bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B159: Heterozygous IDH1 mutations modify the citric acid (TCA) cycle metabolism and sensitize cells to inhibition of mitochondrial respiration/oxidative phosphorylation.
Authors: Grassian Alexandra R. , Parker Seth , Davidson Shawn , Green Courtney , Lin Fallon , Joud-Caldwell Carol , Yin Hong , Chung Franklin , Straub Christopher , Vander Heiden Matthew , Pagliarini Raymond , Metallo Christian 
Published: August 2014

Abstract
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a variety of tumor types. Although these mutations are loss-of-function for conversion of isocitrate to α-ketoglutarate, the mutant enzymes greatly increase the production of the proposed oncometabolite, 2-hydroxyglutarate (2-HG). However the full metabolic consequences of IDH1/2 mutation in their heterozygous cellular context have yet to be fully explored. To address this question, we utilized a panel of isogenic cell lines with wild-type IDH1/2 or clinically relevant IDH1/2 mutations and examined the metabolic consequences of IDH mutation using (13)C metabolic flux analysis (MFA).
We observe a dramatic and consistent decrease in the ability of IDH1 mutant cell lines to utilize reductive glutamine metabolism via the carboxylation of α-ketoglutarate back to isocitrate. This was not seen either in IDH2 mutant cell lines or in wild-type cell lines treated with exogenous 2-HG. Consistent with these changes, the IDH1 mutant cell lines, but not IDH2 mutant or 2-HG treated cells, were deficient in the utilization of glutamine for de novo lipogenesis. Similar trends were observed in endogenous, non-engineered IDH1/2 mutant cell lines.
The decrease in reductive carboxylation in the IDH1 mutant cell lines raises the hypothesis that these cells may be more reliant on mitochondrial metabolism. Indeed, IDH1 mutant cells were more sensitive to either treatment with an electron transport chain inhibitor or growth in hypoxia (which also inhibits mitochondrial metabolism).
These results show heterozygous IDH1 mutation robustly impacts wild-type cellular metabolism in a different manner than IDH2 mutation. Furthermore, these results suggest that IDH1 and IDH2 mutant tumors may be differentially sensitive to inhibitors of specific metabolic pathways.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B159.
Citation Format: Alexandra R. Grassian, Seth Parker, Shawn Davidson, Courtney Green, Fallon Lin, Carol Joud-Caldwell, Hong Yin, Franklin Chung, Christopher Straub, Matthew Vander Heiden, Raymond Pagliarini, Christian Metallo. Heterozygous IDH1 mutations modify the citric acid (TCA) cycle metabolism and sensitize cells to inhibition of mitochondrial respiration/oxidative phosphorylation. [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 B159.
Abstract B169: Hypoxia-inducible factor 1α (HIF-1α) correlates with epithelial-mesenchymal transition (EMT) and tumor growth in thyroid cancer cell lines.
Authors: Yang YJ , Na HJ , Kim Ws , Bong Jp , Baek Sj , Kim Jw , Park Jh , Shin Dy , Hong Hj , Kwon Jh , Lee Ej , Koh Yw , Choi Ec 
Published: August 2014

Abstract
Hypoxia is essential for microenvironment to induce tumor metastasis. Intratumoural hypoxia, followed by stabilization and activation of the HIF-1α transcription complex, is one of the most important mechanisms that promotes metastasis and thereby, increases tumor aggressiveness. EMT (epithelial to mesenchymal transition), one of the central mechanisms that induces invasion and metastasis of tumors. The aim of this study was to investigate the possible role of HIF-1α as one of the microenvironmental influences driving metastatic progression by induction of epithelial to mesenchymal transition in thyroid cancer. In vitro studies revealed a functionally active HIF-1a pathway in several types of thyroid cells with transcriptional activation observed after hypoxia or overexpression. Knock-down of HIF-1α or overexpression of HIF-1α in thyroid cancer cells suggested that HIF-1α promotes epithelial-mesenchymal transition (EMT) and metastastic phenotypes in follicular thyroid cancer cell lines, especially. HIF-1α increases the expression of Vimentin, N-cadherin, Snail, Slug, Twist, MMP2, VEGF but not E-cadherin. Also, wound healing assay and in vitro migration assays showed that the cell migration ability was increased in a HIF1α- dependent manner. Furthermore, knock-down of HIF-1α leads to decreased tumor growth and regulates the expression of EMT marker genes in thyroid tumor xenograft mouse model. Taken together, these results suggest that the HIF-1 signaling induces EMT and metastasis through the regulation of various EMT regulators in vitro as well as in vivo study.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B169.
Citation Format: YJ Yang, HJ Na, Ws Kim, Jp Bong, Sj Baek, Jw Kim, Jh Park, Dy Shin, Hj Hong, Jh Kwon, Ej Lee, Yw Koh, Ec Choi. Hypoxia-inducible factor 1α (HIF-1α) correlates with epithelial-mesenchymal transition (EMT) and tumor growth in thyroid cancer cell lines. [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 B169.
Abstract B190: GDC-0068 is a novel and selective Akt inhibitor that enhances the efficacy of FOLFOX in primary gastric cancer models.
Authors: Ingalla Ellen , Hong Rebecca , Savage Heidi , Punnoose Elizabeth , Rost Sandra , Koeppen Hartmut , Sampath Deepak , Nannini Michelle A. 
Published: August 2014

