bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A206: 2D cell culture can approximate 3D behavior: Applications for screening individual agents and drug combinations.
Authors: Ivanov Igor , Taherzadeh Danial , Nunziante Maximilian 
Published: August 2014

Abstract
Developed and serving over the last 30 years as an indispensible screening tool, 2D in vitro screening has been criticized for poor predictive powers in clinical settings. New tools are under development, e.g. 3D spheroids or “hanging-drops," to overcome these limitations. However, new tools have other restrictions. For example, costs and application for multiple cell lines: model 2D cell lines may not grow as spheroids.
We developed a set of analytical and computational models to approximate cell growth upon drug treatment. We could show that for a common 2D cell culture the effect of drug treatment, and therefore interpretation of the results, depends on several factors: seeding cell density, treatment time, cell doubling time, and compound mode of action.
To address such limitations we further developed a modified 2D culture. In contrast to a common experimental set-up of low cell density to allow exponential cell growth and short 48-96 hours treatment times, we allowed cells to grow to higher ∼80% confluence densities. Treatment was monitored not as an end-point assay, but in a kinetic mode (every 96 hours) over a period of 4 weeks.
We treated 82 cell lines using a set of standard anticancer agents, including 5-FU, paclitaxel, sunitinib, etoposide, lapatinib and eroltinib. Interestingly, some cell lines showing significant responses in classical 2D models, appear to be non-responsive to the drug in dense 2D (D2D) models. This was very obvious for some targeted agents, e.g. EGFRi, probably due to down-regulation of the drug targets in cell lines growing as D2D. In addition, we have applied the same principle to drug combination studies in all 82 cell lines.
These results indicate that D2D cell models can approximate cell growth observed in 3D cell cultures by enhancing cell-cell interactions. D2D screening can be performed in hundreds of cell lines (at least 82 different cancer cell lines, as shown here). In contrast to 3D models and end-point detection, D2D also records the drug response kinetics, and can be easily applied for drug combinations. This is especially relevant for slow acting agents, e.g. cytostatic agents.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A206.
Citation Format: Igor Ivanov, Danial Taherzadeh, Maximilian Nunziante. 2D cell culture can approximate 3D behavior: Applications for screening individual agents and drug combinations. [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 A206.
Abstract A209: Predicting genetic drivers of MEK dependency with gene expression.
Authors: Dry Jonathan R. , Hodgson Darren , Brant Roz , Liptrot Tom , Harrington Elizabeth , Barrett Carl , Smith Paul D. 
Published: August 2014

Abstract
Inhibition of the RAS-RAF-MEK axis holds significant promise for targeted cancer therapy, highlighted by the recent clinical approval of BRAF (vemurafenib) and MEK (trametinib) inhibitors, and ongoing late-stage clinical trials for several other MEK inhibitors. All genetic aberrations resulting in pathway activation and dependency through which optimum patient populations may be selected are as yet not fully determined. Previously we published an 18-gene mRNA expression signature reproducibly predictive of MEK pathway output and response to MEK inhibition with selumetinib. Here we demonstrate that a 6-gene sub-signature shows enhanced reproducibility in cell lines, primary tumor explant in vivo models and fresh/fixed tissue samples, crossing tumor type and gene expression platforms. In published next-generation sequencing datasets we assessed pathway-linked genetic aberrations for their impact on MEK signature output. We show the potential for this signature to dissect MEK dependency amongst RAS mutant tumors. Furthermore we identify a number of genetic aberrations outside of BRAF and KRAS driving high MEK signature expression, including a synthetic lethal-like profile with NF1 deletion. The signature provides a robust and dynamic marker of MEK output applicable to clinical samples, and highlights a number of genetic opportunities to expand the clinical scope for MEK inhibitor based therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A209.
Citation Format: Jonathan R. Dry, Darren Hodgson, Roz Brant, Tom Liptrot, Elizabeth Harrington, Carl Barrett, Paul D. Smith. Predicting genetic drivers of MEK dependency with gene expression. [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 A209.
Abstract A21: Autophagy: A potential target for colorectal cancer therapeutics.
Authors: Amin Amr , Bajbouj Khuloud , Koch Adrian , Gandesiri M. , Schneider-Stock Regine 
Published: August 2014

