bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3369: The importance of dose schedule with Hsp90 inhibitors: Results from a Phase II study in dogs with mast cell tumors.
Authors: London Cheryl A. , Bear Misty D. , Proia David A. 
Published: August 2014

Abstract
Purpose: STA-1474 is the prodrug of ganetespib, currently the most advanced Hsp90 inhibitor in human clinical trials. In a Phase I clinical trial, STA-1474 demonstrated biologic activity in dogs with spontaneous tumors. Data from this trial suggested that longer drug infusion times (8 hours versus 1 hour) were potentially associated with greater biologic activity. The purpose of the following study was to extend these observations and identify the optimum dosing schedule of STA-1474 in dogs with spontaneous mast cell tumors (MCT).
Experimental Design: This was a Phase 2 trial in which dogs with spontaneous MCT received STA-1474 (6 mg/kg, per week) under one of four different dosing schedules: once weekly with a 1 hour infusion (cohort A) or 8 hour infusion (cohort B), or twice weekly with a 1 hour infusion given 24 hour (cohort C) or 72 hour (cohort D) between doses. Toxicities, biomarker changes from pre- and two post-treatment biopsies, and tumor responses were assessed.
Results: Twenty-four chemotherapy and radiation naïve dogs with MCT were enrolled. Toxicities were mild and primarily gastrointestinal in nature consisting of diarrhea, vomiting, inappetence and lethargy. Measurable responses were observed from dogs in cohort A (SD=5, PD=1), cohort B (PR=2, SD=4), cohort C (PR=3, SD=3) and cohort D (PR=2, SD=1, PD=1). Biopsies are currently being evaluated by reverse phase protein array and results will be presented.
Conclusions: This study provides further evidence that prolonged exposure to STA-1474 improves biological activity. Dosing STA-1474 on two consecutive days yielded the greatest objective responses (50%) and a disease control rate of 100%. Given the similarities of canine and human cancers with respect to tumor biology and HSP90 synthesis following its inhibition, it is likely that more frequent exposure to ganetespib will demonstrate comparable anti-cancer activity in human patients and is currently being evaluated in a Phase I study.
Citation Format: Cheryl A. London, Misty D. Bear, David A. Proia. The importance of dose schedule with Hsp90 inhibitors: Results from a Phase II study in dogs with mast cell tumors. [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 3369. doi:10.1158/1538-7445.AM2013-3369
Abstract 3379: Overexpression of CTGF is associated with chemoresistance in esophageal adenocarcinoma.
Authors: Wang Zhuwen , Lin Lin , Thomas Dafydd G. , Orringer Mark B. , Chang Andrew C. , Beer David G. , Lin Jules 
Published: August 2014

Abstract
Esophageal adenocarcinoma is the most rapidly increasing solid malignancy with an overall 5-year survival of only 19%. Neoadjuvant chemoradiation is standard practice in most large centers but results in a complete pathologic response in only 21%, although this subset has an improved 5-year survival. In this study, connective tissue growth factor (CTGF), which is associated with increased cell migration, tissue invasion, and angiogenesis, was evaluated for its role in chemoresistance in esophageal adenocarcinoma. CTGF was found to be overexpressed in 33.3% (5 of 15; mean 3.1-fold) of esophageal adenocarcinomas on oligonucleotide microarray relative to Barrett's metaplasia. Elevated expression of CTGF was also found in 5/5 advanced stage IV esophageal adenocarcinomas on Western blot. Overexpression of CTGF was observed in 70.6% of chemoresistant esophageal adenocarcinomas (n=17) as determined using qRT-PCR and was significantly higher compared to chemo-naïve esophageal adenocarcinomas (n=102; p&lt;0.0005). Stable inhibition with an shRNA against CTGF in the esophageal adenocarcinoma cell line Flo, which expresses endogenous CTGF, led to a significantly increased response to the chemotherapeutic agents 5-FU (9.4-fold increase), cisplatin (5.5-fold), and etoposide (4.4-fold) at 24 hours (p&lt;0.005). These findings suggest that CTGF may be important in mediating chemoresistance in esophageal adenocarcinoma and that inhibition of CTGF could be useful in modulating chemoresistance to current neoadjuvant regimens in esophageal adenocarcinomas overexpressing CTGF.
Citation Format: Zhuwen Wang, Lin Lin, Dafydd G. Thomas, Mark B. Orringer, Andrew C. Chang, David G. Beer, Jules Lin. Overexpression of CTGF is associated with chemoresistance in esophageal adenocarcinoma. [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 3379. doi:10.1158/1538-7445.AM2013-3379
Abstract 3401: Vemurafenib-induced RhoB expression leads to melanoma cell resistance.
Authors: Delmas Audrey , Cherier Julia , Medale-Giamarchi Claire , Pradines Anne , Favre Gilles 
Published: August 2014