Abstract
Background: Akt, a serine/threonine protein kinase, is a key signaling node in the PI3K/Akt/mTOR pathway and plays an essential role in regulating tumor cell proliferation, migration and survival. PI3K/Akt signaling is up-regulated in gastric cancer, mainly due to loss of PTEN, and is associated with poor prognosis and chemoresistance. Chemotherapeutics such as doxorubicin and 5-FU/cisplatin have been shown to upregulate PI3K/Akt signaling in several solid cancers in response to DNA damage. We have previously reported on a potent highly selective ATP-competitive pan-Akt inhibitor, GDC-0068, which inhibits cell cycle progression and viability of cancer cell lines and xenografts driven by Akt signaling, including those with defects in the tumor suppressor PTEN, oncogenic mutations in PIK3CA, and amplification of HER2. Thus, we hypothesized that the combination of FOLFOX and GDC-0068 would induce anti-tumor activity in primary gastric cancer models.
Methods: Gastric cancer cell lines (n=11) were treated with increasing concentrations of GDC-0068 and FOLFOX and evaluated for combinational efficacy over single agent via cell viability assay. For in vivo studies, primary gastric cancer xenograft models were implanted in immuno-compromised mice and treated with GDC-0068 and FOLFOX as single agents or in combination.
Results: In vitro, the combination of GDC-0068 and FOLFOX results in enhanced inhibition of tumor cell viability in the cell lines with activation of the PI3K pathway compared to either single agent alone. These results were recapitulated in vivo, in the primary xenograft models STO#240 and STO#182, where the combination of GDC-0068 and FOLFOX resulted in increased tumor growth inhibition or regressions compared to single agents alone. All combinations tested were well tolerated in vivo based on minimal changes in body weights.
Conclusions: Our preclinical studies demonstrate improved anti-tumor efficacy when GDC-0068 is combined with FOLFOX in gastric cancer models in vitro and in vivo. The data supports the clinical development of GDC-0068 in combination with FOLFOX for the treatment of gastric cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B190.
Citation Format: Ellen Ingalla, Rebecca Hong, Heidi Savage, Elizabeth Punnoose, Sandra Rost, Hartmut Koeppen, Deepak Sampath, Michelle A. Nannini. GDC-0068 is a novel and selective Akt inhibitor that enhances the efficacy of FOLFOX in primary gastric cancer models. [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 B190.
Abstract B221: Hmga2 furthers lung adenocarcinoma progression through function as a competing endogenous RNA.
Authors: Kumar Madhu S. , Armenteros-Monterroso Elena , East Philip , Chakravorty Probir , Matthews Nik , Winslow Monte M. , Downward Julian 
Published: August 2014