Abstract
Colorectal cancer is among the leading causes of death worldwide. Here, we investigate the molecular mechanism of crocin-induced apoptosis in colorectal cancer cells. Crocin was shown here to inhibit proliferation of both HCT wildtype and HCT p53-/- cell lines at a concentration of 10 mM. Flow cytometric analysis of cell cycle distribution revealed that there was an accumulation of HCT wildtype cells in G1 compared to the control after 24 and 48 hours of crocin treatment, respectively. However, crocin induced only mild G2 arrest in HCT p53-/- after 24 hours. Crocin induced apoptosis in both cell lines in a time dependent manner. Nevertheless, p53 deficient cells were not able to repair the damage induced by crocin. Crocin induced inefficient autophagy in HCT p53-/- cells where crocin induced the formation of LC3-II which was combined by a decrease in the protein levels of beclin 1 and Atg7 and no clear p62 degradation. Autophagosome formation was not detected in HCT p53-/- after crocin treatment predicting a nonfunctional autophagosome formation. There was a significant increase of p62 after treating the cells with Bafilomycin A1 (Baf) and crocin compared to crocin exposure alone, indicating an effective autophagic flux. Annexin V staining showed that Baf-pretreatment enhanced the induction of apoptosis in HCT wildtype cells. Baf-exposed-HCT p53-/- cells did not show any enhancement of apoptosis induction despite an increase in the DNA damage sensor accumulation, γH2AX indicating that crocin induced an autophagy-independent classical programmed cell death.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A21.
Citation Format: Amr Amin, Khuloud Bajbouj, Adrian Koch, M. Gandesiri, Regine Schneider-Stock. Autophagy: A potential target for colorectal cancer 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 A21.
Abstract A211: Multiethnic screening for irinotecan sensitivity in FFPE tissue from colorectal cancer patients.
Authors: Hsiang Jack , El-Khoueiry Rita , Lenz Heinz-Josef , Astrow Stephanie H. , Larson Garrett P. 
Published: August 2014

Abstract
The selection of chemotherapies is guided by the analysis of molecular targets in solid tumors for well-known somatic mutations identified in microdissected FFPE tissue. Combining a molecular targeting panel with select pharmacogenomic targets provides additional clinical information useful in customized patient management. We have developed a combined pharmacogenomic/molecular target approach using FFPE tissue from colon cancer patients. Our test, based on FDA guidance for Irinotecan administration to metastatic colorectal cancer (CRC) patients, is a recommended prescreening assay for UGT1A1 [TA] promoter variations to mimimize neutropenia. Meta-analysis of Irinotecan treated CRC patients has demonstrated an association between the [TA]7 allele (UGT1A1*28) and elevated levels of neutropenia in both homozygous and heterozygous carriers suggesting lowered dosing regimens (Liu, et al Pharmacogenomics J, 2013). Additional alleles, while uncommon in Caucasians, contribute to decreased levels of UGT1A1 enzymatic activity, and are restricted to genetic subgroups. Collectively these alleles influence the pharmacodynamic t1/2 of Irinotecan but are often not widely screened. Thus, a screening palate encompassing multiple ethnic-specific variants provides improved predictive information in a cosmopolitan population of cancer patients. As these polymorphisms are germline changes, UGT1A1 genotypes can be derived from either traditional whole blood assessment or more conveniently from FFPE surgical tissue at the time of diagnosis. We have screened paired blood/tumor samples from CRC patients to examine potential loss of heterozygosity in tumor specimens at this locus. In parallel, we screened microdissected tumor and adjacent normal tissue from FFPE samples to verify the potential of using tumor specimens as a routine alternative to blood. The use of FFPE tissue from CRC patients as part of a molecular work-up can provide genotypes for multiple UGT1A1 alleles of reduced activity (including *28), and may be better at predicting neutropenia in distinct Caucasian, Asian or other genetically distinct patient populations. The development of FFPE-based tests for pharmacogenomic tests such as UGT1A1 premised on genetic ancestry provides actionable information that can be used to maximize patient responses.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A211.
Citation Format: Jack Hsiang, Rita El-Khoueiry, Heinz-Josef Lenz, Stephanie H. Astrow, Garrett P. Larson. Multiethnic screening for irinotecan sensitivity in FFPE tissue from colorectal cancer patients. [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 A211.
Abstract A226: Identification of new synergistic compounds for the treatment of NOTCH-driven T-ALL.
Authors: Sanchez Martin Marta , Ambesi Alberto , Herranz Daniel , Ferrando Adolfo 
Published: August 2014

