bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 747: Glutamine, glutaminase and γ-glutamyl-transferase activities are essential for lung tumorigenesis
Authors: Sappington Daniel R. , Siegel Eric R. , Penney Rosalind B. , Boysen Gunnar 
Published: August 2015

Abstract
Increased glutamine uptake has been found to drive cancer cell proliferation, making tumor cells glutamine-dependent or even addicted. Glutamine is believed to provide additional carbon and nitrogen sources for cell growth. The first step in glutamine utilization is its conversion to glutamate by glutaminase (GLS). Glutamate is a precursor for glutathione synthesis, a pathway known to be activated in tumor cells. Additionally, glutathione concentrations are known to be elevated in non-small cell lung cancer (NSCLC) and is believed to protect against oxidative stress. In contrast, glutathione's participation in the γ-glutamyl-cycle is less well studied. Here we investigated the hypothesis that glutamine drives glutathione synthesis and export, drives the γ-glutamyl-cycle, and thereby contributes to NSCLC tumor cell proliferation. Glutamine consumption and glutathione excretion were measured in H460, A549 and MRC-5 cell lines. Treatment with BPTES, a known GLS inhibitor, led to reduced cell proliferation. This was also demonstrated when γ-glutamyl-transferase (GGT) was inhibited with acivicin. GGT transfers glutamyl groups from glutathione to amino acids to facilitate the amino acid transport into the cell. These results suggest active utilization of the γ-glutamyl cycle in the tumor cells. The formation of metabolites downstream of GLS and GGT were essentially abolished at the lowest inhibitor concentrations studied. In contrast, biological endpoints, such as MTT assay response, required up to 30-fold higher inhibitor concentrations. Culturing in stable isotope-labeled glutamine demonstrated that &gt;50% of excreted glutathione and &gt;80% of γ-glutamyl amino acids were derived from glutamine. Together these results demonstrate that glutamine is actively utilized for synthesis and excretion of glutathione which, in turn, is utilized to promote amino acid uptake by the formation of γ-glutamyl amino acids. These findings add yet another important function to the glutamine dependence of tumor cells. In addition to providing TCA cycle intermediates, we show that glutamine promotes glutathione synthesis to increase cellular defense mechanisms, and drives the γ-glutamyl cycle to enhance amino acid uptake.
Citation Format: Daniel R. Sappington, Eric R. Siegel, Rosalind B. Penney, Gunnar Boysen. Glutamine, glutaminase and γ-glutamyl-transferase activities are essential for lung 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 747. doi:10.1158/1538-7445.AM2015-747
Abstract 76: Molecular profiling of AML patient derived xenograft models with deep sequencing using a 109 AML associated gene panel and a 409 gene comprehensive cancer panel
Authors: Huang Stephen , Lira Paul , Wang Kai , Zhang Cathy , Jackson-Fisher Amy , Ching Keith , Rejto Paul 
Published: August 2015

Abstract
We have developed and validated a 109 AML associated gene panel NGS assay based on sequence capture technologies. The overall assay sensitivity was 99.%, and overall assay specificity was 100% when sequenced with reference “gold” standard NA12878. Assay analytical accuracy was evaluated with diluted cell line samples harboring mutations in this gene panel, all diluted mutations with minor allele frequencies were detected, analytical limit of detection (LOD) is &lt; 5%, and assay reproducibility is 96.8%. The assay also demonstrated robustness in sequencing 10 commercial AML patient samples (whole blood and bone marrow) and detecting mutations. Therefore, the AML gene panel deep sequencing assay is sensitive and accurate and is ready to be used for preclinical and clinical studies.
We subsequently sequenced 15 AML patient derived xenograft (PDX) models with this assay. These models were also deep sequenced with a 409 comprehensive cancer gene panel based on multiplex amplicon technologies. The mutation profiles of each model will be summarized in this presentation using two sequencing platforms. By analysis of the mutation profile of each model, sub-clones of mutations were revealed in the early passages of these models. Two of these models with FLT-3 mutations were later treated with Quizartinib and Crenolanib separately, the treated mouse models were profiled with these two targeted gene panels; clonal evolution of mutations in these models treated with FLT-3 inhibitors was documented.
Deep sequencing with target gene panel is a powerful tool to decipher the mutation sub-clones in the early passages of PDX models, and understand the acquired resistance of drug treatment.
Citation Format: Stephen Huang, Paul Lira, Kai Wang, Cathy Zhang, Amy Jackson-Fisher, Keith Ching, Paul Rejto. Molecular profiling of AML patient derived xenograft models with deep sequencing using a 109 AML associated gene panel and a 409 gene comprehensive cancer panel. [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 76. doi:10.1158/1538-7445.AM2015-76
Abstract 760: On the evolution of erlotinib-resistant NSCLC subpopulations
Authors: Ramirez Michael E. , Steininger Robert J. , Wu Lani F. , Altschuler Steven J. 
Published: August 2015