Abstract
Lung adenocarcinoma is the most widespread cancer type worldwide. As the majority of patients are diagnosed with metastatic disease, it is vital to understand that biological basis of adenocarcinoma progression. Hmga2 is among the most over-expressed genes in lung adenocarcinoma, and we have previously shown it is necessary for lung cancer progression in vivo. However, the mechanism of Hmga2-mediated cancer progression is unclear. Here we demonstrate Hmga2 promotes oncogenic transformation by functioning as a competing endogenous RNA (ceRNA) for the let-7 family of microRNAs (miRNAs). First, Hmga2 can promote lung cancer cell transformation independent of its protein-coding function but dependent upon let-7 sites in its 3’ untranslated region. These effects are observed both in vitro and in vivo, where Hmga2 ceRNA activity promotes lung cancer growth and dissemination, impairing survival. Combined analyses of miRNA target prediction and cell line gene expression data suggested the TGF-β co-receptor Tgfbr3 lies downstream of the Hmga2 ceRNA. Follow-up studies demonstrated Hmga2 specifically regulated Tgfbr3 expression through differential recruitment of the miRNA regulatory machinery. This regulation is functionally relevant, as both Tgfbr3 in particular and TGF-β in general are necessary for Hmga2 to promote transformation. To assess the clinical relevance of these experimental findings, we assessed gene expression data from two extensive lung cancer patient gene expression datasets: the Cancer Genome Atlas and the Director's Challenge. Analysis of this gene expression data revealed that HMGA2 and TGFBR3 are coordinately and reciprocally regulated in patients, a necessary prediction of HMGA2 ceRNA function. In total, these results indicate the Hmga2 oncogene functions as both a protein-coding gene and a ceRNA. Such multi-level regulation of gene expression constitutes a novel paradigm by which genes alter cancer development and progression through combined function as both coding proteins and non-coding RNAs.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B221.
Citation Format: Madhu S. Kumar, Elena Armenteros-Monterroso, Philip East, Probir Chakravorty, Nik Matthews, Monte M. Winslow, Julian Downward. Hmga2 furthers lung adenocarcinoma progression through function as a competing endogenous RNA. [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 B221.
Abstract B23: Apoptotic and autophagic effects of Sesbania grandiflora flowers in human leukemic cells.
Authors: Roy Rajneeta , Kumar Deepak , Chowdhury Chinmay , Das Padma 
Published: August 2014

Abstract
Background: Identification of cytotoxic compounds that induce apoptosis has been the mainstay of anticancer therapeutics for several decades. In recent years, focus has shifted to inducing multiple modes of cell death coupled with reduced systemic toxicity. The plant Sesbania grandiflora is widely used in Indian traditional medicine for the treatment of a broad spectrum of diseases. This encouraged us to investigate into the anti-proliferative effect of a fraction (F2) isolated from S. grandiflora flowers in cancer cells and delineate the underlying involvement of apoptotic and autophagic pathways.
Principal Findings: Using MTT based cell viability assay, we evaluated the cytotoxic potential of fraction F2. It was the most effective on U937 cells (IC50: 18.6 µg/ml). Inhibition of growth involved enhancement of Annexin V positivity. This was associated with elevated reactive oxygen species generation, measured by flow cytometry and reduced oxygen consumption– both effects being abrogated by antioxidant NAC. This caused stimulation of pro-apoptotic proteins and concomitant inhibition of anti-apoptotic protein expressions inducing mitochondrial depolarization, as measured by flow cytometry and release of cytochrome c. Interestingly, even with these molecular features of apoptosis, F2 was able to alter Atg protein levels and induce LC3 processing. This was accompanied by formation of autophagic vacuoles as revealed by fluorescence and transmission electron microscopy– confirming the occurrence of autophagy. Eventually, F2 triggered caspase cascade– executioners of programmed cell death and AIF translocation to nuclei. This culminated in cleavage of the DNA repair enzyme, poly (ADP-ribose) polymerase that caused DNA damage as proved by staining with Hoechst 33258 leading to cell death.
Conclusions: The findings suggest fraction F2 triggers pro-oxidant activity and mediates its cytotoxicity in leukemic cells via apoptosis and autophagy. Thus, it merits consideration and further investigation as a therapeutic option for the treatment of leukemia.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B23.
Citation Format: Rajneeta Roy, Deepak Kumar, Chinmay Chowdhury, Padma Das. Apoptotic and autophagic effects of Sesbania grandiflora flowers in human leukemic cells. [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 B23.
Abstract B242: Adipocytes contribute to resistance of human melanoma cells to chemotherapy and targeted therapy.
Authors: Chi Mengna , Chen Jiezhong , Ye Yan , Tseng Hsin-Yi , Lai Fritz , Tay Kwang Hong , Jin Lei , Jiang Chen Chen , Zhang Xu Dong 
Published: August 2014