Abstract
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that accounts for 15% of childhood and 25% of adult ALLs. Constitutive activation of NOTCH signaling as result of activating mutations in the NOTCH1 gene is a hallmark of this disease and small molecule gamma-secretase inhibitors, which effectively block activation of the NOTCH1 receptor, have been proposed as targeted therapy. However, the progress of NOTCH1-blocking agents such as in the clinic has been limited. Here we hypothesized that detailed transcriptional profiling of T-ALL lymphoblasts upon inhibition of NOTCH1 signaling would uncover major effector pathways downstream of NOTCH1. Moreover, we proposed that these signatures would facilitate the identification of new drugs and drug combinations for the treatment of T-ALL. Gene expression profiling of NOTCH1 induced leukemias treated with DBZ, a highly active gamma-secretase inhibitor, identified numerous genes regulated by NOTCH1 in human leukemia. Notably these signatures were enriched in NOTCH1 direct target genes such as Hes1 and revealed a prominent role of NOTCH signaling in the control of cellular metabolic pathways. Following on these results we performed Connectiviy map analysis to identify drugs whose transcriptional effects could antagonize those of oncogenic NOTCH1 in human leukemia. This analysis identified HDAC inhibitors, anti-psychotic agents, anti-malarials and compounds targeting the PI3K and NFKB signaling pathways. Detailed analysis of the effects of these drugs alone and in combination with DBZ demonstrated strong antileukemic activity and strong synergism when combined with inhibition of NOTCH signaling with a gamma-secretase inhibitor. Moreover, biochemical and transcriptional profiling of these drugs identifies agents with unique and related mechanisms of action.
Overall these results identify new antileukemic drugs with strongly synergistic activity in combination with NOTCH1 inhibition for the treatment of T-ALL
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A226.
Citation Format: Marta Sanchez Martin, Alberto Ambesi, Daniel Herranz, Adolfo Ferrando. Identification of new synergistic compounds for the treatment of NOTCH-driven T-ALL. [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 A226.
Abstract A227: The involvement of wild-type KIT overexpression in colon cancers.
Authors: Kim Wonkyu , Park Misun , Kim Hogeun 
Published: August 2014

Abstract
Abnormal signaling through receptor tyrosine kinase (RTK) moieties is crucial in tumor progression and drug targeting of colorectal cancers. Wild-type KIT (WT-KIT), a RTK that is activated upon binding with stem cell factor (SCF), is highly expressed in some colon cancers; however, the functional role of SCF-dependent KIT activation is barely understood in colon cancer pathogenesis. In this study, we aimed to determine the conditions and roles of WT-KIT activation in colon cancer tumorigenesis. We found that WT-KIT was expressed in a subset of colon cancer cell lines and was activated by SCF treatment, leading to activation of downstream AKT and extracellular signal-regulated kinase (ERK) signaling pathways. We also demonstrated that KIT expression gradually decreased, after prolonged SCF stimulation, due to lysosomal degradation. Degradation of WT-KIT after SCF binding was significantly rescued when PKC-δ was activated. We also showed that activated PKC-δ directly binds to SCF bound WT-KIT, facilitating the recycling of WT-KIT. We further showed that a subset of colorectal cancers exhibit expressions of both WT-KIT and activated PKC-δ and that expression of KIT is correlated with poor patient survival (P = 0.004). We herein for the first time demonstrated that continuous downstream signal activation after KIT-SCF binding is accomplished through PKC-δ-mediated recycling of KIT. This sustained KIT activation may contribute to tumor progression in a subset of colon cancers with KIT expression and might provide the rationale for a therapeutic approach targeting KIT.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A227.
Citation Format: Wonkyu Kim, Misun Park, Hogeun Kim. The involvement of wild-type KIT overexpression in colon cancers. [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 A227.
Abstract A230: An anti-leishmanial thiadiazine agent induces multiple myeloma cell apoptosis by suppressing the nuclear factor kappaB signaling pathway.
Authors: Chen Guodong , Han Kunkun , Xu Xin , Du Xiaolin , Zhang Zubin , Tang Juan , Shi Min , Wang Man , Li Jie , Cao Biyin , Mao Xinliang 
Published: August 2014

Abstract
Nuclear factor kappaB (NF-κB) is a nuclear transcription factor that regulates expression of a large number of genes critical for cell proliferation, survival, inflammation, and tumorigenesis. Recent evidence indicates that NF-κB and its signaling pathways are constitutively activated both in myeloma cell lines and in primary myeloma cells. Downregulated NF-κB signaling by bortezomib and other compounds has demonstrated that the NF-κB signaling could be a promising therapeutic target of MM. In the present study, we found that one of the tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives displayed potent anti-myeloma activity by inhibiting the NF-κB signaling pathway. DETT downregulated IKKα, β, p65, and p50 expression and inhibited phosphorylation of p65 (Ser536) and IBα. Simultaneously, DETT increased IκBα, an inhibitor of the p65/p50 heterodimer, even in the presence of stimulants lipopolysacharride, tumor necrosis factor alpha or interleukin-6. DETT inhibited NF-κB transcription activity and down-regulated NF-κB targeted genes including Bcl-2, Bcl-XL, and XIAP. Deregulation of NF-κB signaling by DETT resulted in MM cell apoptosis characterized by cleavage of caspase-3, caspase-8, and PARP. Notably, this apoptosis was partly blocked by activation of NF-κB signaling in the presence of TNFα and IL-6. Moreover, DETT delayed myeloma tumor growth in nude mice without overt toxicity. DETT is therefore a potent candidate for MM therapy as an inhibitor of the NF-κB signaling pathway.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A230.
Citation Format: Guodong Chen, Kunkun Han, Xin Xu, Xiaolin Du, Zubin Zhang, Juan Tang, Min Shi, Man Wang, Jie Li, Biyin Cao, Xinliang Mao. An anti-leishmanial thiadiazine agent induces multiple myeloma cell apoptosis by suppressing the nuclear factor kappaB signaling pathway. [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 A230.
Abstract A236: The orphan G-protein coupled receptor GPR161 is an oncogene in triple negative breast cancer.
Authors: Feigin Michael E. , Xue Bin , Hammell Molly , Muthuswamy Senthil K. 
Published: August 2014

