bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B156: An epithelial to mesenchymal transition (EMT) gene expression signature predicts resistance to PI3K/Akt pathway inhibitors in non-small cell lung cancer.
Authors: Byers Lauren Averett , Wang Jing , Diao Lixia , Girard Luc , Peyton Michael , Coombes Kevin R. , Weinstein John N. , Gandi Varsha , Krett Nancy , Rosen Steven T. , Minna John D. , Heymach John V. 
Published: June 2012

Abstract
Background: Epithelial/mesenchymal transition (EMT) is associated with loss of cell adhesion molecules such as E-cadherin and increased invasion, migration, and proliferation in epithelial cancers. In non-small cell lung cancer (NSCLC), EMT is associated with greater resistance to EGFR inhibitors. However, its potential to predict response to other targeted drugs or chemotherapy has not been well characterized. Using a previously-derived EMT gene signature, we tested the association between EMT and drug response in a panel of &gt;50 NSCLC cell lines.
Materials/Methods: NSCLC cell lines were classified as epithelial or mesenchymal by a previously described 76-gene EMT gene expression signature. IC50s for more than 30 drugs or drug combinations were determined by MTS assay. Differences in IC50 between epithelial and mesenchymal lines were assessed by t-test (p-values ≤ 0.05 were considered significant).
Results: As expected, EGFR mutated cell lines were classified by the EMT signature as epithelial and were highly sensitive to EGFR inhibition by erlotinib. Among wild-type EGFR cell lines, those that had undergone EMT were significantly more resistance to erlotinib (p=0.029). NSCLC cell lines with mesenchymal signatures were also more resistant to drugs targeting the PI3K/Akt pathway such as GDC0941 (p=0.037) and 8-amino-adenosine (p=0.009). A trend towards greater resistance was also seen in mesenchymal cells treated with the Akt inhibitor MK2206 (p=0.12). There was no association between EMT and response to cytotoxic chemotherapies, including cisplatin, carboplatin, gemcitabine, pemetrexed, docetaxel, paclitaxel, and platinum-doublets (p-values ≥0.2).
Conclusion: EMT is associated with greater resistance to PI3K/Akt pathway inhibitors and may be a useful predictive marker for patients treated with these drugs. The EMT signature is being investigated prospectively in patients treated with an Akt inhibitor in an ongoing clinical trial. Supported in part by the NIH Lung Cancer SPORE grant P50 CA70907.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B156.
Abstract B166: Defining the mechanism of action and enzymatic selectivity of psammaplin A against its epigenetic targets.
Authors: Fuchter Matthew J. , Baud Matthias G. J. , Leiser Thomas , Samlal Sharon , Wong Ai Ching , Wood Robert J. , Gunaratnam Mekala , Hughes Siobhan M. , Buluwela Lakjaya , Turlais Fabrice , Neidle Stephen , Meyer-Almes Franz-Josef 
Published: June 2012

