bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B161: SLC1A5 inactivation induces apoptosis-mediated cells death in non-small cell lung cancer.
Authors: Hassanein Mohamed , Qian Jun , Hoeksema Megan , Jacobovitz Marie , Harris Fredrick T. , Harris Bradford , Massion Pierre P. 
Published: August 2014

Abstract
Introduction: We recently reported that solute carrier family A1 member 5 (SLC1A5) controls glutamine (GLN) uptake and modulates cell growth, oxidative stress and mTOR signalling pathway. SLC1A5 is a transmembrane, high affinity glutamine transporter that is overexpressed and located at the plasma membrane in non-small cell lung cancer (NSCLC). GLN deprivation has been shown to induce cell death in several types of cancers, however the exact mechanism by which SLC1A5 targeting affects NSCLC survival remains unknown. We hypothesize that inhibition of SLC1A5 deprives cells from GLN which induces autophagy which eventually leads to cell starvation and ultimately apoptotic cell death.
Methods: To test our hypothesis we targeted SLC1A5 by siRNA or by its specific inhibitor, GPNA, in a panel of 6 NSCLC lung cancer cell lines (express high level of SLC1A5). For comparison 2 human bronchial epithelial cell lines (HBEs) (express low level of SLC1A5) were used. The effects of targeting SLC1A5 on growth, GLN uptake, ATP level, autophagy, and cell death were examined. Markers of autophagy and cell death were analysed using western blot, nuclear staining and cell cycle analysis.
Results: SLC1A5 inactivation by GPNA or by siRNA resulted in a significant decrease in cellular GLN uptake in NSCLC cell lines, while HBE cell lines were unaffected. Decrease in GLN uptake was accompanied by an increase in autophagy as evident by decrease in cell size, increase of LC3-II and decrease if LC3-I markers of autophagy. In addition, we observed a significant drop in ATP levels by 2 folds with increasing doses of GPNA. Markers of internal apoptotic pathway that include decrease of mitochondrial potential and cleaved caspases-3 and 9 were detected in response to increasing doses of GPNA. No change was observed in external apoptotic markers, caspases 8 or 1. In addition a 2-10 fold increase (based on the cell line) of sub-G1 was observed in NSCLC cell lines but not in HBE cell lines.
Conclusion: Our results show that targeting SLC1A5 in NSCLC cells induces apoptotic cell death. Cells starve due to GLN deprivation and undergo autophagy which leads to a decrease in ATP level resulting in apoptotic cell death. These findings suggest that targeting SLC1A5 may have therapeutic implications in NSCLC.
Grant funding: Lung Cancer Research Foundation
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B161.
Citation Format: Mohamed Hassanein, Jun Qian, Megan Hoeksema, Marie Jacobovitz, Fredrick T. Harris, Bradford Harris, Pierre P. Massion. SLC1A5 inactivation induces apoptosis-mediated cells death in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B161.
Abstract B165: The antitumor efficacy of eribulin is mediated via suppression of invasion and profound induction of cell death in triple negative breast cancer.
Authors: Hu Jing , Horwitz Susan Band , McDaid Hayley M. 
Published: August 2014

