bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B1: Antitumor activity of TSU-68 in PDGF-BB overexpressing U-87MG xenograft model: contribution of PDGFR blocking action.
Authors: Hosoi Fumihito , Yokoi Hiromi , Nameki Daisuke , Hayashi Hiroaki , Ito Kenjiro , Masuko Norio , Minamiguchi Kazuhisa , Matsuo Ken-ichi , Utsugi Teruhiro 
Published: June 2012

Abstract
PDGFR is an important target for novel anticancer therapeutics because it is overexpressed in a wide variety of malignancies. TSU-68, a new drug under clinical study that inhibits an angiogenic receptor tyrosine kinase KDR, which play a crucial role in tumor-induced vascularization, inhibits angiogenesis and the growth of human tumor xenografts in vivo. This compound is also a potent inhibitor of PDGFRα and PDGFRβ kinases. In this study, PDGF-BB overexpressing human tumor model was used to characterize the in vivo activity of TSU-68 as a PDGFR blocking agent.
In vivo xenograft mice study, TSU-68 treatment (once daily p.o. dosing for 28 days) exhibited potent antitumor activity in PDGF-BB overexpressing U-87MG (U-87MG/PDGF-9) xenograft (T/C 28.2%) in comparison to parental U-87MG xenograft (T/C 69.7%). Expression level of VEGF of U-87MG/PDGF-9 cells was similar to that of parental U-87MG cells. PDGF-BB was only detected in plasma of mice bearing U-87MG/PDGF-9 xenograft. To identify the action of TSU-68 on U-87MG/PDGF-9 tumor, in vitro cell proliferation assay, ex vivo study, and immunohistological examination of xenografts were carried out. TSU-68 inhibited cell proliferation of U-87MG cells induced by PDGF-BB but not by FBS. In U-87MG/PDGF-9 xenograft tumors, PDGFR was highly phosphorylated and a single oral dose of TSU-68 (200 mg/kg) inhibited phosphorylation of PDGFR in the tumors. Immunohistochemical analyses revealed reduced Ki-67 staining in the tumors from TSU-68-treated mice relative to the vehicle control. The Ki-67 labeling index, calculated as the percentage of positive staining cells of total nucleated cells in a field was 47.0 ± 8.5 vs. 31.8 ± 4.5 (p&lt;0.01) for vehicle control and TSU-68-treated U-87MG/PDGF-9 tumor samples, respectively. And, the microvessels in U-87MG/PDGF-9 xenografts were quantified by immunostaining of CD31. A significant decrease in microvessel area (MVA) was detected in the tumors from TSU-68-treated mice compared with vehicle control (13.5 ± 3.1 vs. 4.6 ± 1.0, p&lt;0.01). Similar results were also obtained in microvessel density (MVD). These data support that the in vivo antitumor effect of TSU-68 on PDGF-BB overexpressing U-87MG is associated with the inhibition of PDGF/PDGFR axis of tumor and neoangiogenesis. TSU-68 has some programs currently under clinical evaluation for the therapy of cancer. PDGF/PDGFR axis is one of the possible biomarkers for stratification of patients in future 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 B1.
Abstract B103: HSP90 inhibition targets the dysregulated signal and transcription factor network and malignant phenotype of head and neck squamous cell carcinoma.
Authors: Gouveia Christopher J. , Wise Stephanie , Friedman Jay , Hu Michael , Freudlsperger Christian , Kannabiran Vishnu , Arun Pattatheyil , Mitchell James , Kan Julie , Brega Nicolleta , Chen Zhong , Van Waes Carter 
Published: June 2012