Abstract
Naturally isolated products continue to play a significant role in anticancer drug discovery. In line with our interest in small molecule compounds which effect epigenetic gene regulation, we are interested in the structural and biological properties of the natural product Psammaplin A. While it has been implicated as an inhibitor of numerous targets such as mycothiol-S-conjugate amidase, topoisomerase II and aminopeptidase N, studies by Crews and co-workers showed it to be an extremely potent inhibitor of both histone deacetylase (HDAC) and DNA methyltransferase (DNMT) enzymes. Our goal was to establish structure-activity relationships around psammaplin A, probing the molecular features responsible for the chemical biology of this natural product. We developed a number of versatile synthetic routes towards small compound libraries based on the psammaplin core [1]. We subsequently assessed the activity of these compounds against a selection of histone deacetylases, DNMT1, and in cell based assays. Analysis of the data revealed psammaplin A to be a natural prodrug; the central disulphide being reduced to a free thiol. Indeed, we showed the corresponding thiol not only to be a potent inhibitor of HDAC1 (IC50 0.001 μM), but to have remarkable selectivity against HDAC6 (IC50 0.360 μM), HDAC7 (IC50 17.4 μM) and HDAC8 (IC50 1.34 μM) in cell-free assays. Cell-based (MCF7) studies confirmed the HDAC targeting potential of psammaplin A and confirmed the selectivity observed in vitro. Curiously, our psammaplin A derivatives demonstrated no activity against DNMT1 in cell-free assays. Taken together with other reports, this data suggests psammaplin A may not be an inhibitor of DNMT1 as previously reported. In conclusion, we have explored the epigenetic activity of psammaplin A and have found it to have significant potency and selectivity against HDACs, whereas we find no evidence for DNMT1 activity.
Reference:
1. “New synthetic strategies towards Psammaplin A, access to natural product analogues” Baud, M. G. J.; Leiser, T.; Meyer-Almes, F.-J.; Fuchter, M. J. Org. Biomol. Chem. 2011, 9, 659–662.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B166.
Abstract B182: Nuclear sequestration of ErbB4 receptor tyrosine kinase by PIAS3.
Authors: Korhonen Anna , Sundvall Maria , Vaparanta Katri , Anckar Julius , Halkilahti Kalle , Salah Zaidoun , Aqeilan Rami , Palvimo Jorma J. , Sistonen Lea , Elenius Klaus 
Published: June 2012

Abstract
Background: ErbB4 is a member of EGFR/ErbB family of receptor tyrosine kinases (RTK). ErbB4 is subjected to regulated intramembrane proteolysis (RIP), resulting in the release of a soluble ErbB4 intracellular domain (ICD) into the cytosol. ErbB4 ICD can translocate to the nucleus and function as a transcriptional coregulator. Although nuclear ErbB4 immunoreactivity is frequently observed in breast cancer sections and has been associated with poor clinical outcome compared to membranous or cytosolic ErbB4, little is known how the subcellular localization and functions of ErbB4 ICD are regulated.
Results: In search of regulatory mechanisms of ErbB4 ICD localization and function, we identified protein inhibitor of activated STAT3 (PIAS3) as a novel interaction partner of ErbB4 ICD. According to the small ubiquitin-related modifier (SUMO) E3 ligase function of PIAS3, we showed that ErbB4 ICD is post-translationally modified by SUMO-1, and that PIAS3 stimulates SUMOylation of ErbB4 ICD. Upon overexpression of PIAS3, ErbB4 ICD generated from the full-length receptor accumulated into the nucleus and colocalized with PIAS3 and SUMO-1 in promyelocytic leukemia (PML) nuclear bodies, nuclear domains involved in regulation of transcription. Accordingly, PIAS3 overexpression had repressive effects on the transcriptional coregulatory activity of ErbB4. Finally, knockdown of PIAS3 with siRNA decreased nuclear ErbB4, and partially rescued the inhibitory effect of ErbB4 ICD on differentiation of MDA-MB-468 breast cancer and HC11 mammary epithelial cells.
Conclusions: We demonstrate that PIAS3 regulates the nuclear sequestration and functions of ErbB4 RTK. Our findings indicate the importance of subcellular distribution of ErbB4 ICD in determining the outcome of ErbB4 signaling in normal and malignant breast cell lines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B182.
Abstract B190: Pharmacokinetics of the AKT inhibitor CCT128930 from dried blood spots sampled from caudal bleeding compared with conventional cardiac puncture.
Authors: Raynaud Florence I. , Hayes Angela , Asad Yasmin J. , Johnson Louise , Henley Alan T. , Caldwell John J. , Collins Ian , Garrett Michelle D. 
Published: June 2012

