bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A246: Development of an IGF2 super-antagonist by directed evolution of IGF2R.
Authors: Frago Susana , Strickland Madeleine , Hughes Jennifer , Williams Christopher , Nicholls Ryan , Garner Lee , Rezgui Dellel , Crump Matthew P. , Hassan A. Bassim 
Published: August 2014

Abstract
Insulin-like growth factor 2 (IGF2) plays an important role both in human and mouse embryonic development and in tumour growth. IGF2 causes IGF1R and insulin receptor isoform A, IR(A), dependent activation of proliferation (MAPK) and survival pathways (AKT-PI3K). IGF2 bioavailability is tightly regulated by six IGF binding proteins and by the IGF2/mannose 6-phosphate receptor (IGF2R). IGF2R is a 15-domain extracellular receptor, frequently mutated in cancer, which clears IGF2 via binding to domain 11 and internalising it for lysosomal degradation. Increased supply of IGF2 occurs in hepatocellular, breast, prostate, colorectal and ovarian tumours. Excessive amounts of IGF2 secreted by some tumours, mainly sarcoma, can lead to activation of IR(A) and cause non-islet cell tumour induced hypoglycaemia. Approaches aiming to counteract the activity of IGF2 by targeting IGF1R often fail due to IGF2-mediated activation of IR(A). A ligand trap that exploits the high specificity and affinity of IGF2R for IGF2 has been designed by the fusion of a mutated form of human domain 11 of IGF2R to a C-terminal human IgG1 Fc domain (Fc-dom11). For the ligand trap to function as a clinically useful IGF2 super-antagonist, the binding affinity of domain 11 to IGF2 was further improved. The binding affinity optimisation strategy consisted of random mutagenesis of domain 11 loops involved in IGF2 binding, followed by yeast surface display in P. Pastoris, FACS and SPR screening, as well as structure-directed mutagenesis, complemented with NMR studies. Several mutants showing enhanced IGF2 binding have been identified, the combination of separately identified mutations improving affinity up to 100 fold. In particular, the mutant domain 113-4D shows an increase in affinity through both on- and off-rate modification attributed to the decrease in flexibility of one of the loops involved in IGF2 binding, as suggested by NMR results. The ability of Fc-dom113-4D to function as an IGF2 antagonist has been tested in vitro, using hepatocellular carcinoma cell lines, and in vivo, where it counteracts IGF2-induced hypoglycaemia in mice.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A246.
Citation Format: Susana Frago, Madeleine Strickland, Jennifer Hughes, Christopher Williams, Ryan Nicholls, Lee Garner, Dellel Rezgui, Matthew P. Crump, A. Bassim Hassan. Development of an IGF2 super-antagonist by directed evolution of IGF2R. [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 A246.
Abstract A259: Characterization of next generation (Gen2.5) KRAS antisense inhibitors in NSCLC, PDAC, and CRC models.
Authors: Revenko Alexey S. , Bhattachrjee Gourab , May Chris , Monia Brett P. , MacLeod A. Robert 
Published: August 2014

Abstract
KRAS is among the first described oncogenes and one of the most frequently mutated genes in human solid tumors. Despite substantial efforts to identify specific KRAS inhibitors, no effective therapeutic strategies to target KRAS directly have been identified. Here we describe the selective inhibition of KRAS with next generation (Gen2.5) antisense oligonucleotides.
We recently demonstrated preclinical and clinical activity of a next-generation constrained-ethyl (cEt) modified (Gen 2.5) antisense oligonucleotides (ASOs) targeting STAT3 mRNA (STAT3Rx/AZD9150). Systemic delivery of unformulated STAT3Rx/AZD9150 produced robust target RNA and protein reductions in a broad range of xenograft models (AACR 2013). More importantly, STAT3Rx/AZD9150 showed striking clinical activity in the phase I dose escalation study, producing anti-tumor activity in 4 out of 6 patients with advanced treatment-refractory lymphoma (ASCO 2013). In this study, we generated a panel of high affinity Gen2.5 ASO targeting KRAS. Anti-proliferative effects of the KRAS ASOs were evaluated on a panel of colorectal carcinoma (CRC), non-small cell lung carcinoma (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) cell lines. KRAS ASOs potently and selectively inhibited growth of KRAS mutant CRC lines but did not affect the growth of KRAS WT CRC cells in 2D growth assays. Evaluation of KRAS depletion in NSCLC and PDAC lines revealed that sensitivity of these lines to growth inhibition in 2D assays required mutant KRAS status and the presence of a previously described “KRAS addiction” gene expression signature (Singh et al 2009). Surprisingly, further evaluation of KRAS ASO mediated depletion of NSCLC and PDAC lines in 3D growth assays (e.g. soft agar colony formation and polystyrene sponge (Alvetex)) resulted in strong inhibition of colony formation in all mutant KRAS lines, but not WT KRAS lines, and the sensitivity to KRAS depletion was independent of the expression of the “KRAS addiction” signature.
Collectively, we have shown that KRAS mutational status confers specific sensitivity to the ASO-mediated KRAS knockdown (KRAS oncogene addiction). Our data also highlights that antisense-mediated inhibition of KRAS may represent a promising and translatable approach to target KRAS therapeutically.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A259.
Citation Format: Alexey S. Revenko, Gourab Bhattachrjee, Chris May, Brett P. Monia, A. Robert MacLeod. Characterization of next generation (Gen2.5) KRAS antisense inhibitors in NSCLC, PDAC, and CRC 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 A259.
Abstract A265: L-methionine restriction sensitizes triple-negative breast cancer cells to a TRAIL receptor-2 agonist by reducing the expression of the melanoma-associated antigen MAGE-D2.
Authors: Strekalova Elena , Malin Dmitry , Good David , Cryns Vincent 
Published: August 2014

