bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR-3: Antitumor efficacy on glioma models of the dual CDK/TRKA inhibitor PHA-848125, able to cross the blood brain barrier
Authors: Albanese Clara , Pastori Wilma , Locatelli Giuseppe , Alzani Rachele , Fiorentini Francesco , Festuccia Claudio , Pesenti Enrico , Galvani Arturo , Isacchi Antonella , Mercurio Ciro , Brasca Maria Gabriella , Ciomei Marina 
Published: June 2012

Abstract
Malignant gliomas, the most common primary brain tumors, are highly invasive and neurologically destructive tumors with very poor prognosis due to the impossibility of removing tumor tissue completely by surgery and the limited activity of therapeutic agents.
PHA-848125 is a dual CDKs and TRKA inhibitor and is therefore potentially active against two major pathways involved in glioma pathogenesis: signaling mediated by tyrosine kinase growth factor receptors and control of G1-S phase progression of the cell cycle.
PHA-848125 has demonstrated good antitumor activity in many preclinical tumor models, good tolerability in Phase 1 studies and it is currently undergoing Phase 2 clinical trials.
To explore the rationale for pursuing brain tumors as a clinical indication for PHA-848125, we firstly analyzed distribution of the 14C-labeled compound, demonstrating that it is able to efficiently cross the blood brain barrier. Next, we tested in vitro activity of the compound on a panel of glioma cell lines showing that it was able to inhibit cell proliferation (IC50: 1.4–2.5 µM), DNA synthesis (inhibition of BrdU incorporation ranging from 39 to 92 %), cell cycle markers (inhibition of Phospho-pRb, cdc6, cyclin A and cyclin B1 expression) and signal transduction markers (inhibition of Phospho-TRKA, Phospho-MAPK and Phospho-AKT). Significantly, it was also able to induce cell death through autophagy (mainly in cells with functional Retinoblastoma protein) or apoptosis (in cells with disrupted Retinoblastoma pathway). Antitumor efficacy in vivo was evaluated both in subcutaneous and intracranially implanted tumors. PHA-848125 showed significant antitumor efficacy by oral route: tumor growth inhibition of 71% and 80% on U87MG and U251 subcutaneous xenograft models, respectively and a 30% increase in survival time in the intracranial U251 model. Finally, in the U87MG xenograft model, the combination of PHA-848125 with temozolomide resulted in a synergistic effect and a clear therapeutic gain was also observed with a triple treatment adding PHA-848125 to radiotherapy and temozolomide. In conclusion, preclinical data obtained to date suggest that PHA-848125 may become a useful agent in chemotherapy regimens for glioma patients and support its evaluation in Phase 2 trials for this indication.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PR-3.
Abstract A120: Morphological assessment of apoptosis in HeLa cervical cancer cell line by Dox-loaded magnetic nanocluster.
Authors: Kumar Sunil , Daverey Amita , Bhahdur Dhirendra 
Published: June 2012

Abstract
A facile one step procedure to prepare amine functionalized MgFe2O4 nanocluster of size less than 50nm in a simple solvothermal reaction using sodium borohydride as reducing agent has been developed. The Amine group was confirmed by FTIR and its magnetization at room temperature were found to be 38 emu/g. The specific absorption rate (SAR) of the magnesium-ferrites nano-cluster were found to be 45.38 and 153.98 W/g of Fe with an applied field of 7.64 and 10.0 kA/m respectively at fixed frequency of 425kHz. Succinic anhydride were used to coat the nano-particle to load the Doxorubicin. The loading efficiency of was determined to be 79.4%. The high loading efficiency of Dox was observed due to porous nature of particle which was confirmed by Nitrogen adsorption-desorption isotherm. MTS assay results indicated that no significant cytotoxicity effect was detected with MgFe2O4 nano-cluster at concentration upto 0.4mg/ml after 24 and 48h of incubation with L929 cells. At 24h and 48h, the IC50 value of the Dox-MgFe2O4 nano-conjugates against HeLa cells was observed 3.5 and 1 μg/ml respectively. After 48 h of incubation of Dox loaded MgFe2O4 nano-cluster with HeLa cells, almost 99% cells were undergone apoptosis, which was observed by Confocal microscope. In conclusion MgFe2O4 nano-cluster have a potential for synergistically combine the effect of two therapeutics modalities chemotherapy and hyperthermia to induce apoptosis in HeLa cancer cell.
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 A120.
Abstract A128: Dual properties of fluorescence probe and anticancer agent of small molecules developed for cancer research.
Authors: Chang TaChau , Huang Wei-Chun , Wang Zi-Fu , Cho Chih-Chien 
Published: June 2012