Abstract
There has been much increase in the use of blood spots in recent years as a result of the ease of storage and transport of blood dried on cards compared with frozen plasma. In preclinical studies in oncology, mice are the model used for therapy experiments and blood spots allow full pharmacokinetic (PK) studies in 3–4 animals versus 21–27 for conventional plasma pharmacokinetics analysis, saving animals and decreasing compound usage. We here apply the blood spots technology to the early pharmacokinetic analysis of the AKT inhibitor CCT128930 dosed i.v. at 10mg/kg and bled from the tail vein.
The PK are very reproducible between individual mice and the blood levels are not affected by the type of anticoagulant used (heparin or EDTA) or by use of the FTA-DMPK card. CCT128930 shows a blood clearance of 0.092L/h (&lt;liver blood flow) and volume of distribution of 140mL. However, the PK parameters evaluated in blood water by conventional methods (cardiac puncture) differ significantly to those from the blood spot experiments. The overall blood clearance is 1.6-fold higher following blood measurement in samples taken by cardiac puncture versus serial tail bleed. The 6h post-dosing concentrations of CCT128930 following caudal sampling are 10-fold higher than that measured after cardiac puncture although there is no difference in Cmax. These data suggest that the serial bleeding from the tail vein affects the PK parameters of this compound compared with conventional bleeding. We have used blood spots extensively in our drug discovery programs checking the 6h sample versus conventional cardiac bleed and this strategy has allowed us to save over 50% of animals in the last year in our preclinical PK evaluations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B190.
Abstract B201: Identification of miRNA modulators to PARP inhibitor response.
Authors: Neijenhuis Sari , Bajrami Ilirjana , Campbell James , Lord Christopher J. , Ashworth Alan 
Published: June 2012

Abstract
Many pre-clinical and clinical studies have shown that inhibitors of the DNA repair protein PARP can have potentiating effects when combined with DNA damaging treatment modalities such as IR and temozolomide. Moreover, PARP inhibitors can be used as an efficient single agent in treatment of tumors carrying homologous recombination (HR) gene defects such as BRCA1 and BRCA2.
Genetic screens have previously been used to identify additional genetic deficiencies, which render tumor cells sensitive to PARP inhibitors. As yet, the contribution of microRNAs (miRNAs) to PARP inhibitor sensitivity has not been comprehensively studied. In this study our aim was to identify miRNA determinants of PARP inhibitor sensitivity and resistance, and in doing so potentially refine the eventual clinical use of these agents.
The human genome encodes over 1000 well annotated miRNAs. We used a high throughput method of miRNA mimetic screening to identify novel modulators of PARP inhibitor response. The assay involved transfecting cells with a library of approximately 900 miRNA mimics in a 384-well plate format. 48 hours after transfection half of the cells were treated with PARP inhibitor Olaparib and the other half with the drug vehicle. We identified several miRNA mimetics that modulate the response to Olaprib. Hits were validated by long-term survival assays as well as by analyses of DNA damage foci.
We used several strategies to determine the target genes of our hits. We performed westerns, qRT-PCR, luciferase reporter assays and immunoprecipitation assays and demonstrated several miRNAs involved in regulating the HR repair pathway.
Genes that modulate the response to PARP inhibitors are often implicitly involved in controlling DNA repair by HR and thus frequently found to be mutated in cancers. Our future work will focus upon whether the miRNAs identified in our screen drive HR dysfunction in human tumors and could be used as biomarkers to direct the use of therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B201.
Abstract B212: Inhibition of Gli transcriptional factors sensitizes multiple carcinoma cell lines to erlotinib treatment.
Authors: Li Hui , Do Hanh , Sheng Qing , Cheng Tiffany , Liu Natalie , Xu Fengfeng , Jablons David , He Biao 
Published: June 2012