Abstract
Most of melanoma harbour mutations leading to the constitutive activation of the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) pathway (i.e: activating mutations of BRAF, NRAS, c-KIT). Addiction of melanoma to the MAPK pathways led to the development of inhibitors targeting either mutant BRAF, such as Vemurafenib (PLX4032), or MEK. Melanoma treatment recently met a breakthrough with the clinical evaluation of Vemurafenib that demonstrated an unprecedented 80% response rate among patients with BRAF V600E melanomas treated with Vemurafenib, but rapidly limited by drug resistance, which still requires to be elucidated.
The MAPK pathway regulates the expression of many genes which can mediate therapeutic response but also resistance, such as RhoGTPases. We analysed the mRNA expression of the RhoGTPases in two BRAF mutated melanoma cell lines, WM266-4 and A375, in response to inhibition of the MAPK pathway by PLX4032. We observed that the mRNA of RhoB was increased by PLX4032 treatment. This result was confirmed in many other BRAF mutated melanoma cell lines by inhibition of the MAPK pathway with BRAF inhibitors (PLX4032 or SB-590885) as well as MEK inhibitors (AZD6244 or AS703026). MEK inhibitors (AZD6244 or AS703026) upregulate RhoB in BRAF wild-type melanoma cells harbouring N-Ras, K-Ras or c-KIT mutation suggesting that inhibiting MAPK pathway is critical for RhoB expression modulation. It is noteworthy that this modulation is cell type dependent, while it was not found in BRAF mutated non-melanoma cells as colon carcinoma cells (Colo205 and RKO).
To investigate the role of RhoB induction in cellular responses to BRAF and MEK inhibitors, the RhoB induction was suppressed using RNA interference. The cells treated with siRNA targeting RhoB, WM266-4 and A375 cells, were more sensitive to PLX4032 and AZD6244. Moreover the blockade of RhoB induction led to a significant increase of PLX4032-induced apoptosis as shown by the increase of the subG1 population and PARP cleavage.
Our findings show that RhoB upregulation is involved in PLX4032 response and both inhibitions of MAPK pathway and RhoB expression trigger cell death and should prompt a search for agents. Indeed co-targeting MAPK and RhoB pathways, could lead to a synthetic lethality and prevent resistance to either BRAF or MEK inhibitors. Ongoing work focuses on confirming this role in tumour-xenografted mouse models.
Citation Format: Audrey Delmas, Julia Cherier, Claire Medale-Giamarchi, Anne Pradines, Gilles Favre. Vemurafenib-induced RhoB expression leads to melanoma cell resistance. [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 3401. doi:10.1158/1538-7445.AM2013-3401
Abstract 3404: Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma.
Authors: Girotti Maria R. , Pedersen Malin , Sanchez-Laorden Berta , Viros Amaya , Turajlic Samra , Niculescu-Duvaz Dan , Zambon Alfonso , Sinclair John , Hayes Andrew , Gore Martin , Springer Caroline , Larkin James , Jorgensen Claus , Marais Richard 
Published: August 2014

