepatitis C virus (HCV) infection and B-cell lymphoma, however, the mechanisms by which HCV causes B-cell lymphoproliferative disorder are still unclear. Herein, we demonstrate the expression of HCV viral proteins in B-cells of HCV-infected patients and show that HCV up-regulates BCR signaling in human primary B-cells. HCV nonstructural protein NS3/4A interacts with CHK2 and down-regulates its activity, modulating HuR posttranscriptional regulation of a network of target mRNAs associated with B-cell lymphoproliferative disorders. Strikingly, the BCR signaling pathway was found to have the largest number of transcripts with increased association with HuR and up-regulated by NS3/4A. Our study reveals a previously unidentified role of NS3/4A in regulation of host BCR signaling during HCV infection, lending further insight into the molecular mechanisms underlying HCV-associated B-cell lymphoproliferative disorders.
Citation Format: Bojie Dai, Ari Landon, Simone Houng, Ronald B. Gartenhaus. Hepatitis C virus NS3/4A hijacks the host B-cell receptor signaling pathway. [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-035. doi:10.1158/1538-7445.AM2015-LB-035
Abstract LB-038: Caspase-mediated iASPP cleavage inhibits NF-kB
Authors: Hu Ying , Ge Wenjie , Wang Xinwen , Lu Xin 
Published: August 2015

Abstract
Constitutive activation of the transcription factor nuclear factor-kB (NF-κB) plays an important role in oncogenesis and drug resistance of several types of human cancers. Inhibiting NF-κB pathways is therefore emerging as a promising approach to treat cancer. iASPP was first reported as an NF-κB binding partner and inhibitor in a yeast-two-hybrid system. However, it remains unknown how this activity is regulated in cells. For the first time, we show that the activity of iASPP is regulated by caspase-dependent cleavage at cellular level. iASPP was cleaved by caspases at a very early stage of treatment. Interestingly, in contrast to full-length iASPP that is predominantly cytosolic, the iASPP fragment accumulates in the nucleus. Cleaved iASPP shows increased interaction with NF-kB, which correlates with reduced activity of κB reporter. Overexpression iASPP fragment results in increased apoptosis. It also sensitizes cancer cells’ response to paclitaxe. Thus, this study reveals a novel mechanism by which caspase cleavage relocates iASPP from cytoplasm to the nuclear compartment and to pro-apoptotic machinery by binding and subsequent inhibiting NF-κB. This study also provides insights into new strategies to conquer drug resistance of NF-kB constitutive activated malignancies.
Citation Format: Ying Hu, Wenjie Ge, Xinwen Wang, Xin Lu. Caspase-mediated iASPP cleavage inhibits NF-kB. [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-038. doi:10.1158/1538-7445.AM2015-LB-038