Abstract
Eribulin, a microtubule-targeting antitumor drug, is FDA-approved for the treatment of certain patients with advanced or metastatic breast cancer. Some patients treated with this drug have evidence of reduced metastatic dissemination. Triple-negative breast cancer (TNBC), which accounts for approximately 15%-20% of all breast cancers, does not respond to hormone therapies so patients are dependent on chemotherapy. A subset of these patients are intrinsically resistant to chemotherapy, or subsequently relapse and develop metastatic disease, eventually leading to mortality. We explored the mechanistic basis for the antitumor efficacy of eribulin in a panel of triple negative breast cancer cell lines that histologically are classified as basal-like or claudin-low. Specifically, we determined the ability of eribulin to induce cell death versus senescence, and secondly to modulate cancer cell invasion and epithelial to mesenchymal transition (EMT) gene expression. Senescence is a clinically relevant cell fate following chemotherapy that can propel tumor progression and EMT. Eribulin was efficacious at inducing cell death in both subtypes of TNBC, and had a remarkably low propensity to induce senescence in TNBC compared to non-small cell lung cancer and colon cancer cells. A 24-hour treatment with eribulin partially prevented tumor cell invasion in the claudin-low subtype, as assayed by Boyden chamber analysis. Drug-tolerant claudin-low cells that survived high-dose eribulin treatment were also found to have a reduction in EMT markers. In summary, in vitro analysis of cell fate and metastasis indicate that eribulin has an ability to modulate invasiveness and EMT characteristics in preclinical models of TNBC.
This research was funded by Eisai Inc.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B165.
Citation Format: Jing Hu, Susan Band Horwitz, Hayley M. McDaid. The antitumor efficacy of eribulin is mediated via suppression of invasion and profound induction of cell death in triple negative breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B165.
Abstract B168: Investigating the role of SOX2- HEY1 signaling loop in Glioma Invasion.
Authors: Ramadoss Archana , Boulay Jean Louis , Tostado Cristobal , Ritz Marie-Francoisse , Mariani Luigi 
Published: August 2014

Abstract
Gliomas are the most frequent and the most aggressive tumors of CNS. Invasiveness and existence of glioma stem-like cells resistant to conventional therapy contribute to the aggressive phenotype of the tumor. Current treatment efforts (surgery and radiation therapy) fail to prevent the relapse of secondary gliomas.
Measurement of thickness of the infiltration zone surrounding the tumor mass, visualized by MRI, allows classification of patient glioma into Grade I (2-3 mm), Grade II (3-10 mm) and Grade III (&gt;10 mm). Microarray data from classified biopsies indicate that SOX2 and HEY1 mRNAs expressions correlated with tumor invasion grade. This suggested a possible role for SOX2 and HEY1 in regulating genes involved in invasion. Lentiviruses expressing shRNAs against either SOX2 or HEY1 were used to knockdown human glioma cell lines U373 and LN319. Boyden chamber assays and wound healing assays were used as readouts for invasion and migration respectively.
Gene expression analysis on glioma cells depleted for SOX2 revealed 2-5 fold down-regulation of HEY1 mRNA. Interestingly, we observed that glioma cells depleted for HEY1 showed 1-1.5 fold up-regulation for SOX2. This suggested that these transcription factors could be regulating each other. We observed that invasion and migration was strongly enhanced in SOX2 depleted cells. Consistently, our microarray data on these cells showed that mRNA of genes related to epithelial-mesenchymal-transition (EMT) were 1-3.5 fold overexpressed. In contrast, glioma cells depleted for HEY1 showed significant reduction in invasion and migration and the mRNA of genes related to EMT were 2- 5-fold downregulated.
These results are consistent in supporting the hypothesis that a SOX2- HEY1 signaling loop participates in EMT and in glioma invasion. Confirmation of these observations is currently being carried out on a genetic mice model of glioma. Definition of the effectors of glioma invasion might ultimately contribute to identify targets for the development of customized therapies aimed at controlling glioma invasion.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B168.
Citation Format: Archana Ramadoss, Jean Louis Boulay, Cristobal Tostado, Marie-Francoisse Ritz, Luigi Mariani. Investigating the role of SOX2- HEY1 signaling loop in Glioma Invasion. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B168.
Abstract B17: Decreased expressions in autophagy-related proteins is associated with poor prognosis in patients with colorectal adenocarcinoma.
Authors: Lee Han Hong , Choi Ji Hye , Choi Young-Seok , Ko Yoon Ho 
Published: August 2014