Abstract
Purpose: Activation of multiple oncogenic signaling pathways and transcription factors, concurrent with defective tumor suppressor TP53, have been implicated in pathogenesis and therapeutic resistance of epithelial cancers. Many proteins upon which these cancers depend are stabilized by the chaperone, heat shock protein 90 (HSP90). Here we characterized the effects of HSP90 inhibitor, PF-04928473, against the dysregulated network and malignant phenotype in head and neck squamous cell carcinoma (HNSCC).
Experimental Design: HSP90 expression was analyzed in HNSCC tissue array and cell lines. Expression and function of oncogenic molecules and cytokines were analyzed by Western blot, reporter gene, and multiplex Luminex assays. Drug effects on proliferation, cell cycle, and radiosensitivity were evaluated by MTT, flow cytometry, and clonogenic assays. Anti-tumor effects and modulation of immunohistochemical markers were evaluated in a TP53-deficient xenograft model resistant to targeted therapies.
Results: HNSCC tissues and lines overexpressed HSP90. PF-04928473 inhibited dysregulated EGFR, c-MET, AKT, ERK1/2, IKK signal molecules, AP-1, STAT3, and NF-B reporter genes, and expression of target oncogenes and angiogenic cytokines. PF-04928473 induced re-expression of TP53 and targets p21 and PUMA in TP53-deficient HNSCC. Corresponding to effects on these molecules implicated in HNSCC pathogenesis, PF-04928473 inhibited proliferation, induced G2/M block, apoptosis, and enhanced radiosensitivity in vitro. PF-04928473 similarly modulated key targets, inducing apoptosis, and inhibiting proliferation, angiogenesis and xenograft tumorigenesis in vivo.
Conclusion: HSP90 antagonist PF-04928473 modulated the dysregulated signal and transcriptional network, inhibited the malignant phenotype, and radiosensitized HNSCC.
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 B103.
Abstract B121: Influence of affinity tags on the biochemical properties of recombinant human tyrosine kinase ALK.
Authors: Mueller Daniel , Totzke Frank , Beisenherz-Huss Christian , Heidemann-Dinger Caroline , Weber Thomas , Ketterer Constance , Kubbutat Michael H.G. 
Published: June 2012

Abstract
Anaplastic lymphoma kinase (ALK) is a human receptor tyrosine kinase which has important functions in the development and maintenance of the peripheral and central nervous system. It has also been shown to be one causative agent in the development of several human malignancies including neuroblastoma, anaplastic lymphoma and non small cell lung cancer (NSCLC). One mechanism of pathological activation of ALK occurs by chromosomal translocation of the ALK gene to EML4 giving rise to an abnormal fusion protein. In order to develop small molecule inhibitors targeting ALK, in-vitro kinase assays have been developed which use recombinant ALK fragments fused to affinity tags to facilitate purification. Here we present data which demonstrate that biochemical parameters of recombinant ALK fusion proteins, like substrate specificity, ATP Km, Vmax and effects of chemical compounds, are significantly influenced by the type of affinity tag used. That influence partially persists even after cleavage of the affinity tag during the purification process. Since affinity-tagged recombinant proteins are widely used in drug discovery, a careful evaluation of potential tag-related effects should be considered.
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 B121.
Abstract B144: Elesclomol, an inducer of oxidative stress, targets oxidative phosphorylation (oxphos) in melanoma cells.
Authors: Moschos Stergios J. , de Moura Michelle Barbi , Fayewicz Shelley , Bateman Nicholas , Sun Mai , Duensing Stefan , Yin Yan , Sander Cindy , Becker Dorothea , Kirkwood John , Conrads Thomas , Van Houten Bennet 
Published: June 2012