Abstract
The prognosis for most women with metastatic breast cancer remains poor due to a dearth of effective adjuvant therapies for this advanced stage of the disease. We have previously demonstrated that targeting TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) suppressed metastases in a murine model of triple-negative breast cancer (TNBC). However, many TNBCs are resistant to TRAIL receptor agonists. Restriction of the essential amino acid L-methionine has been reported to inhibit growth of transformed cells in preclinical models. We postulated that methionine restriction would sensitize TNBC cells to TRAIL-R2 agonists such as the humanized monoclonal antibody lexatumumab. Here we demonstrate that methionine restriction sensitized TNBC cells to lexatumumab-induced caspase activation and apoptosis. Intriguingly, methionine restriction also sensitized transformed MCF10A-RasV12 cells, but not untransformed MCF10A-Vector cells, to lexatumumab. Methionine restriction enhanced the cell surface expression of TRAIL-R2. To delineate the underlying mechanism(s), we performed proteomics analyses of TNBC cells grown in methionine restricted media and observed that methionine restriction dramatically reduced the expression of the melanoma-associated antigen MAGE-D2, which has recently been reported to inhibit TRAIL-R2 expression. siRNAs targeting MAGE-D2 mimicked the actions of methionine restriction by augmenting cell surface expression of TRAIL-R2 and sensitizing TNBC cells to lexatumumab. Overall, our results demonstrate that methionine restriction sensitizes TNBC cells to TRAIL-R2 agonists and suggest that dietary methionine restriction may be a strategy to augment the antitumor effects of TRAIL receptor agonists in vivo.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A265.
Citation Format: Elena Strekalova, Dmitry Malin, David Good, Vincent Cryns. L-methionine restriction sensitizes triple-negative breast cancer cells to a TRAIL receptor-2 agonist by reducing the expression of the melanoma-associated antigen MAGE-D2. [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 A265.
Abstract A268: TAS-119, a selective Aurora A inhibitor, enhanced the antitumor efficacy of taxanes in multiple human tumor cell lines including paclitaxel-resistant cells.
Authors: Miura Akihiro , Sootome Hiroshi , Ishihara Keiko , Masuko Norio , Hirai Hiroshi , Utsugi Teruhiro 
Published: August 2014

Abstract
Background: Aurora A is a serine/ threonine kinase that plays a critical role in regulating multiple mitosis processes. Aberrant expression of Aurora A has been associated with spindle checkpoint dysfunction and increased resistance to the microtubule-polymerizing agents, paclitaxel and docetaxel (1). Aurora A has been identified as one of the genes associated with enhancement of paclitaxel cytotoxicity in a siRNA library screen (2). Moreover, Aurora A overexpression/ gene amplification has been reported in various types of human cancers. In this report, we demonstrate that a selective Aurora kinase A inhibitor, TAS-119, synergistically enhances the activity of paclitaxel in multiple cell lines in vitro.
Materials and Methods: Evaluation of synergistic effects in combination was conducted by curve-shift analysis and Bliss additivity model, based on cell viability. Cell viability was assayed by using CellTiter-Glo™ which measures cellular ATP. Selectivity of TAS-119 for three isotypes of Aurora kinases was determined via monitoring the auto-phosphorylation of kinases by Western blot. Apoptosis induction was assessed by cleaved-PARP detection. As paclitaxel-resistant cell lines, both A549.T12 (3) and PTX10 (4) were used in combination experiments. A549.T12 and PTX10 were reported to have altered expression of β-tubulin isotypes and β-tubulin mutation, respectively.
Results: TAS-119 selectively inhibited cellular auto-phosphorylation of Aurora A without affecting the activity of both Aurora B and Aurora C. TAS-119 showed a synergistic effect with paclitaxel or docetaxel in multiple tumor cell lines from different origins, even in cells insensitive to TAS-119 treatment alone. Furthermore, TAS-119 also showed synergistic effects in paclitaxel-resistant cell lines. Cleaved-PARP analysis revealed that the cytotoxic synergism in combination with paclitaxel was induced by promoting the caspase-dependent apoptotic cell death.
Conclusion: The unique characteristic of TAS-119 as a highly selective Aurora A inhibitor contributed to the synergistic enhancement of antiproliferative effects of taxanes in multiple cell lines, possibly mediated by apoptotic pathways. These findings provide a rationale for the clinical development of TAS-119 as a combination therapy with taxanes.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A268.
Citation Format: Akihiro Miura, Hiroshi Sootome, Keiko Ishihara, Norio Masuko, Hiroshi Hirai, Teruhiro Utsugi. TAS-119, a selective Aurora A inhibitor, enhanced the antitumor efficacy of taxanes in multiple human tumor cell lines including paclitaxel-resistant 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 A268.
Abstract A287: Discovery of c-Met kinase inhibitors for anticancer therapeutics.
Authors: Yun Chang-Soo , Cho Sung Yun , Kim Hyoung Rae , Jung Hee Jung , Ha Jae D. , Lee Kwangho , Kim Pilho , Park Chi Hoon , Lee Chong Ock 
Published: August 2014