Abstract
Triple negative breast cancer (TNBC) accounts for 20% of breast cancer in women and lacks an effective targeted therapy. Therefore, finding common vulnerabilities in these tumors represents an opportunity for more effective treatment. Recent large-scale analyses of hundreds of tumor samples have provided a deluge of information on the genetic changes occurring during tumorigenesis. However, determining which changes drive tumor initiation and progression, and which are bystanders remains a difficult biological problem. Utilizing this genomic information we have discovered that the orphan G-protein coupled receptor (GPCR) GPR161 is overexpressed specifically in TNBC. TNBC patients expressing higher levels of GPR161 have an increased probability of disease relapse. Overexpression of GPR161 in human non-transformed mammary epithelial cells increases cell proliferation and multiacinar structure formation in three-dimensional (3D) culture through activation of mTORC1 signaling. Knockdown of GPR161 impairs proliferation of a human basal breast cancer cell line. Furthermore, GPR161 expression induces cell migration and invasion of cells in 3D culture. This is accompanied by disrupted cell adhesion and intracellular accumulation of E-cadherin. Cells overexpressing GPR161 show a reduction in IQGAP1 phosphorylation, consistent with mTOR activation and E-cadherin disruption. Furthermore, we find GPR161 in a signaling complex with the scaffold proteins β-arrestin 2 and IQGAP1. These results suggest that GPR161 may provide prognostic value and serve as a potential drug target in TNBC.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A236.
Citation Format: Michael E. Feigin, Bin Xue, Molly Hammell, Senthil K. Muthuswamy. The orphan G-protein coupled receptor GPR161 is an oncogene 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 A236.
Abstract A239: T-type calcium channels as a novel molecular target for tumor therapy.
Authors: Dziegielewska Barbara , Valerie Nicholas C.K. , Hosing Amol S. , Larner James M. , Brautigan David L. , Gray Lloyd S. , Dziegielewski Jaroslaw 
Published: August 2014

Abstract
T-type Ca2+ channels are a group of low voltage-gated calcium channels which seem to be crucial for embryonic or stem cell proliferation and differentiation; however, they could be also aberrantly expressed in several human tumors. Since calcium entry is required for smooth transition through the cell cycle, it has been hypothesized that the inhibition of T-type Ca2+ channels blocks cells in G0/G1 phase of cell cycle, while a release from inhibition leads to increased number of cells entering cell cycle and thus increased susceptibility to conventional antitumor therapy. In this study we investigated the effects of T-type channel inactivation, or downregulation, on cell cycle progression, cell death and survival, and resistance to radiotherapy (RT). The experiments were conducted using several cancer cell lines expressing T-type Ca2+ channels (glioblastoma, colon and prostate) and selective and structurally unrelated calcium channels antagonists, including Mibefradil, a drug that is currently undergoing clinical trial for its antitumor properties, and is planned to be tested as radiosensitizing agent in recurrent gliobastoma tumors. The effects of T-type Ca2+ channel inhibition on cell cycle progression, cell death and the expression/activation of cell cycle regulated proteins were assessed. Finally, the combination treatments including T-type channel antagonist and radiotherapy were assayed. We show that T-type Ca2+ channels are important for cell cycle progression and resistance to RT, and that their inhibition leads to enhanced cell death and reduced survival. Our study demonstrates that one of the earliest events evoked by T-type channel inhibition is a deregulation of pro-survival pathway PI3K/Akt/mTOR and activation of pro-apoptotic stress-activated p38MAPK pathway. The results support the idea of T-type Ca2+ channel as a novel molecular target for antitumor therapy and provide a rational and plausible biological mechanism responsible for the effects induced by T-type Ca2+ channel antagonists in cancer cells.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A239.
Citation Format: Barbara Dziegielewska, Nicholas C.K. Valerie, Amol S. Hosing, James M. Larner, David L. Brautigan, Lloyd S. Gray, Jaroslaw Dziegielewski. T-type calcium channels as a novel molecular target for tumor 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 A239.