Abstract
Mitochondria are important gatekeepers of cell survival in melanoma cells and their role as oxygen sensors, ATP producers, or inducers of reactive oxygen species are established. However, the role(s) of metabolic processes other than glycolysis are not well characterized in melanoma development and progression. Here we show that melanoma cells exhibit higher levels of oxidative phosphorylation (Oxphos) compared to human epidermal melanocytes. Furthermore, we present several independent lines of evidence (bioenergetics analysis using Seahorse XF24, stable isotope labeling of melanoma cells in culture, immunoblot analysis of isolated mitochondria, electron microscopy, and rho zero cells) that elesclomol, an inducer of oxidative stress, suppresses Oxphos in melanoma cells without a significant effect on glycolysis in vitro. Melanoma cells with intrinsically high levels of glycolysis are less sensitive to elesclomol. In addition, following chronic continuous drug exposure, resistant cells manifest a high glycolytic phenotype. Finally hypoxia inducible factor 1 alpha, a master metabolic switch of cell metabolism towards glycolysis, is upregulated following elesclomol treatment in a number of melanoma cell lines examined. Our results suggest that Oxphos is an important therapeutic target and that elesclomol specifically impinges on this process.
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 B144.
Abstract B149: Yes-associated protein (YAP) is associated with aggressive characteristics of BRAFV600E thyroid cancer.
Authors: Lee Seong Eun , Lee Jung Uee , Lee Min Hee , Ryu Min Jeong , Kim Soung Joong , Kim Yong Kyung , Kim Koon Soon , Choi Min Jeong , Jo Young Suk , Shong Minho 
Published: June 2012

Abstract
Up regulation of Yes-associated protein (YAP), a transcriptional co-activator regulated by Hippo (MST-LAST-YAP) pathway, has been reported to mediate oncogenic transformation in animal models of hepatocellular carcinomas. However, the expression status and molecular biological role of YAP in thyroid cancer remained to be investigated. We evaluated YAP expression and identified increased nuclear YAP expression in PTC and ATC. Interestingly, we could observe nuclear YAP staining more frequently in BRAFV600E(+) PTC. We also performed immunofluorescence staining to verify intracellular localization of YAP in TPC1 (harboring RET/PTC1), 8505C (harboring BRAFV600E) and BRAFV600E stably transfected HEK293T cells. Consistently, we could detect nuclear YAP in 8505C and BRAFV600E expressed cells, but not in TPC1. Although cell viability assays did not show any difference between YAP knockout cells and control cells generated by using shYAP in 8505C and shCTL (control) 8505C, YAP knockout cells showed remarkably decreased migration ability in the scratch assays. Using orthotopic mice models, shYAP 8505C injected mice showed decreased local invasion ability and less frequent lung metastasis. In conclusions, Nuclear YAP could be more frequently detected in BRAFV600E(+) thyroid cancer compared to BRAFV600E(−) thyroid cancer. Furthermore, nuclear YAP in BRAFV600E(+) thyroid cancer was associated with local invasiveness and distant metastasis, presenting that YAP could affect the aggressive phenotype of BRAFV600E(+) thyroid 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 B149.
Abstract B15: The use of micro-CT imaging and histology in a clinically relevant Foxn1nu mouse intrafemoral model of metastatic prostate cancer.
Authors: Batey Michael A. , Brown Matthew , Booth Catherine 
Published: June 2012

Abstract
Subcutaneous tumor xenograft models using transplantation of human tumour cell lines into immunodeficient mice are routinely used for the preclinical testing of anticancer therapies. These models do not however fully represent the clinical situation, and as such there can be difficulties in translating the results of promising preclinical data into a successful patient treatment. There is therefore a need to develop more clinically relevant preclinical models, particularly in metastatic disease. The development of preclinical imaging strategies, such as micro-CT gives us the ability to follow disease progression at orthotopic sites, and the efficacy of treatment longitudinally in a similar way to the clinical situation.
At autopsy, approximately 84% of patients with prostate cancer will be found to have skeletal metastases, and in those patients who first present with bony disease the 5 year survival rate is less than 25%, making this an important focus for the development of novel therapies. Intrafemoral (i.f.) transplantation is a technically feasible and convenient method for the study of cancer types associated with bone or bone marrow, as this technique implants cells directly into the biological niche of interest, correlating with the environment in which disease develops in patients.
Previously, severely compromised immunodeficient mice have been used to study metastatic prostate cancer development. For the studies described here, using the immunocompromised Foxn1nu mouse strain, the human prostate cancer cell lines PC3 (prostate membrane specific antigen negative, androgen resistant) or LNCaP (prostate membrane specific antigen positive, androgen sensitive) were injected i.f. into the bone marrow cavity of the femur via the knee joint. Animals were followed over a period of several weeks, and micro-CT imaging used to assess the growth and development of tumour in bone. Areas of interest, identified by imaging, were taken for histological assessment of patient relevant markers, and data compared to clinical imaging and histopathology of human disease.
We have found that this model offers a clinically relevant preclinical representation of bony metastasis of prostate cancer. The described use of micro-CT imaging and detailed histological analysis allows for a clearer translation between preclinical testing and clinical observation, and as such represents a valuable new tool for the assessment of novel therapeutics.
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 B15.
Abstract B161: PIK3CA mutations H1047R are associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials.
Authors: Janku Filip , Naing Aung , Stepanek Vanda T. , Falchook Gerald S. , Hong David S. , Tsimberidou Apostolia M. , Fu Siqing , Lee J. Jack , Luthra Rajyalakshmi , Wheler Jennifer J. , Kurzrock Razelle 
Published: June 2012