Abstract
The dual properties of fluorescence probe for cancer diagnosis and G-quadruplex (G4) stabilizer for cancer treatment of 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide (BMVC) [1,2] inspire us to develop second-generation BMVC derivatives. A number of distinct BMVC derivatives were synthesized to investigate the correlation between cellular response and biological function of BMVC derivatives for cancer treatment. The fluorescence properties of BMVC derivatives allow us to visualize the cellular localization and possibly monitor the drug-target interaction. Together with their biological and toxicological analyzes, the correlation between cellular response and biological function of BMVC derivatives may allow us to elucidate their therapeutic mechanisms for cancer treatments.
Here we have evaluated the efficacy of two BMVC derivatives, 3,6-bis(1-methyl-4-vinylpyridinium iodide)-9-(1-(1-methyl-piperidinium iodide)-3,6,9-trioxaundecane) carbazole (BMVC-8C3O) and 3,6-bis(1-methyl-4-vinylpyridinium iodide)-9-(1-(1-methyl-piperidinium iodide) dodecyl) carbazole (BMVC-12C), in CL1-0 cancer treatment. Both molecules are mainly detected in lysosome of MRC-5 normal cells. However, BMVC-12C is mainly accumulated in mitochondria of cancer cells, while BMVC-8C3O is distributed in nucleus and mitochondria of cancer cells. Although BMVC-8C3O is a better G4 stabilizer than BMVC-12C to human telomeres, BMVC-12C inhibits population doubling of CL1-0 cancer cells earlier than BMVC-8C3O. Apparently, they have different therapeutic mechanisms. Fluorescence imaging showed competition of BMVC-12C with Mitotracker red into mitochondria, implying that BMVC-12C probably accumulates into mitochondria inner membrane. The accumulation of BMVC-12C in mitochondria induces cytochrome C release and cell death. In addition, CL1-0 cancer cells treated by BMVC-12C for 72 h will lose mitochondria membrane potential and increase the level of reactive oxygen species. Our results suggest that BMVC-12C is a novel mitochondriotoxic molecule.
References:
1. L.J. Liao, et al. Analyst 134, 708 (2009).
2. F.Z. Huang, et al. Mol. Cancer Res. 6, 955 (2008).
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 A128.
Abstract A160: Recognition of UbcH5c and the nucleosome by the Bmi1/Ring1b ubiquitin ligase complex.
Authors: Bentley Matthew L. , Corn Jacob E. , Dong Ken C. , Phung Qui , Cheung Tommy K. , Cochran Andrea G. 
Published: June 2012