Abstract
One of the foremost challenges to cancer treatment is the emergence of drug resistance. Adding complexity to this problem is the recent realization that drug resistance can stem from selection for both intrinsically resistant subpopulations as well as subpopulations that adapt to the drug challenge through epigenetic and/or signaling state changes. Because of this complexity, cells have many ways to survive in response to targeted inhibitors, resulting in a diversity of resistance states between and even within patient tumors. Ongoing strategies are aimed at finding the best second-line therapies for resistant tumors. However, the extent to which drug-resistant subpopulations exhibit similar or divergent sensitivities to second-line treatments is unknown. How different are drug-resistant subpopulations from one another? Do these differences affect the types of inhibitors that will be effective in killing these drug-resistant colonies, resulting in a variety of strategies for managing drug-resistant populations? What are the molecular changes that correspond to differences in secondary drug response? Here, we aim to determine the degree of heterogeneity between drug-resistant clonal populations by profiling their response to a panel of second-line therapies and examining mutational states to secondary drug response. This study will provide insight into whether or not drug-resistant subpopulations adopt similar or disparate drug-resistant states.
Citation Format: Michael E. Ramirez, Robert J. Steininger, Lani F. Wu, Steven J. Altschuler. On the evolution of erlotinib-resistant NSCLC subpopulations. [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 760. doi:10.1158/1538-7445.AM2015-760
Abstract 77: Genomic characterization of aggressive subtype of neuroblastoma without MYCN amplification
Authors: Ohira Miki , Tatsuno Kenji , Tsutsumi Shuichi , Yamamoto Shogo , Nakamura Yohko , Kamijo Takehiko , Aburatani Hiroyuki , Nakagawara Akira 
Published: August 2015

Abstract
Neuroblastoma is known to exhibit wide ranges of clinical behavior, from spontaneous regression to highly resistant to chemotherapy, and one of the challenges in the clinic is to develop adequate therapeutic strategies for the intermediate risk-type of patients (stage 3 or 4 without MYCN amplification) whose prognosis sometimes tends to be poor in long-time follow-up (10 years survival rate (SR) was 51% in our database, n = 161). To discover the key target genes or pathways for the unfavorable subset in this patient group, we have analyzed 44 primary tumors (dead:24, alive:20) without MYCN amplification nor ALK alteration by integrated genomic analyses such as array CGH, gene expression profiling and whole exome sequencing (SureSelect 50Mb, average read depth:157, x20 coverage:95%). We found 816 non-synonymous somatic single nucleotide variations (SNVs) in coding genes and alteration number in each tumor strongly associates with age at diagnosis (p&lt;0.0001) and patient prognosis (p = 0.187). A novel ATRX mutation was identified in a tumor with 1p and 11q losses isolated from a male patient (age:93 months). Recurrent SNVs (n = 2 to n = 6) were found in 44 genes, 20 of those were involved only in the tumors from the patient with poor prognosis, in the 44 tumor set. Validation of these 20 SNVs is ongoing by using additional clinical samples. These features of genomic alterations could be useful for risk classification for each tumor and constructing new therapeutic strategies for aggressive neuroblastomas without MYCN amplification.
Citation Format: Miki Ohira, Kenji Tatsuno, Shuichi Tsutsumi, Shogo Yamamoto, Yohko Nakamura, Takehiko Kamijo, Hiroyuki Aburatani, Akira Nakagawara. Genomic characterization of aggressive subtype of neuroblastoma without MYCN amplification. [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 77. doi:10.1158/1538-7445.AM2015-77
Abstract 771: Preclinical characterization of the selective FGFR inhibitor INCB054828
Authors: Liu Phillip CC , Wu Liangxing , Koblish Holly , Bowman Kevin , Zhang Yue , Klabe Ronald , Leffet Lynn , DiMatteo Darlise , Rupar Mark , Gallagher Karen , Hansbury Michael , Zhang Colin , He Chunhong , Collier Paul , Covington Maryanne , Wynn Richard , Yeleswaram Swamy , Vaddi Kris , Burn Timothy , Yao Wenqing , Huber Reid , Scherle Peggy , Hollis Gregory 
Published: August 2015