Abstract
Background: Activating mutations in the PIK3CA gene have been identified in many malignancies. Preclinical and early clinical data suggest that these mutations predict response to PI3K/AKT/mTOR inhibitors in subsets of patients. Sensitivity and resistance mutation have not been reported to date.
Methods: Patients with diverse cancers referred to the Phase I Clinical Trials Program for targeted therapy starting from October 2008 were analyzed for PIK3CA, and if, possible for KRAS mutations using PCR-based DNA sequencing. Patients with any tumor type and any PIK3CA mutation were treated whenever possible with agents targeting the PI3K/AKT/mTOR signaling pathway. Treatment outcomes with respect to mutation types were analyzed.
Results: Overall, 1012 patients were tested and 105 (10%) had PIK3CA mutations. Of the 105 patients with PIK3CA mutations, 66 (median number of prior therapies, 3) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Of these 66 patients, 11 (17%) achieved a partial response (PR) and 4 (6%) stable disease ≥ 6 months (SD≥6). The total of SD≥6/PR was 15 (23%). Patients with PIK3CA H1047R mutation (n=16) compared to patients with other PIK3CA mutations (n=50) had higher PR rate (6/16, 37.5% vs. 5/50, 10%; p=0.018), higher rate of SD≥6/PR (7/16, 44% vs. 8/50, 16%; p=0.037), and trend toward longer median progression-free survival (PFS) (5.7 months, 95%CI 0.4–11.0 vs. 2.0 months, 95%CI 1.8–2.2; p=0.064). Patients with a PIK3CA E542K mutation (n=11) compared to others (n=55) trended toward a worse median PFS (1.8 months, 95%CI 1.4–2.2 vs. 2.6 months, 95%CI 1.4–3.8; p=0.058). Of the 66 treated patients with PIK3CA mutations, 55 (83%) had enough tissue for KRAS testing. None of the 16 patients with PIK3CA and simultaneous KRAS mutations in codon 12 or 13 had a PR (0/16, 0% vs. 9/39, 23%; p=0.046) or SD≥6/PR (0/16, 0% vs. 13/39, 33.3%; p=0.011) as compared to patients with PIK3CA, but not KRAS codon 12 or 13 mutations, whereas 2 of 2 (100%) patients with PIK3CA and Q61H KRAS mutation in codon 61 had SD≥6 (n=1) and PR (n=1).
Conclusion: Despite the small number of patients, our data suggest that PIK3CA mutations H1047R are associated with response to PI3K/AKT/mTOR inhibitors, whereas codon 12 and 13, but not codon 61 KRAS mutations are associated with resistance.
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 B161.
Abstract B186: Knockdown of a chromatid segregation mediator gene impairs tumor growth in glioblastoma multiforme.
Authors: Mughal Awais , Stangeland Biljana , Ramsnes Ingunn , Grieg Zanina , Joel Mrinal , Fjerdingstad Hege , Sandberg Cecilie , Vik-Mo Einar Osland , Murrell Wayne , Langmoen Iver Arne 
Published: June 2012