Abstract
Background and Objectives: The Polycomb repressive complex 1 (PRC1) mediates gene silencing, in part by monoubiquitination of histone H2A on lysine 119 (uH2A). Bmi1 and Ring1b are critical components of PRC1 that heterodimerize via their N-terminal RING domains to form an active E3 ubiquitin ligase. A longstanding question in this field is how a single lysine residue in the nucleosome is singled out for ubiquitin modification and why only one ubiquitin is added rather than a chain of ubiquitins. To better understand how Bmi1/Ring1b controls monoubiquitination of H2A, we structurally characterized the E2 and nucleosome interaction sites on Bmi1/Ring1b.
Methods: X-ray crystallography was used to determine the structure of a complex between Bmi1/Ring1b and UbcH5c, its cognate E2 enzyme. Fluorescence-polarization assays were used to measure the binding of Bmi1/Ring1b to a synthetic DNA duplex. Site-directed mutagenesis was used to assess the importance of residues at the potential Bmi1/Ring1b-DNA interface, and in vitro ubiquitin ligase assays were used to measure the catalytic activity of mutant complexes. Molecular modeling studies were performed using HADDOCK v2.0.
Results: We have determined the crystal structure of a complex between the Bmi1/Ring1b RING-RING heterodimer and the E2 enzyme UbcH5c and find that UbcH5c interacts with Ring1b only, in a manner fairly typical of E2-E3 interactions. However, we further show that the Bmi1/Ring1b RING domains bind directly to duplex DNA through a basic surface patch unique to the Bmi1/Ring1b RING-RING dimer. Mutation of residues on this interaction surface leads to a loss of H2A ubiquitination activity. Through site-directed mutagenesis we have been able to uncouple the E2 binding and the DNA binding activities of Bmi1/Ring1b, indicating that Bmi1/Ring1b uses distinct binding surfaces to recognize E2 and the nucleosomal substrate. Computational modeling of the interface between Bmi1/Ring1b-UbcH5c and the nucleosome suggests that Bmi1/Ring1b interacts with both nucleosomal DNA and an acidic patch on histone H4 to achieve specific mono-ubiquitination of H2A.
Conclusions: Our data show that the direct interaction of the RING domains with nucleosomal DNA is crucial for the ubiquitin ligase activity of Bmi1/Ring1b. To our knowledge, this is the first example of a RING-domain E3 ligase binding directly to its substrate via the RING domain. Our results point to a novel mechanism of substrate recognition, and control of product formation, by Bmi1/Ring1b.
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 A160.
Abstract A165: mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling.
Authors: Rodrik-Outmezguine Vanessa S. , Chandarlapaty Sarat , Pagano Nen C. , Poulikakos Poulikos I. , Scaltriti Maurizio , Moskatel Elizabeth , Baselga Jose , Guichard Sylvie , Rosen Neal 
Published: June 2012

Abstract
mTORC1 inhibitors relieve feedback inhibition of receptor tyrosine kinases (RTKs) and cause mTORC2-dependent phosphorylation of AKT S473 and activation of AKT kinase and signaling. mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with the mTORC1 inhibitor rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT S473 dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of RTKs leading to subsequent PI3K activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound inhibition of mTORC1 and accumulation of activated AKT phosphorylated on T308 but not S473. Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in profound cell death and tumor regression in vivo. These results reveal the adaptive capabilities of oncogenic signaling networks, as AKT signaling may be driven by a loss-of-feedback-induced AKT species lacking S473 phosphorylation. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regressions in vivo, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways.
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 A165.
Abstract A184: Integrative molecular and functional profiling of HER2 amplified breast cancers to identify new gene targets.
Authors: Shiu Kai-Keen , Wetterskog Daniel , Mackay Alan , Natrajan Rachael , Lambros Maryou , Sims David , Bajrami Ilirjana , Brough Rachel , Frankum Jessica , Horlings Hugo , van der Vijver Marc , Turner Nicholas , Reis-Filho Jorge , Lord Christopher , Ashworth Alan 
Published: June 2012

Abstract
Up to 15% of all breast cancers are defined as HER2+ve where overexpression is due to amplification of the HER2 oncogene. Treatment of patients with these clinically aggressive tumors has been dramatically improved by the use of trastuzumab and lapatinib. However a significant proportion of patients' tumors remain resistant to these therapies. Therefore new biomarkers and additional therapeutic targets are urgently required for what remains a clinically challenging and biologically heterogeneous disease.
We describe an integrated genetic, transcriptomic and functional analysis of a wide panel of genes amplified and overexpressed in HER2 amplified breast tumors to identify new gene targets. Molecular profiling of 45 sporadic primary HER2 amplified breast cancers, 14 commercially available HER2 amplified and 9 non HER2 amplified breast cancer cell lines was performed. Genome wide copy number and transcriptomic array data were integrated and identified 511 genes that were significantly overexpressed when amplified in the tumors. The functional significance of 369 of these genes, which were recurrently amplified in the cell lines, was examined using parallel high throughput siRNA screens.
Multiple genetic dependencies were observed. We demonstrate that loss of cell viability following silencing of HER2 by multiple siRNAs significantly correlated with sensitivity to lapatinib and other HER2 targeted agents. We also show that silencing of TFAP2C caused significant loss of cell viability when amplified and overexpressed in multiple HER2 amplified breast cancer cell lines. Down regulation of HER2 expression and cell apoptosis was also observed. The potential clinical value of TFAP2C overexpression for patients with HER2+ve breast cancer is currently being explored in adjuvant HER2+ breast cancer trials of chemotherapy +/− HER2 targeted agents. We propose that TFAP2C amplification and overexpression represents a genetic dependency in HER2+ breast cancer and is a clinically relevant candidate biomarker.
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 A184.
Abstract A195: A population pharmacokinetic (PPK) model of bosutinib (BOS).
Authors: Hsyu Poe-Hirr , Mould Diane , Abbas Richat , Pearce Stuart , Amantea Michael 
Published: June 2012