Abstract
Aberrant signaling through Fibroblast Growth Factor Receptors (FGFR) has been reported in multiple types of human cancers. Genomic analyses of squamous cell lung, gastric and urothelial tumors have revealed recurrent genetic alterations in FGFR1, FGFR2 and FGFR3 genes, respectively. FGFR proteins contribute to the development of malignancies by promoting tumor cell proliferation, survival, and migration and supporting angiogenesis. Therefore targeting FGFR kinases may provide therapeutic benefit to patients with cancers that have genetic alterations in genes encoding components of the FGF-FGFR axis. INCB054828 is a potent inhibitor of FGFR1, FGFR2, and FGFR3 that has selective pharmacological activity against cancer cells with FGFR alterations.
In vitro, INCB054828 potently inhibited the kinase activity of recombinant FGFR1, FGFR2 and FGFR3 enzymes and was highly selective against a panel of kinases including VEGFR2. In cellular assays, INCB054828 inhibited the autophosphorylation of FGFR proteins with low nanomolar IC50 values and blocked signal transduction by FGFR to downstream markers of pathway activation. Cancer cell lines that have genetic alterations in FGFR1, FGFR2 and FGFR3 were uniquely sensitive to growth inhibition by INCB054828, with IC50 values generally in the range of 3-50 nM, compared with cancer cell lines or normal cells without FGFR dependence (IC50 &gt; 1500 nM). In vivo, once-daily oral administration of INCB054828 inhibited the growth of tumors that are dependent upon FGFR1, FGFR2 and FGFR3 activity at tolerated doses. Suppression of tumor growth was dose-dependent and correlated with pharmacodynamic inhibition of FGFR. Collectively, these preclinical studies demonstrate that INCB054828 potently and selectively inhibits models of FGFR-dependent cancers in vitro and in vivo, supporting the compound's clinical evaluation in patients harboring oncogenic FGFR activation.
Citation Format: Phillip CC Liu, Liangxing Wu, Holly Koblish, Kevin Bowman, Yue Zhang, Ronald Klabe, Lynn Leffet, Darlise DiMatteo, Mark Rupar, Karen Gallagher, Michael Hansbury, Colin Zhang, Chunhong He, Paul Collier, Maryanne Covington, Richard Wynn, Swamy Yeleswaram, Kris Vaddi, Timothy Burn, Wenqing Yao, Reid Huber, Peggy Scherle, Gregory Hollis. Preclinical characterization of the selective FGFR inhibitor INCB054828. [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 771. doi:10.1158/1538-7445.AM2015-771
Abstract 773: Alectinib shows potent antitumor activity against both ALK- and RET-rearranged non-small cell lung cancers
Authors: Kodama Tatsushi , Tsukaguchi Toshiyuki , Satoh Yasuko , Yoshida Miyuki , Watanabe Yoshiaki , Kondoh Osamu , Sakamoto Hiroshi 
Published: August 2015

Abstract
We have shown that alectinib is a potent ALK inhibitor and is being evaluated in clinical trials for the treatment of ALK fusion-positive non-small cell lung cancer (NSCLC). Recently, RET and ROS1 fusion genes have been implicated as driver oncogenes in 1-2% of NSCLC and have been developed into promising molecular targets for antitumor agents. Here, we investigate the additional target indication of alectinib by testing its ability to inhibit the activity of RET and ROS1 kinases. In enzyme assay, alectinib showed kinase inhibitory activity against RET as wells as ALK but did not show against ROS1. Alectinib inhibited the growth of LC-2/ad cells harboring CCDC6-RET and Ba/F3 cells expressing KIF5B-RET by suppressing RET phosphorylation. Alectinib also showed antitumor activity in mouse models of RET fusion-positive tumors (LC-2/ad cells and Ba/F3 cells expressing KIF5B-RET) and of ALK fusion-positive tumors (NCI-H2228 cells harboring EML4-ALK). In addition, alectinib showed kinase inhibitory activity against RET gatekeeper mutations (RET V804L and V804M) and blocked KIF5B-RET gatekeeper mutation-driven cell growth. Our results suggest that alectinib is effective against RET fusion-positive tumors, as observed in ALK fusion-positive tumors. Thus, alectinib might be a therapeutic option for patients with RET fusion-positive NSCLC.
Citation Format: Tatsushi Kodama, Toshiyuki Tsukaguchi, Yasuko Satoh, Miyuki Yoshida, Yoshiaki Watanabe, Osamu Kondoh, Hiroshi Sakamoto. Alectinib shows potent antitumor activity against both ALK- and RET-rearranged non-small cell lung cancers. [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 773. doi:10.1158/1538-7445.AM2015-773
Abstract 79: An androgen response element-based reporter assay for the detection of androgen receptor activity in prostate cells
Authors: Azeem Waqas , Hellem Margrete R. , Olsen Jan R. , Hua Yaping , Marvyin Kristo , Li Lisha , Qu Yi , Lin Biaoyang , Ke Xisong , Oyan Anne M. , Kalland Karl-Henning 
Published: August 2015