Abstract
We generated melanoma cell lines resistant to BRAF inhibitors and show that the EGF receptor (EGFR)-SRC family kinase (SFK)-STAT3 signaling pathway was upregulated in these cells. In addition to driving proliferation of resistant cells, this pathway also stimulated invasion and metastasis. EGFR inhibitors cooperated with BRAF inhibitors to block the growth of the resistant cells in vitro and in vivo, and monotherapy with the broad specificity tyrosine kinase inhibitor dasatinib blocked growth and metastasis in vivo. We analyzed a tumor from a BRAF mutant patient with intrinsic resistance to vemurafenib. Vemurafenib treatment induced SFK activation in this tumor and we show that dasatinib blocked its growth and metastasis in immunocompromised mice. Our data shows that BRAF inhibitor-mediated activation of EFGR/SFK/STAT3 signaling can mediate resistance in BRAF mutant melanoma patients. We describe two treatments that appear to overcome this resistance and could deliver therapeutic efficacy in drug-resistant BRAF mutant melanoma patients.
Citation Format: Maria R. Girotti, Malin Pedersen, Berta Sanchez-Laorden, Amaya Viros, Samra Turajlic, Dan Niculescu-Duvaz, Alfonso Zambon, John Sinclair, Andrew Hayes, Martin Gore, Caroline Springer, James Larkin, Claus Jorgensen, Richard Marais. Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. [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 3404. doi:10.1158/1538-7445.AM2013-3404
Abstract 3409: Inhibition of checkpoint kinase 2 enhances sensitivity of pancreatic adenocarcinoma cells to Gemcitabine.
Authors: Duong Hong-Quan , Kim Jung Soon , Lee Hee-Seok , Seong Yeon-Sun , Bae Insoo ,   Dept. Oncol and Dept. of Rad. Medicine, Lombardi Comprehensive Cancer Center, Georgetown University.
Published: August 2014

Abstract
Checkpoint kinase 1/2 (Chk1/2) plays pivotal function as effectors of cell cycle checkpoint regulation following DNA damage. Small molecule inhibitors of Chk1/2 are under clinical evaluation in combination with chemotherapeutic agents. We examined whether NSC109555, a competitive inhibitor of Chk2 inhibitor could enhance the synergistic antitumor effect(s) of Gemcitabine(GEM) in pancreatic adenocarcinoma cell model. In the present study, the combination treatment by NSC109555 plus GEM demonstrated strong synergistic antitumor effect in four pancreatic cancer cells. In addition, the combination treatment of NSC109555 plus GEM significantly increased the generation of intracellular reactive oxygen species (ROS), followed by induction of apoptotic cell death. Furthermore, the inhibition of ROS generation by N-acetyl cysteine (NAC) significantly prevented the decrease in cell survival and increase in apoptotic cell death by combination treatment of NSC109555 plus GEM. Small interfering RNA (siRNA) mediated knockdown of Chk2 also enhanced GEM-inhibited cell survival and GEM-induced apoptotic cell death. Our findings suggest that NSC109555 would be beneficial therapeutic agents when combined with GEM and support the novel synthetical lethal approach for cancer therapy by these combinations for preclinical and clinical treatment of pancreatic cancer.
Citation Format: Hong-Quan Duong, Jung Soon Kim, Hee-Seok Lee, Yeon-Sun Seong, Insoo Bae, Dept. Oncol and Dept. of Rad. Medicine, Lombardi Comprehensive Cancer Center, Georgetown University. Inhibition of checkpoint kinase 2 enhances sensitivity of pancreatic adenocarcinoma cells to Gemcitabine. [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 3409. doi:10.1158/1538-7445.AM2013-3409
Abstract 3441: Dynamin inhibitors as anticancer agent in cervical carcinoma.
Authors: Lee Jeong-Won , Jeon Hye Kyung 
Published: August 2014