Abstract
BOS is an orally active, dual Src/Abl kinase inhibitor. BOS has demonstrated efficacy and acceptable safety in patients (pts) with Philadelphia chromosome-positive (Ph+) leukemia. A PPK model was developed for BOS using pooled clinical data from a phase 1 trial of pts with advanced solid tumors given BOS 50 to 600 mg/d with food; a phase 1/2 trial of pts with tyrosine kinase inhibitor-resistant/intolerant Ph+ leukemia given BOS 400 to 600 mg/d with food; and a phase 3 trial of pts with newly diagnosed Ph+ chronic phase chronic myeloid leukemia given BOS 500 mg/d with food. 870 pts contributed to the PK analysis (typically 6–9 PK samples/pt). Pts were aged 18 to 91 y and weighed 35 to 221 kg. The final BOS PPK model was a 2-compartment model with first-order absorption and an absorption lag. PPK parameters were estimated with acceptable precision (see Table). The volume of the peripheral compartment was large with a slow turnover, and time to peak concentration was 5 to 6 h. The estimated alpha half-life was 19 h, with 68% and 32% of area under the curve (AUC) attributable to the alpha and beta half-lives, respectively. Residual unexplained variability was 30% at doses ≤100 mg and 32% at doses &gt;100 mg. Dose-dependency in relative bioavailability (F) was seen, mostly at lower doses. PPK showed high inter-individual variability (IIV), consistent with high variability in BOS absorption. The lower F inferred for low doses could be accounted for by saturable active transport of bosutinib into the gut lumen, which shows more variability than absorption by passive diffusion. Baseline demographics and lab results could not account for the high IIV, and adjusting the BOS dose for body size was not beneficial. Model simulations showed that median AUC and peak concentration (Cmax) at steady-state were 4,322 ng/mL•h and 215 ng/mL, respectively, for BOS 500 mg/d. Within individuals, differences between peak and trough concentrations were relatively small, with a population fluctuation ratio (Cmax/Cmin) of 152%. BOS approached steady-state after 4 days, but concentrations were predicted to rise slowly during maintenance, characteristic of a drug with a large peripheral distribution volume. The model-based accumulation index was 2.45, which is in agreement with the 2- to 3-fold increase inferred from noncompartmental analysis. In conclusion, the PPK model of BOS showed acceptable descriptive and predictive performance, suitable for deriving individual exposure metrics for subsequent pharmacodynamic analyzes.

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 A195.
Abstract A236: Human liposarcoma growth inhibition by novel CDK4/6 inhibitor LEE011.
Authors: Zhang Yixiang , Sicinska Ewa , Moss Samuel , Czaplinski Jeffrey T. , Wang Yuchuan , Brain Christopher , Demetri George D. , Kim Sunkyu , Kung Andrew L. , Wagner Andrew J. 
Published: June 2012