Abstract
Increasing epidemiological evidence has linked the development and progression of several cancers including melanoma with obesity. However, whether obesity impinges on responses of cancer cells to treatment remains less understood. Here we report that human adipocytes contribute to resistance of melanoma cells to various therapeutic agents. Exposure to media from adipocyte cultures (adipocyte media) increased cell proliferation and reduced sensitivity of melanoma cells to apoptosis induced by diverse chemotherapeutic drugs, including the DNA-damaging drug cisplatin, the microtubule-targeting agent docetaxel, and the histone deacetylase inhibitor SAHA. This was associated with increased activation of PI3K/Akt and MEK/ERK signaling, and was attenuated by a PI3K or MEK inhibitor. The effect of adipocyte media on melanoma cells was, at least in part, due to the interaction between the adipokine leptin and its long form receptor OB-Ob, in that immunodepletion of leptin in adipocyte media or siRNA knockdown of OB-Rb in melanoma cells reversed the increase in Akt and ERK activation, enhancement in cell proliferation, and importantly, protection of melanoma cells against the drugs. In support, recombinant leptin partially recapitulated the effect of adipocyte media on melanoma cells. Of note, OB-Rb was increased on the surface of melanoma cells compared to melanocytes, whereas leptin short form receptors appeared to be suppressed post-transcriptionally, suggesting that OB-Rb was selectively upregulated in melanoma cells. Collectively, these results indicate that adipocytes contribute to resistance of melanoma cells to chemotherapeutic drugs and agents targeting the PI3K/Akt and MEK/ERK pathways, and suggest that inhibition of the leptin/ OB-Rb system may be useful to improve the efficacy of multiple therapeutic approaches in the treatment of melanoma.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B242.
Citation Format: Mengna Chi, Jiezhong Chen, Yan Ye, Hsin-Yi Tseng, Fritz Lai, Kwang Hong Tay, Lei Jin, Chen Chen Jiang, Xu Dong Zhang. Adipocytes contribute to resistance of human melanoma cells to chemotherapy and targeted therapy. [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 B242.
Abstract B280: Histone deacetylase (HDAC) 6 inhibition potentiates the cytotoxicity of lapatinib and PI3K inhibitors on Her2+ breast cancer cell lines.
Authors: Yang Min , Tamang David , Jones Simon 
Published: August 2014

Abstract
ACY-1215 is a novel and selective oral inhibitor of HDAC6 currently in Phase I clinical trials in combination with bortezomib or lenalidomide in relapsed/refractory multiple myeloma. Inhibitors of HDAC6 have demonstrated anti-cancer proliferative activity in various cancer types, including Her2+ breast cancer. Blocking HDAC6 activity has been shown to cause Her2+ breast cancer cell growth inhibition through various mechanisms, including destabilization of Her2 mRNA and protein. In the present work, the impact of HDAC6 inhibition has been investigated on Her2+ breast cancer cell growth and cell migration using HDAC6 inhibitor alone or in combination with either a Her2 inhibitor (lapatinib) or a PI3K inhibitor (GDC-0941, IPI-145 and CAL-101).
Anti-tumor activity of ACY-1215 was investigated using a panel of nearly 100 human tumor cell lines derived from the major cancer types and Her2+ breast cancer cells were among the most sensitive cells to ACY-1215. Combinations of ACY-1215 with either the Her2 inhibitor lapatinib or PI3K inhibitor GDC-0941 demonstrated synergistic cytotoxicity against these cancer cells. To illustrate the effects are due to HDAC6 inhibition, we used a highly HDAC6 selective inhibitor ACY-775, which has greater than 1,500 fold of selectivity against HDAC6 over Class I HDACs (HDAC1, 2 and 3), in our experiments. ACY-775 is able to sensitize Her2+ breast cancer cells MDA-MB-453 and BT-474 to lapatinib, and PI3K inhibitors (IPI-145, GDC-0941 and CAL-101). ACY-775 also blocks cancer cell migration in the presence of absence of epidermal growth factor (EGF). In agreement with the proposed mechanism of HDAC6 mediated Her2+ breast cancer cell death, ACY-1215 treatment correlated with decrease of Her2 protein, p-EGFR and p-AKT in a Her2+ breast cancer cell line MDA-MB-453.
By taking advantage of our highly selective HDAC6 inhibitor ACY-775, we have shown growth and migration suppressive activities by HDAC6 inhibition in Her2+ breast cancer cells. These findings suggest selection of metastatic Her2+ breast cancer for further in vitro and in vivo validation and mechanism of action studies with ACY-1215 in combination with novel and approved standard of care therapeutics for breast cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B280.
Citation Format: Min Yang, David Tamang, Simon Jones. Histone deacetylase (HDAC) 6 inhibition potentiates the cytotoxicity of lapatinib and PI3K inhibitors on Her2+ breast cancer cell lines. [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 B280.
Abstract B285: A novel, potent, highly selective inhibitor of c-Met kinase, Simm559, inhibits c-Met-dependent neoplastic phenotypes in vitro and in vivo.
Authors: Ai Jing , Zhan ZhengSheng , Wang Ying , Chen Fang , Peng Xia , Chen Yi , Ji Yinchun , Ding Jian , Geng Meiyu , Duan Wenhu 
Published: August 2014