Abstract
Dynamin is a 96 kDa GTPase enzyme involved in membrane constriction and fission during endocytosis. Among the three human dynamin genes, dynamin I is expressed in neurons and neuro-endocrine cells, dynamin II is expressed in most cell types, and dynamin III is strongly expressed in the testis, brain, and lung tissue. Dynamin II plays an essential role in the completion of the final stage of mitosis, cytokinesis. MiTMAB (myristyl trimethyl ammonium bromides) and OcTMAB (octadecyltrimethyl ammonium bromide) are small-molecule inhibitors of dynamin that competitively interfere with the ability of dynamin to bind phospholipids and prevent receptor-mediated endocytosis. In this study, we investigated whether dynamin inhibitor could inhibit survival, proliferation, and invasion of cervical cancer cell lines. To evaluate the role of dynamin II in cell proliferation, we performed MTT assays with Hela and SiHa cells after incubation with various doses of MiTMAB or OcTMAB. To confirm the apoptosis after MiTMAB and OcTMAB treatment, active caspase-3 ELISA and FACS were performed. And to identify the role of dynamin II in cell invasion, we evaluated the secretion of MMP-9 after dynamin II inhibitor treatment by ELISA assay. We found that MiTMAB and OcTMAB had a growth-inhibiting effect at 2 or 3 day after treatment in both cells. Active caspase-3 expression and Annexin V intensity were increased by MiTMAB and OcTMAB. And the secretion of MMP-9 was increased after dynamin II inhibitor treatment. MiTMAB and OcTMAB are the first compounds reported to exclusively block cytokinesis without affecting progression through any other stage of the cell cycle. Cytokinesis failure induces cell death. These data revealed that dynamin II modulates cancer cell survival, proliferation, and invasion and suggest that dynamin II could be a key target for new strategies in cervical cancer treatment.
Citation Format: Jeong-Won Lee, Hye Kyung Jeon. Dynamin inhibitors as anticancer agent in cervical carcinoma. [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 3441. doi:10.1158/1538-7445.AM2013-3441
Abstract 3450: ABT-348 in combination with inhibition of CDK4/6 highlights a strategy to target RB mutant cells while sparing RB wild-type cells.
Authors: Guo Jun , Curtin Michael L. , Chen Zehan , Albert Daniel H. , Tapang Paul , Dai Yujia , Bui Mia-Ha , Kovar Peter , Michaelides Michael R. , Glaser Keith B. , Tse Chris , Shah O. Jameel 
Published: August 2014

Abstract
ABT-348 is a novel, potent and orally bioavailable inhibitor of the Aurora kinases as well as the VEGF and PDGF families of receptor tyrosine kinases. ABT-348 is broadly efficacious preclinically as a single agent against a wide range of tumor types and is currently in Phase I/II clinical trials. Several published studies have supported the potential utility of combining targeted anti-proliferative agents with cytotoxic chemotherapies. Herein, the efficacy of combining the neocytotoxic agent, ABT-348, with CDK4/6 inhibition in the treatment of solid tumor cells has been evaluated. Inhibition of CDK4/6 via siRNA elicits a potent cytostatic response in cells that harbor a wild-type, functional RB. We demonstrate that features of cellular senescence are induced in human tumor cells with siRNAs targeting both CDK4 and CDK6. Dual inhibition of CDK4 and CDK6 is required for antiproliferative activity in most cancer cell lines and this is not accompanied by induction of apoptosis. In RB wild-type cells, CDK4/6 inhibition antagonizes the activity of ABT-348 by inducing G0/G1 arrest. Conversely, CDK4/6 inhibition does not alter the therapeutic response of RB-deficient cells to ABT-348, indicating that the effects of ABT-348 are dependent on cells progressing into mitosis. A preponderance of evidence from previous publications and our studies indicate that CDK4/6 inhibition attenuates the cellular response to cytotoxic chemotherapies in RB wild-type cells providing a potential to expand the therapeutic window for ABT-348. Thus combination with ABT-348 and a CDK4/6 inhibitor may provide an opportunity to selectively target RB mutant cells.
Citation Format: Jun Guo, Michael L. Curtin, Zehan Chen, Daniel H. Albert, Paul Tapang, Yujia Dai, Mia-Ha Bui, Peter Kovar, Michael R. Michaelides, Keith B. Glaser, Chris Tse, O. Jameel Shah. ABT-348 in combination with inhibition of CDK4/6 highlights a strategy to target RB mutant cells while sparing RB wild-type 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 3450. doi:10.1158/1538-7445.AM2013-3450
Abstract 3454: Bcl-xL anti-apoptotic network is dispensable for emergence and maintenance of CML but required for disease progression, and represents an alternative target for halting survival of blast crisis CML progenitors.
Authors: Harb Jason , Neviani Paolo , Ellis Justin E. , Ferenchak Gregory J. , Chyla Brenda I. , Hokland Peter , Roy Denis Claude , Caligiuri Michael A. , Marcucci Guido , Huettner Claudia S. , Perrotti Danilo 
Published: August 2014