Abstract
c-Met recepter tyrosine kinase (RTK) and its ligand, hepatocyte growth factor (HGF), have been reported to be involved in tumorigenesis and metastatic progression. Also, aberrant c-Met signaling has been reported in a wide variety of cancers such as gastric, lung, colon, breast, bladder, head and neck, ovarian, prostate, thyroid, pancreatic, hematological malignancies, and central nervous system tumors. We have synthesized a series of triazolopyridazine derivatives and their c-Met (mesenchymal-epithelial transition factor) inhibitory activities have been evaluated. A potent c-Met kinase inhibitor by structural modification of the parent pyrimidine scaffold with particular focus on the aryl substituent on the triazolopyridazines will be discussed. Several triazolopyridazine derivatives were found to be potent as c-Met inhibitors in enzyme assays and cell-based assays (c-Met addicted cell lines). We found KRC-00831 is a highly potent and selective c-Met receptor tyrosine kinase inhibitor over other kinases (c-Met enzyme, IC50=3 nM) and exhibit excellent cellular activities in c-Met driven cell lines (Hs746T, GI50=0.1 nM; H1993, GI50=27 nM, MKN45, GI50=15 nM; SNU-5, GI50=8 nM). KRC-00831 is chemically and metabolically very stable and showed no CYP inhibition, hERG binding activity. KRC-00831 strongly suppressed the growth of c-Met over-expressed cancer cells, while not in c-Met absent cancer cell lines. In xenograft animal models, we observed not only dose dependent tumor growth inhibitions but complete tumor regressions. In summary, we suggest that KRC-00831 wil be a novel drug candidate with the therapeutic potential of targeting c-Met in human cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A287.
Citation Format: Chang-Soo Yun, Sung Yun Cho, Hyoung Rae Kim, Hee Jung Jung, Jae Du Ha, Kwangho Lee, Pilho Kim, Chi Hoon Park, Chong Ock Lee. Discovery of c-Met kinase inhibitors for anticancer therapeutics. [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 A287.
Abstract A291: A highly selective dual insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an ERK inhibitor.
Authors: Duong-Ly Krisna C. , Anastassiadis Theonie , Deacon Sean W. , Lafontant Alec , Ma Haiching , Devarajan Karthik , Dunbrack Roland L. , Wu Jinhua , Peterson Jeffrey R. 
Published: August 2014

Abstract
Dual inhibitors of the closely related receptor tyrosine kinases insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) are promising therapeutic agents in cancer. Here we report an unusually selective class of dual inhibitors of IGF-1R and IR identified in a parallel screen of known kinase inhibitors against a panel of 300 human protein kinases. Biochemical and structural studies indicate that this class achieves its high selectivity by binding to the ATP-binding pocket of inactive, unphosphorylated IGF-1R/IR and stabilizing the activation loop in a native-like inactive conformation. One member of this compound family was originally reported as an inhibitor of the serine/threonine kinase ERK, a kinase that is distinct in the structure of its unphosphorylated/inactive form from IR/IGF-1R. Remarkably, this compound binds to the ATP-binding pocket of ERK in an entirely different conformation to that of IGF-1R/IR, explaining the potency against these two structurally distinct kinase families. These findings suggest a novel approach to polypharmacology in which two or more unrelated kinases are inhibited by a single compound that targets different conformations of each target kinase.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A291.
Citation Format: Krisna C. Duong-Ly, Theonie Anastassiadis, Sean W. Deacon, Alec Lafontant, Haiching Ma, Karthik Devarajan, Roland L. Dunbrack, Jinhua Wu, Jeffrey R. Peterson. A highly selective dual insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an ERK inhibitor. [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 A291.
Abstract A297: Microtubule targeting antimitotic drugs induce a lower mitotic arrest than clinically less effective antimitotic Eg5 inhibitors in mouse xenografts.
Authors: Florian Stefan , Chittajallu Deepak R. , Kohler Rainer H. , Orth James D. , Sorger Peter K. , Weissleder Ralph , Danuser Gaudenz , Mitchison Timothy J. 
Published: August 2014