Abstract
Despite the vigorous activity in the development of c-Met inhibitors, none of the c-Met inhibitors or c-Met pathway antagonists has been approved for clinical use. Notably, most of the reported c-Met kinase inhibitors across the clinical trials lack selectivity and target multiple kinases, which will likely result in unwanted off-target toxicities. The discovery of highly selective c-Met inhibitors may represent an important direction to increase chances of targeting c-Met for cancer therapy. Simm559 is identified as a highly selective and potent c-Met inhibitor, with IC50 = 0.24 ± 0.04 nM against c-Met kinase, while it barely inhibited kinase activity of a panel of tyrosine kinases, including c-Met family member and its highly homologous kinases. Simm559 significantly inhibited c-Met-driven cell proliferation, in particular c-Met constitutively activated NSCLC and gastric cancer cells, with an average IC50 at 0.66 nM. Such potency was over 10,000-fold of that in cells with low c-Met expression or activity. Oral dosing of Simm559 at 25 mg/kg (BID) resulted in significant antitumor activity in several c-Met-driven xenograft models, especially in NSCLC EBC-1 xenograft, gastric SNU5 xenograft and a patient-derived NSCLC xenograft model with MET amplification. Complete tumor regressions were observed in both cell line-based and patient-derived lung cancer xenograft models. Safety evaluation and pharmacokinetic analysis showed that Simm559 is safe and well tolerant with acceptable pharmacodynamic properties. All these evidence promise Simm559 as a therapeutic candidate for c-Met-driven human cancers.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B285.
Citation Format: Jing Ai, ZhengSheng Zhan, Ying Wang, Fang Chen, Xia Peng, Yi Chen, Yinchun Ji, Jian Ding, Meiyu Geng, Wenhu Duan. A novel, potent, highly selective inhibitor of c-Met kinase, Simm559, inhibits c-Met-dependent neoplastic phenotypes in vitro and in vivo. [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 B285.
Abstract B288: 17AAG enhances cisplatin-induced cytotoxicity to induce p53-mediated apoptosis in head and neck cancer.
Authors: Kwon Minsu , Kim Eun Hye , Park Hyun Bae , Kim Sang Yoon , Roh Jong-Lyel 
Published: August 2014

Abstract
Purpose: Tumor suppressor p53 is often inactivated in head and neck cancer (HNC) because of TP53 mutations or the overexpression of MDM2 or MDMX. Restroation of p53 function through counteracting these p53 repressors is considered a promising strategy for cancer treatment. Therefore, we examined the role of a heat shock protein 90 inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), in inducing apoptosis in HNC by restoring p53 function.
Experimental Design: In five HNC cell lines, we tested the effects of 17AAG treatment, either individually or in combination with 17AAG or cisplatin and assessed growth suppression, cell cycle arrest, and apoptosis assay.
Results: 17AAG activated and stabilized p53 in an HNC cell line bearing wild-type TP53 by disrupting the p53-MDMX interaction. 17AAG upregulated expression of p21 and proapoptotic genes and promoted apoptosis, in a dose-dependent manner. 17AAG exerted the highest growth suppression in tumor cells with MDMX overexpression. The apoptotic response was blocked by inhibition of p53 or MDMX expression, demonstrating that the effects of 17AAG depend on p53 and MDMX. In combination treatments, 17AAG acted synergistically with Nutlin-3a to inhibit growth of HNC cells. 17AAG also synergized the antitumor effect of cisplatin by inducing p53-mediated apoptosis.
Conclusion: 17AAG effectively induced p53-mediated apoptosis in HNC cells by MDMX inhibition, suggesting a promising strategy for treating HNC.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B288.
Citation Format: Minsu Kwon, Eun Hye Kim, Hyun Bae Park, Sang Yoon Kim, Jong-Lyel Roh. 17AAG enhances cisplatin-induced cytotoxicity to induce p53-mediated apoptosis in head and neck 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 B288.