Abstract
The dismal outcome of blast crisis chronic myelogenous leukemia (CML-BC) patients underscores the need for a better understanding of the mechanisms responsible for the development of drug-resistance and disease progression. We generated an inducible mouse model in which simultaneous expression of p210 BCR-ABL1 and deletion of bcl-x occurs within hematopoietic stem and progenitor cells. Absence of Bcl-xL did not affect the development of the chronic phase-like myeloproliferative disease; however, none of the deficient mice progressed to an advanced phenotype, suggesting the importance of the anti-apoptotic Bcl-xL signaling network for the progressing early progenitor cell survival. Indeed, pharmacologic inhibition of Bcl-xL with the Bcl-xL/Bcl-2 antagonist ABT-263, combined with activation of the Bcl-xL-regulator BAD, through the PP242-mediated inhibition of mTORC1/2, markedly augmented apoptosis of BCR-ABL1+ cell lines and primary CD34+ progenitors from CML-BC but not from healthy donors, regardless of the drug-resistance effect induced by bone marrow stromal cell-generated signals. Accordingly, shRNA-mediated downregulation of BAD and the BCR-ABL1-target hnRNP A1, which promotes translation of Bcl-xL but not Bcl-2, impaired the ability of PP242 to potentiate the effect of ABT-263, and mimicked the anti-leukemic activity of ABT-263, respectively, in primary leukemic CD34+ progenitors and/or CML-BC cell lines. Thus, suppression of the antiapoptotic potential of Bcl-xL together with activation of Bad represents a novel potential pharmacologic approach for treatment of those patients undergoing blastic transformation.
Citation Format: Jason Harb, Paolo Neviani, Justin E. Ellis, Gregory J. Ferenchak, Brenda I. Chyla, Peter Hokland, Denis Claude Roy, Michael A. Caligiuri, Guido Marcucci, Claudia S. Huettner, Danilo Perrotti. Bcl-xL anti-apoptotic network is dispensable for emergence and maintenance of CML but required for disease progression, and represents an alternative target for halting survival of blast crisis CML progenitors. [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 3454. doi:10.1158/1538-7445.AM2013-3454
Abstract 3475: Progranulin as a prognostic biomarker of advanced epithelial ovarian cancer.
Authors: Fitzgerald Sharon , Yu Minshu , Hays John , Di Santo Nicola , Havrilesky Laura , Kohn Elise 
Published: August 2014

Abstract
Late diagnosis and early recurrence make epithelial ovarian cancer (EOC) the leading cause of gynecologic cancer death in the US. Indicators of early relapse may allow triage of high-risk patients to earlier therapy. Progranulin (PGRN) is a growth and survival factor overexpressed in EOC. We hypothesize that elevated serum (s)PGRN concentrations after clinical complete response (CCR) to primary platinum and taxane-based combination chemotherapy prognosticates disease recurrence and decreased survival in advanced EOC patients. We previously demonstrated high plasma (p)PGRN concentration (cutoff 59ng/ml) at first CCR distinguished early from late recurrence and predicted long-term survival (ROC AUC=0.944; sensitivity 93%; specificity 100%). In multivariate analysis, high pPGRN concentration predicted early recurrence (HR=23.5; 95%CI: 2.49-221; P&lt;0.006). As PGRN is cleaved into proinflammatory granulins by neutrophil elastase, we wished to investigate the reliability of sPGRN as a biomarker. We compared PRGN concentrations in ten blinded, paired serum and plasma samples, using commercial PRGN ELISA assays; paired two-tailed t-test demonstrated comparability (P=0.90, R2= 0.002). A cohort of 35 blinded serum samples from a different institution was analyzed using the ELISA. The optimal dichotomization concentration of sPGRN, 49.5ng/ml, was determined by ROC statistics at a specificity of 90%, and applied to outcome analyses using Cox proportional hazards and Kaplan-Meier modeling. This PGRN cutoff significantly differentiated progression-free survival (PFS; P=0.0013). Subjects with low sPGRN had 100% survival (OS) at 2 years (N=11; range 2-12). Further validation of PGRN's discriminatory value could lead to its clinical investigation as a prognostic biomarker to stratify those at high risk for recurrence to closer monitoring or maintenance therapy, as well as its examination as a predictive biomarker for response to initial therapy.
Citation Format: Sharon Fitzgerald, Minshu Yu, John Hays, Nicola Di Santo, Laura Havrilesky, Elise Kohn. Progranulin as a prognostic biomarker of advanced epithelial ovarian cancer. [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 3475. doi:10.1158/1538-7445.AM2013-3475