Abstract
Background: The androgen receptor (AR) transcription factor plays pivotal roles in the development and progression of prostate cancer. AR is activated and maintained throughout prostate cancer progression even in castration-resistant prostate cancer (CRPC). AR and its classical target genes such as PSA (KLK3) are, however, efficiently shut off in basal epithelial prostate cells and possibly in prostate cancer stem cells (CSCs). There is limited information on the mechanisms that keep the AR OFF in these cells, and the conditions that turn the AR and target genes ON.
Results: Fluorescent and luminescent reporters were constructed to develop a functional assay for AR activity. These reporters contain the repeated AR binding promoter sequences and were designed in a way that the AR can activate these AR element (ARE) reporters. The 241B reporter was selected among the constructed ARE reporters on the basis of higher activity. The AR positive prostate cancer cell line, LNCaP, was transduced with the lentiviral 241B-mCherry fluorescence reporter. FACS analysis quantitated the ARE reporter activity when reporter cells were treated with androgen and with the AR antagonist, enzalutamide, or the anti-androgen, abiraterone. AR expression vectors were also constructed with the AR open reading frames cloned into lentiviral expression vectors. All constructs were sequenced to verify the correct AR DNA sequence and their activity were tested using ARE reporter system.
Conclusion: The developed ARE reporter system is useful to understand the mechanisms of AR and AR target gene activation in different subpopulations of prostate cancer cells. It will help us to investigate the role of the AR in differentiation and proliferation of prostate cells and to study the AR activity in two and three dimensional cell cultures. This system can also be useful in screening for drugs with activity against the AR.
Citation Format: Waqas Azeem, Margrete R. Hellem, Jan R. Olsen, Yaping Hua, Kristo Marvyin, Lisha Li, Yi Qu, Biaoyang Lin, Xisong Ke, Anne M. Oyan, Karl-Henning Kalland. An androgen response element-based reporter assay for the detection of androgen receptor activity in prostate cells. [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 79. doi:10.1158/1538-7445.AM2015-79
Abstract 795: Dovitinib exerts potent antitumor effects in gastrointestinal stromal tumors
Authors: Hung Huynh T. , Ong Richard , Chow Pierce 
Published: August 2015

Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumours of the gastrointestinal (GI) tract. Although Imatinib is the current first-line therapy for patients not suitable for surgical resection, 10 - 20% of GIST patients taking Imatinib do not respond to this therapy and 40-50% of the patients develop acquired resistance to Imatinib following partial response or stable disease. Thus, novel treatments are needed for GIST. In the present study, four different patient-derived xenograft (PDX) GIST models were used to demonstrate that Imatinib effectively caused tumor regression in GIST26-0208A and GIST09-0210 models with the common exon 11 KIT W557-K558 mutation (Imatinib-sensitive models), inhibited tumor growth of GIST27-0510 model with Y568-I571 and P573-L576 deletion and delayed tumor growth in GIST27-0612 with wild-type KIT. Unlike Imatinib, Dovitinib effectively caused tumor regression in all four PDX models tested regardless of their KIT mutational status. On GIST27-0510 model, tumor regression was observed as early as day 3 of Dovitinib treatment and continued to approximately 22% of the initial tumor volume. Dovitinib provided longer progression-free period than Imatinib after a 21-day treatment cycle. In the GIST26-0208A model, signs of tumor regrowth were observed on day 2 for Imatinib and day 59 for Dovitinib following a 21-day treatment. Dovitinib treatment took approximately 3.7 - 5 times longer to reach initial tumor volume than Imatinib following a 21-day treatment. Utilizing micro-Positron Emission Tomography (mPET), both Imatinib and Dovitinib treatment showed decreased SUV and TLG readings after 8-day treatment in GIST26-0208A. A trend of increasing activity was observed in Imatinib but not in Dovitinib-treated tumors at day 11 and day 21 following an 8-day treatment, suggesting mPET could potentially be used to access tumor response to Dovitinib. In Imatinib/Dovitinib-sensitive models, Imatinib and Dovitinib induced significant reduction in expression of p-ERK1/2, Bim, p-AKT (Ser473) and p-Cdc2 at 72 hours post treatment. Although inhibition of p-c-Kit (Tyr568/570) was observed, higher levels of p-Histone H2A-X (Ser139) and Cleaved PARP expression were observed in Dovitinib than Imatinib treatment, suggesting that Dovitinib was more effective than Imatinib in inducing cell death. Our data showed that Dovitinib treatment is able to provide greater advantages over Imatinib in all four PDX models regardless of their KIT mutational status, suggesting that Dovitinib may offer an alternative treatment for GIST that are insensitive to Imatinib.
Citation Format: Huynh T. Hung, Richard Ong, Pierce Chow. Dovitinib exerts potent antitumor effects in gastrointestinal stromal tumors. [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 795. doi:10.1158/1538-7445.AM2015-795
Abstract 796: Alofanib, a novel allosteric FGFR2 inhibitor, shows potent antitumor activity in ovarian cancer with FGFR2 expression
Authors: Tjulandin Sergei , Byakhov Mikhail , Stepanova Evgenia , Khochenkov Dmitry , Harrison Daniel , Tsimafeyeu Ilya 
Published: August 2015

Abstract
Alofanib (formerly known as RPT835) is a novel allosteric FGFR2 inhibitor with activity in FGFR2-expressing triple-negative breast cancer [Tjulandin S, et al. San Antonio Breast Cancer Symposium 2014]. Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity [Cole C, et al. Cancer Biol Ther. 2010]. We investigated antitumor activity of alofanib in ovarian cancer in vitro and in vivo.
To assess the efficacy of alofanib on FGF-mediated cell proliferation, ovarian cancer (SKOV-3) FGFR2-expressing cells were incubated in a 96-well microculture plate and were treated with serially diluted RPT835. Basic FGF was added at a concentration of 25 ng/ml. Control wells were left untreated. Cell growth inhibition was determined using Promega's Cell Titer-Glo® assay. Immunocompromised mice were used for xenotransplantation of FGFR2 high-expressing ovarian cancer cells (SCOV-3). Seventy animals with measurable tumors were selected on day 10 and randomized into control groups (no treatment or chemotherapy alone (paclitaxel + carboplatin) and treatment groups (alofanib orally or intravenously (different dose levels) in combination with chemotherapy). Measurements of tumor volume (mm3) were performed by digital calipers every 3 days during 30 days after tumor inoculation.
Basic FGF significantly increased proliferation of the ovarian cancer cells in untreated control group (P = 0.001). Alofanib treatment resulted in growth inhibition of SKOV-3 cell line in vitro. Treatment of alofanib in combination with paclitaxel/carboplatin demonstrated significant tumor growth delay phenotype in all treatment groups compared to control non-treatment groups. Alofanib exhibited a dose-dependent effect on tumor growth. Daily intravenous regimen of alofanib (total maximum dose per week was 350 mg/kg) demonstrated dramatic effect (inhibiting growth by 80% and by 53% in comparison with vehicle and chemotherapy group alone, respectively (P&lt;0.001). Alofanib decreased number of vessels in tumor on 49% compared with chemotherapy alone (P&lt;0.05). There were tumor necrosis and cell degeneration in alofanib group.
These results provide strong rationale for evaluation of alofanib in combination with paclitaxel and carboplatin in patients with ovarian cancer.
Citation Format: Sergei Tjulandin, Mikhail Byakhov, Evgenia Stepanova, Dmitry Khochenkov, Daniel Harrison, Ilya Tsimafeyeu. Alofanib, a novel allosteric FGFR2 inhibitor, shows potent antitumor activity in ovarian cancer with FGFR2 expression. [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 796. doi:10.1158/1538-7445.AM2015-796