Abstract
Background: Autophagy, a cellular degradation process, has paradoxical roles in tumorigenesis and progression of human cancers. The aim of this study was to investigate the expression of autophagy-related proteins in colorectal cancer (CRC), and to evaluate their prognostic significance.
Methods: We analyzed the expression of 3 autophagy-related proteins (LC3B, beclin-1, ATG5) in 263 resected colorectal cancer specimens by immunohistochemistry using tissue microarray.
Results: Of the 263 patients, autophagy-related protein expression frequencies were 71.3% (174/244) for beclin-1, 74.7% (186/249) for LC3B, and 65.1% (151/232) for Atg5. The correlation between the expressions of autophagy-related proteins was significant for all protein pairs. Kaplan-Meier analysis showed that low LC3B expression was positively linked to poor prognosis of the patients with CRC. Cox's proportional hazard model demonstrated that curative resection status, lymph node metastasis, LC3B expression, and the alteration of autophagy-related proteins were independent prognostic factor for CRC.
Conclusion: Alterations in the expression of autophagy-related proteins are closely associated with prognosis of CRC, suggesting that expression patterns may be used as a prognostic marker.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B17.
Citation Format: Han Hong Lee, Ji Hye Choi, Young-Seok Choi, Yoon Ho Ko. Decreased expressions in autophagy-related proteins is associated with poor prognosis in patients with colorectal adenocarcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B17.
Abstract B179: Targeted next generation sequencing for somatic mutations in human cancer.
Authors: Peterson Jason D. , de Abreu Francine , Gallagher Torrey L. , Burchard Paul R. , Amos Christopher I. , Wells Wendy A. , Pipas J. Marc , Ernstoff Marc S. , Fadul Camilo E. , Rigas James R. , Tsongalis Gregory J. 
Published: August 2014

Abstract
Objective: We have replaced single gene PCR-based methods for the detection of BRAF, KRAS and EGFR variants in routine clinical practice with next generation sequencing assays for the Ion Torrent AmpliSeq Cancer Hotspot Panel v2 (50 genes) and the Illumina TruSeq Amplicon Cancer panel (48 genes). Implementation of these panels requires constant optimization of technical and analytical procedures as reagents and software continue to be developed. In this study we describe somatic mutation findings from our clinical laboratory service.
Methods: DNA was extracted from 90 formalin fixed, paraffin embedded tissue specimens that included 50 lung cancer, 24 colon cancer and 16 other cancers. Barcoded libraries were prepared from up to 10ng of extracted DNA and multiplexed on single 318 chips. Data analysis was performed using Golden Helix SVS for the Ion Torrent panel and Variant Studio for the Illumina panel. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer (IGV).
Results: Of the 90 cancer cases sequenced, each panel returned on average 20 variants. Of these, there was 100% concordance between the two panels with respect to the clinically actionable mutations identified.
Conclusions: We have implemented next generation sequencing technologies for the detection of somatic mutations in human cancers. Two platforms, the Ion Torrent PGM and the Illumina MiSeq, have been used for the routine analysis of FFPE cancer tissues in a clinical setting with actionable and non-actionable variants reported and archived.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B179.
Citation Format: Jason D. Peterson, Francine de Abreu, Torrey L. Gallagher, Paul R. Burchard, Christopher I. Amos, Wendy A. Wells, J. Marc Pipas, Marc S. Ernstoff, Camilo E. Fadul, James R. Rigas, Gregory J. Tsongalis. Targeted next generation sequencing for somatic mutations in human cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B179.
Abstract B18: Induction of tumor cell apoptosis by a proteasome deubiquitinase inhibitor is associated with oxidative stress and activation of JNK/AP1 mediated signaling.
Authors: D'Arcy Padraig , Brnjic Slavica , Mazurkiewicz Magdalena , Linder Stig 
Published: August 2014