Abstract
Background: Well-differentiated and de-differentiated liposarcomas (WD/DDLPS) are characterized by high-level chromosomal amplification of 12q13–15, a region including the cyclin-dependent kinase 4 (CDK4) oncogene. In this study, we explored the effects of LEE011, a novel selective inhibitor of CDK4/CDK6 on human liposarcoma cell lines and primary tumor xenografts.
Materials and Methods: We examined the expression of cell cycle regulatory proteins in human liposarcoma cell lines and human normal preadipocytes/adipocytes. CDK4 small interfering RNA (siRNA) or LEE011 was applied to liposarcoma cell lines and the biological consequences were determined by phospho-RB immunoblot, cell cycle assay and cell enumeration. In addition, liposarcoma cells were transfected with RB siRNA to determine the specificity of the effects of LEE011. Nude mice implanted with human liposarcoma cell lines or primary tumors were treated with LEE011 or vehicle by oral gavage. After 3 daily doses, in vivo BrdU incorporation assay, immunostains for phospho-RB, and 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan were performed. Tumor size and animal weight were serially measured during 3 weeks of dosing.
Results: CDK4 and p-Rb are highly expressed in human liposarcoma cell lines in comparison with normal preadipocytes/adipocytes. Both CDK4 siRNA and LEE011 inhibited RB phosphorylation at the CDK4/6-specific sites Ser780 and Ser807/811 in a dose-dependent manner and dramatically inhibited liposarcoma cell growth. Cell cycle analysis demonstrated arrest at G0/G1. siRNA-mediated knockdown of RB1 rescued the inhibitory effects of LEE011, suggesting that LEE011 inhibited proliferation as expected through the RB pathway. Oral administration of LEE011 to mice bearing human liposarcoma xenografts reduced tumor 18F-FDG uptakes by approximately 50% and dramatically decreased biomarkers including RB phosphorylation and BrdU incorporation in vivo. Continued LEE011 treatment inhibited growth of established cell line xenografts as well as primary human liposarcoma tumor xenografts without detrimental effects on mouse weight.
Conclusions: LEE011 decreases cell cycle progression, hypermetabolism, and proliferation of human liposarcomas in an RB-dependent manner, consistent with inhibition of CDK4. Clinical trials of LEE011 in patients with liposarcoma are warranted.
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 A236.
Abstract A39: Measurement of CUDC-101 target inhibition in circulating tumor cells using a fluorescent-based quantitative assay.
Authors: Davis Darren 
Published: June 2012

Abstract
Introduction: The occurrence of receptor signaling redundancy in multiple cancer pathways has led to the growing development of more potent, multi-kinase inhibitors that have the capability to block a broad array of tumor-related activation pathways. CUDC-101, is a clinical stage, network targeted agent designed to simultaneously inhibit EGFR, HER2 and HDAC in tumor cells. The ability to monitor the various activities of CUDC-101 in readily assessable clinical samples is critical for drug development processes including: (i) providing evidence of a pharmacodynamic effect in early clinical studies and (ii) facilitating the patient stratification strategy in advanced clinical studies.
Objective: To identify optimal biomarkers of CUDC-101 inhibition for pharmacodynamics monitoring by developing an assay to measure total and phosphoylated EGFR and HER2 proteins, and aceylated histone H3 (inhibition of HDAC leads to hyperacetylation of histones) in circulating tumor cells (CTCs).
Methods: CTCs were enriched from head and neck, or breast cancer patient blood samples treated ex vivo with CUDC-101 using CellSeach® Profile Kit. In parallel, two head and neck cancer cell lines, SCC-9 and SCC-15, were treated with vehicle or CUDC-101. The expression of pathway-specific proteins (total and phosphorylated) was quantified by laser scanning cytometry.
Results: Significant reduction in pEGFR (3 out of 5 patients) or pHER2 (2 out of 5 patients) was observed in enriched CTCs from CUDC-101 ex vivo treated blood compared with vehicle ex vivo treated blood samples. Among the patients that had reduced pEGFR and/or pHER2, a corresponding significant increase was also observed in acetylated histone H3. This data is consistent to parallel ex vivo treatment cell line studies which demonstrated that treatment of SCC-9 and SCC-15 cell lines with CUDC-101 at 10 uM led to a 21–33% reduction in pEGFR, a 22–40% reduction in pHER2 and conversely, a 51–177% increase in acetylated histone H3.
Conclusion: CUDC-101 was shown to successfully inhibit EGFR, HER2 and HDAC in ex vivo treated cancer patient blood CTCs. These assays are currently being applied in an ongoing phase I study of CUDC-101 in head and neck cancer.
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 A39.