Abstract
The aberrant activation of Hedgehog/Gli transcriptional factor has been implicated with a broad spectrum of lethal tumors. Targeted inhibition at cell membrane level of the Hh pathway, i.e. Smo and Hh inhibitors, has shown promising anti-tumor activity in both preclinical and clinical trials. A growing body of evidence has revealed additional mechanisms of Gli activation which are independent of Hh/SMO regulation and are stimulated by the crosstalk between components downstream of Hh/Smo and several other oncogenic signaling pathways, such as the Epidermal Growth Factor Receptor (EGFR) pathways. We hypothesized that the simultaneous inhibition of the EGFR pathway and Gli function could abrogate the interaction and result in synergistic anti-tumor effects. In order to test this hypothesis, we have undertaken studies in multiple lung cancer and mesothelioma cell lines. Effects of combination treatments with EGFR tyrosine kinase inhibitor erlotinib and an Hh pathway inhibitor were examined by using MTS assay. In our studies, the application of the Hh pathway inhibitor sensitized lung cancer cells to erlotinib treatment with a higher than 10 fold decrease of IC50. We also used the CalcuSyn software to calculate Combination Index (CI), in order to evaluate the effects of combination treatments (CI&lt;1 indicates Synergism, CI=1 indicates Additive effects, and CI&gt;1 indicates Antagonisim). In many lung and mesothelioma cell lines, the dual treatment of the Hh inhibitor and erlotinib showed synergistic effects with a Combination Index (CI) lower than 0.7. To elucidate the mechanism of the crosstalk between the two pathways, we have examined the activities of EGFR and Hh pathways upon single and dual treatments. Based on our studies, we speculate that dual inhibition of Hh/Gli and EGFR pathways may become a promising targeted therapy for lung cancers and mesothelioma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B212.
Abstract B216: A soil-to-seeds anticancer strategy: Targeting stroma to kill cancer cells.
Authors: Ni Yicheng 
Published: June 2012

Abstract
Rationale: We propose a dual targeting anticancer theragnostic strategy called OncoCidia, with which we intend to destroy and radioactively contaminate tumor stroma (soil) in order to eradicate all cancer cells (seeds) using vascular disrupting agents (VDAs) followed by radiolabeled necrosis-avid compounds (NACs), both of which are small molecular, naturally or synthetically derivable, systemically injectable, and of unique and complementary targetabilities.
Methods: Combretastatin A4 phosphate (CA4P) and Hypericin, as a representative of VDAs and NACs respectively, were tested among liver and subcutaneous tumor models (Ø &gt; 0.8 cm) in rats, mice and rabbits (n &gt; 100). We first injected CA4P intravenously at a dose of 10 mg/kg to cause tumor necrosis that became the next target. Hypericin was labeled with iodine-131 to form 131I-Hypericin (131I-Hyp), which was then iv injected at 300 MBq/kg 24h after administration of CA4P. 131I-Hyp accumulated in necrotic tumor, killing adjacent residual cancer cells by cross-fire irradiation and preventing tumor re-growth. We studied OncoCidia by comparing vehicle-control, single-targeting (either CA4P or 131I-Hyp) and dual-targeting (CA4P plus 131I-Hyp) groups using in vivo MRI and scintiscans, and ex vivo gamma-counting, autoradiography and histology.
Results: Eight days after only one dosage of each drug, typically the tumor size in vehicle-controls doubled that in single-targeting groups (p &lt; 0.001), and was 5-times that in dual-targeting group (p &lt; 0.0001), without treatment-related animal death. Tumors in OncoCidia groups appeared as hot-spots on scintiscans even weeks after treatment, corresponding to &gt; 3.34% ID/g of 131I-Hyp and a target-to-liver ratio &gt; 20. Significantly prolonged survival and reduced lung metastases occurred in tumor-bearing mice and rabbits respectively. Such encouraging results with histomorphological proofs were independent of animal species and tumor types.
Conclusion: Our preclinical experiments suggest that OncoCidia may present a simple, workable, affordable and general solution for treatment, detection and therapeutic monitoring of diverse solid malignant tumors, and deserve further exploitation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B216.
Abstract B223: NKP-1339 synergistic activity in both in vitro and in vivo preclinical models highlights the therapeutic opportunity for NKP-1339 combination trials with a broad range of antitumor agents.
Authors: Baerga Rebecca , Cobb Jenel , Ogden Angela , Sheshbaradaran Hooshmand 
Published: June 2012