Abstract
Tumor cells are dependent on a functioning ubiquitin-proteasome system (UPS), making it an ideal target for the development of anti-cancer therapies. The approval of bortezomib has verified this, however several problems have emerged including dose-limiting toxicity and tumor relapse. Thus there is an urgent need not only to identify new drugs but also new drug targets for the improved treatment of cancer patients. We recently identified the small molecule b-AP15 as an inhibitor of proteasome de-ubiquitinase (DUB) activity. b-AP15 inhibits the activity of two proteasome-associated DUBs, UCHL5 and USP14, resulting in defective poly-ubiquitin processing, proteasome shutdown, apoptosis and cell death in vitro and in vivo cancer models. Investigations into the mechanism of action showed that b-AP15 induced apoptosis via the induction of oxidative stress and activation of JNK/AP1 mediated stress signaling. Inhibition of the UPS with bortezomib or b-AP15 induced a similar stress response, characterized by ER stress, activation of the JNK/AP1 pathway and production of reactive oxygen species (ROS). Importantly pharmacological inhibition of JNK or treatment with ROS scavengers inhibited b-AP15-induced apoptosis without altering UPS inhibition. Our data suggests a role for ROS production and JNK signaling in proteasome DUB inhibitor induced apoptosis.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B18.
Citation Format: Padraig D'Arcy, Slavica Brnjic, Magdalena Mazurkiewicz, Stig Linder. Induction of tumor cell apoptosis by a proteasome deubiquitinase inhibitor is associated with oxidative stress and activation of JNK/AP1 mediated signaling. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B18.
Abstract B181: TP53 mutation screening in patients with recurrent platinum-sensitive ovarian cancer.
Authors: Brana Irene , Moore Kathleen , Welch Stephen , Shapira-Frommer Ronnie , Gibbon Darlene , Hirte Hal , Rivkin Saul , Coleman Robert , Prendergast Gerry , Moxley Katherine M. , Jou Ying-Ming , Marinucci Michelle , Freshwater Tomoko , McCarthy Sharon , Anthony Mark Lee , Rose Shelonitda , Oza Amit M. 
Published: August 2014

Abstract
Background: TP53 is commonly mutated in ovarian cancer. As potential agents targeting TP53 mutant or wt are under development, the efficiency and accuracy for determination of TP53 mutations in a clinical trial was evaluated.
Methods: Eligible patients, including relapsed, platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer, underwent pre-screening for a clinical trial with MK1775, eligibility for which was determined by the presence of functional TP53 mutations (Brana I et al, ASCO 2013). Single base substitution and single base deletion mutations in exons 2 - 11 and the flanking splice junction in the TP53 gene were analyzed using AmpliChip p53 Assay (Roche Molecular Diagnostics, California) on archival tumor specimens.
Results: Seventy-five women were screened for eligibility based on TP53; 43 had TP53 mutations, 27 were TP53 wild-type (wt), and 5 undetermined (Table 1). No clustering of mutations to define hot spots was evident. The most commonly mutated region was exon 5 (11 mutations). Missense mutations were the most common mutation type (69.7%); although, nonsense (14 %), splice (14 %), and frame shift mutations (2.3%) were also observed (Table 1). Most of the missense mutations were in exons 5 to 8 (90%). The mean turnaround time from sample reception to final TP53 status report was 3 days (range 1:14).
Conclusions: The TP53 mutational status has been successfully determined in 93.3% of patients with a short turnaround time, supporting the feasibility of TP53 determination in the clinical setting. In our patient population, 57.3% had a TP53 mutation. Potential geographic differences in the incidence TP53 mutations cannot be evaluated due to the limited sample size; this hypothesis should be further evaluated in a larger patient population

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B181.
Citation Format: Irene Brana, Kathleen Moore, Stephen Welch, Ronnie Shapira-Frommer, Darlene Gibbon, Hal Hirte, Saul Rivkin, Robert Coleman, Gerry Prendergast, Katherine M. Moxley, Ying-Ming Jou, Michelle Marinucci, Tomoko Freshwater, Sharon McCarthy, Mark Lee Anthony, Shelonitda Rose, Amit M. Oza. TP53 mutation screening in patients with recurrent platinum-sensitive ovarian cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B181.
Abstract B184: In vitro and in vivo profiling of novel mTORC1/2 inhibitor DS-3078a.
Authors: Wakita Kenichi , Kiga Masaki , Togashi Noriko 
Published: August 2014