Abstract
Despite immense progress in targeted cancer drug design, to date, the most important drugs in chemotherapy remain traditional cytotoxic drugs which are thought to kill proliferating cells, no matter if malignant of not. This "antiproliferative" hypothesis is based on results from the 1970s coming from mouse leukemia models or cell culture experiments. Microtubule binding drugs are clinically important antiproliferative drugs which arrest cultured cancer cells in mitosis. As opposed to empirically found microtubule binding drugs, newer drugs designed from scratch to induce mitotic arrest have repeatedly failed in clinical trials, suggesting that the antitumor effect of microtubule binding drugs is still not well understood. Alas, tissue culture assays are not predictive of their respective clinical success, suggesting that more realistic models are needed to understand why there are such huge differences in antitumor efficacy. Therefore, in this project, we used in vivo microscopy of mouse xenografts to compare the cell cycle effects of microtubule drugs to those of newer, targeted antimitotic drugs in the form of inhibitors of the mitotic kinesin Eg5. Image analysis with a custom developed software for automated three dimensional segmentation and cell cycle classification revealed that the microtubule interacting drugs Paclitaxel and Eribulin which are in wide clinical use induce a much lower mitotic arrest than the Eg5 inhibitor Ispinesib which failed clinical trials. This suggests that, rather than mitotic arrest, a different mechanism, intrinsically coupled to microtubule binding, might be essential for the antitumor effect of microtubule drugs in vivo.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A297.
Citation Format: Stefan Florian, Deepak R. Chittajallu, Rainer H. Kohler, James D. Orth, Peter K. Sorger, Ralph Weissleder, Gaudenz Danuser, Timothy J. Mitchison. Microtubule targeting antimitotic drugs induce a lower mitotic arrest than clinically less effective antimitotic Eg5 inhibitors in mouse xenografts. [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 A297.
Abstract A47: Study of promoter methylation pattern of 14-3-3 sigma gene in serum of patients with breast cancer: A potential biomarker for diagnostic anf prognostic factor.
Authors: Joaquina Martínez-Galán , Delgado Juan Ramón , Torres-Torres Blanca , Del Moral Rosario , Rios Sandra , Núñez M. Isabel 
Published: August 2014

Abstract
Background: Expression of 14-3-3 σ is a tumor suppressor gene induced in response to DNA damage, and has been implicated in G2/M cell cycle arrest by p53. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as an important mechanism for gene inactivation.
Objective: To correlation methylation levels of promoter 14-3-3σ with association prognostic factors in breast cancer.
Material and Methods: This is a prospective study we quantified methylation levels of promoter 14-3-3σ gene in 107 women with breast cancer and 108 control subjects by real time QMS-PCR SYBR green and analyzed association with prognostics factor in breast cancer.
Results: Median age was 58 years (32-88); 69% were postmenopausal women.Nodal involvement N0;63%,N1;30%,N2;7%), tumor size (T1;58%,T2;35%,T3;4%,T4;4%) and grade G1; 20%, G2; 37%, G3; 30%). The methylation of 14-3-3σ were 60% of sporadic breast cancer patients and were 34% of normal breast (p=0.0047).The methylation of 14-3-3σ gene in serum was markedly related with T3-4 stage (p&lt;0.05),nodal positive status (p&lt;0.05) and poor outcome. With a median follow up 6 years we saw more probability of developing distance metastasis in patients with methylation 14-3-3σ (p&gt;0.05).
Conclusions: Hypermethylation of the 14-3-3σ a promoter is an early and frequent event in breast neoplastic transformation, leading to the suggestion that silencing of 14-3-3σ may be an important event in tumor progression and particularly in breast carcinogenesis.Therefore, it is possible that loss of σ expression contributes to malignant transformation by impairing the G2 cell cycle checkpoint function, thus allowing an accumulation of genetic defects. Perhaps in the detection of CpG methylation of 14-3-3σ may be used for diagnostic and prognostic purposes.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A47.
Citation Format: Martínez-Galán Joaquina, Juan Ramón Delgado, Blanca Torres-Torres, Rosario Del Moral, Sandra Rios, M. Isabel Núñez. Study of promoter methylation pattern of 14-3-3 sigma gene in serum of patients with breast cancer: A potential biomarker for diagnostic anf prognostic factor. [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 A47.