Abstract
Background: NKP-1339 is a novel transferrin targeted ruthenium based compound that has shown promising single agent anti-cancer activity in preclinical models and in man. The compound has a novel mechanism of action, with GRP78 down-regulation included in its target pathways. In an ongoing Phase I study, the side effects are all mild and do not include those associated with standard cytotoxics or targeted agents, suggesting that NKP-1339 could be safely combined with standard anticancer therapies. The aim of this study was to evaluate the anti-tumor effects of NKP-1339 combination with these agents.
Methods: In vitro combination studies were performed in breast, colon, lung, gastric, prostate, pancreatic and liver tumor cell lines with cisplatin, oxaliplatin, 5-FU, docetaxel, doxorubicin, gemcitabine, erlotinib or sorafenib as appropriate for that tumor type. Cells were exposed to NKP-1339 and a combination agent, both agents at their respective ED50, for 72hrs. Cytotoxicity was determined using the MTT assay and combination index (CI) values were calculated using the Chou-Talalay method. The effect of the NKP-1339 and cisplatin combination was further studied in vivo in a gastric carcinoma xenograft model.
Results: The in vitro combination studies demonstrated NKP-1339 synergism with other anti-cancer agents in varied tumor types. The CI values ranged from 0.8 (synergism) to 0.1 (strong synergism): cisplatin (CI 0.1), doxorubicin (CI 0.2), 5-FU (CI 0.3), oxaliplatin (CI 0.4), sorafenib (CI 0.5), docetaxel (CI 0.5), erlotinib (CI 0.6), gemcitabine (0.8). In vivo studies on the combination of NKP-1339 and cisplatin in gastric carcinoma xenografts showed significant (P&lt;0.05) tumor growth delay and extended survival when compared to the single agent activity for either compound.
Conclusions: NKP-1339's novel mechanism of action and its favorable safety profile in humans suggest that it could be safely combined with standard anti-cancer therapies. The marked synergistic effects of NKP-1339 in combination with a broad range of anti-tumor agents in vitro and in vivo supports the study of this novel agent with standard anticancer therapies in Phase I combination clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B223.
Abstract B230: NMS-P948, a potent dual FLT3/KIT inhibitor, also active on secondary resistance mutations.
Authors: Ciomei Marina , Fraietta Ivan , Cribioli Sabrina , Marsiglio Aurelio , Casero Daniele , Nesi Marcella , Donati Daniele , Isacchi Antonella , Pesenti Enrico , Galvani Arturo , Borgia Andrea Lombardi 
Published: June 2012

Abstract
FMS-like tyrosine kinase 3 (FLT3) and KIT are both members of the class III receptor tyrosine kinase family characterized by an autoinhibitory juxtamembrane (JM) domain that docks with the kinase domain to stabilize a catalytically inactive conformation. Therefore, mutations or deletion in this or in adjacent regions cause constitutive activation of these kinases as observed in 30% of AML patients for FLT3 and in 70% of adult GIST and a subset of melanoma patients for KIT.
NMS-P948 is an alkoxy-indazole derivative potent dual inhibitor of FLT3 and KIT (IC50 26 and 89 nM, respectively), active also against FLT3 and KIT mutations that confer secondary resistance, such as the gatekeeper mutation T670I of KIT.
It is a very selective compound, resulting, when tested on a panel of more than 150 human tumor cell lines, strongly active only on cell lines whose proliferation is driven by one of these two kinases (for FLT3: Eol-1, IC50= 8 nM; MV-4–11, IC50= 8 nM; MOLM-13, IC50= 18 nM and for KIT: GIST-430 IC50= 7 nM and GIST-882 IC50= 99 nM). Mechanism of action is demonstrated on both kinases, with activating and resistance mutations, at low nanomolar concentrations.
NMS-P948 has good oral bioavailability in rodents. Antitumor efficacy is observed at as low as 10 mg/kg in xenograft models and no toxicity in terms of body weight loss was observed up to 60 mg/kg.
In disseminated human AML MOLM-13 model (FLT3-ITD) NMS-P948 produces a very prolonged survival of treated mice (T/C= 390 at 60 mg/kg OS daily × 10) and this antitumor efficacy results superior to that of quizartinib administered with the same schedule at the MTD (T/C= 207 at 40 mg/kg).
In conclusion, NMS-P948 is a promising dual inhibitor of mutated FLT3 and KIT with good in vitro and in vivo pharmacological and pharmacokinetic characteristics and with the potential to act also on patients that developed resistance to first line therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B230.