Abstract
DS[[Unable to Display Character: &#8209;]]3078a is a potent, selective small molecule inhibitor of the catalytic site of the mammalian target of rapamycin (mTOR). Our previous study showed DS-3078a to inhibit mTOR kinase activity in a concentration-dependent manner with an IC50 (concentration resulting in 50% of maximum inhibition) of approximately single digit nano molar. Here the antitumor potency of DS-3078a against various cancer cell lines in vitro and in vivo is shown. DS-3078a was applied to a 230 cell line panel assay to evaluate cell growth inhibition and apoptosis induction activity. In this study, DS-3078a was found to be a highly cytostatic compound with strong cell growth inhibiting activity. DS-3078a exhibited GI50s lower than 500 nM against over 200 cell lines and a 5-fold and higher caspase activation against only 36 cell lines. Among 12 in vivo xenograft models, 9 of 12 xenograft models demonstrated greater than a 50% tumor growth inhibition response at half of MTD dosing. There are several well-known selective mTOR kinase inhibitors including AZD8055 and OSI-027. When comparing the cellular response among these compounds, DS-3078a was found to have a weaker induction of the sub G1 population against AN3 CA human endometrial carcinoma cell line than the other two compounds, despite its similar kinase inhibiting profile against them. In a previous study, an increase of the phospho Akt(T308) by DS-3078a treatment in A498 human renal cell carcinoma, which was a sign of negative feedback loop disruption by inhibition of mTORC1 was demonstrated. In this model, AZD8055 and OSI-027 did not increase phospho Akt(T308), which implies inhibition of the PI-3K signal at higher concentrations. To understand the impact of the cytostatic characteristics of DS-3078a, in vivo mTOR signal inhibition at MTD using tumor bearing mouse was measured and compared to the signal inhibition pattern of AZD8055 and the PI-3K/mTOR dual inhibitor DS-7423. DS-3078a fully inhibited mTORC1 and mTORC2 downstream signals for 24 hr, while signal inhibition by DS-7423 was reduced by 18 hr. AZD8055 showed a similar pattern to DS-7423 at MTD dosing. This study highlights the unique characteristics of DS-3078a which may offer a unique differentiation of response and toxic profile compared to other mTOR inhibiting compounds in the clinical setting.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B184.
Citation Format: Kenichi Wakita, Masaki Kiga, Noriko Togashi. In vitro and in vivo profiling of novel mTORC1/2 inhibitor DS-3078a. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B184.
Abstract B195: MAGI3-Akt3, a novel fusion protein in the PI3K pathway in cancer.
Authors: Brown Kristin , Toker Alex 
Published: August 2014

Abstract
Aberrant activation of the PI3K/Akt pathway is found in approximately 70% of breast cancers. We recently identified a recurrent rearrangement that produces an in-frame fusion protein containing Akt3 and the scaffolding protein MAGI3. MAGI3-Akt3 is the first fusion protein that has been identified in the PI3K pathway. We propose that MAGI3-Akt3 is a novel oncogene in breast cancer and that the oncogenic activity of the fusion protein results from disruption of the PI3K/Akt pathway. Within the fusion, Akt3 has a disrupted PH domain prior to glutamate 17 (E17). As a result the fusion protein is constitutively phosphorylated in the Akt3 kinase domain and expression of MAGI3-Akt3 in breast cancer cells enhances Akt substrate phosphorylation. Constitutive MAGI3-Akt3 kinase activity can be inhibited by ATP-competitive small molecule Akt inhibitors but is resistant to the allosteric Akt inhibitor MK2206 which is currently in phase II clinical trials. Our results indicate that ATP competitive Akt inhibitors should be evaluated in clinical trials for the treatment of fusion-positive breast cancers. The fusion protein also contains a severely truncated portion of the scaffolding protein MAGI3. In particular, the fusion lacks the second PDZ domain of MAGI3 that has been reported to bind to PTEN and be required for the inhibitory effect of PTEN on PI3K pathway activity. We have demonstrated that disruption of MAGI3 in breast cancer cell lines does indeed promote PI3K pathway hyperactivity in a PTEN-dependent manner. In addition, the fusion lacks the fifth PDZ domain of MAGI3 and our studies indicate that this disrupts the interaction of MAGI3 with PHLPP2, a phosphatase that directly dephosphorylates Akt at pS473. Our studies therefore demonstrate that the MAGI3-Akt3 translocation significantly perturbs PI3K pathway activity via activation of an oncogene (Akt3) and dysregulation of two tumor suppressors (PTEN and PHLPP2). We are currently continuing studies to elucidate the oncogenic mechanism(s) of MAGI3-Akt3 in breast cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B195.
Citation Format: Kristin Brown, Alex Toker. MAGI3-Akt3, a novel fusion protein in the PI3K pathway in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B195.