Abstract
Glioblastoma Multiforme (GBM) is the most common primary brain malignancy and despite multimodal therapy including surgery, irradiation and chemotherapy median survival remains 12–15 months. Increasing body of evidence from our and other groups is confirming the existence of a stem-like cell population within these tumors believed to confer tumor growth, invasiveness, and therapy resistance. Adult human neural stem cells (aHNSCs) are suggested to be the cells of origin for the glioblastoma stem-like cells (GSCs).
To identify new molecular targets we performed a micro-array analysis on the transcriptome of 33000 genes identifying differentially expressed genes in 5 aHNSC and 9 GSC cultures. Amongst the genes highly up-regulated in GBM, several were involved in cell division and the regulation of cell cycle. For further analysis, we chose the Chromatid Segreration Mediator (CSM), a centromere specific gene important for appropriate chromatid segregation during mitosis. This candidate gene was strongly expressed in GSCs but was almost undetectable in aHNSCs. Abundance of the CSM protein may lead to aneupleudy, which is a common feature of GBMs.
The high levels of CSM mRNA were confirmed by analyzing 16 GSC cultures with micro-array and qPCR. CSM was also over-expressed on protein level, and was found to be highly immunopositive in glioblastoma biopsies compared to the normal human brain. In silico analysis, using Rembrandt, identifies CSM-gene over-expression as a negative prognostic indicator in glioma patients.
In order to study the functional role of this gene in GBM, we used lentiviral-based knock-down (KD) technology to obtain specific down regulation of the gene. We transduced different shRNA constructs in 2 GBM cultures and achieved KD-efficieny of 55–65%.
Growth of tumors was measured by proliferation assay and the relative number of sphere-forming cells (widely known as GSCs) was quantified with a sphere-formation assay.
In our KD-cultures we observed a moderate reduction of proliferation (25%). Interestingly, the sphere forming capacity was dramatically reduced by 60–70%, indicating a significant decrease in number of GSCs. Cell-cycle analysis revealed that it was 30–40% less cells in G2/M-phase and 15–20% more cells in G0/G1-phase in the KD compared to non-silencing control.
We find our results very promising and suggest that Chromatid Segregation Mediator gene might have potential as a novel therapeutic target for GBM management.
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 B186.
Abstract B187: ErbB4 ectodomain as a biomarker and a potential therapeutic target for breast cancer.
Authors: Hollmén Maija , Liu Ping , Wildiers Hans , Reinvall Irene , Vandorpe Thijs , Smeets Ann , Deraedt Karen , Vahlberg Tero , Joensuu Heikki , Leahy Daniel J. , Schöffski Patrick , Elenius Klaus 
Published: June 2012

Abstract
ErbB4 function in breast cancer is controversial and influenced by alternative splicing of the ERBB4 gene. Here we evaluated the cleavable ErbB4 JM-a isoform as a potential drug target and biomarker. Matched serum and tissue samples from a series of 243 breast cancer patients were analyzed for ErbB4 cleavage products by ELISA and immunohistochemistry. Elevated serum ectodomain level (≥40 ng/mL) was present in 21% of the patients and significantly associated with the premenopausal status at diagnosis (P = 0.04). Consistent with the in vivo data, estradiol enhanced ErbB4 shedding and TACE activity in vitro. Selective targeting of ErbB4 JM-a by mAb 1479 inhibited ErbB4 cleavage and reduced tumor formation in a mouse xenograft model. The 3.4 Å X-ray crystal structure of the sErbB4:1479Fab complex localized the binding site of mAb 1479 on ErbB4 to a region on subdomain IV encompassing JM-a-specific residues. These data demonstrate that ErbB4 cleavage can be specifically targeted in vivo, and introduce serum ErbB4 ectodomain concentration as a biomarker for monitoring the activity of compounds that target ErbB4 cleavage.
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 B187.