bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4533: In vivo activation of the p53 pathway leading to tumor regression by a novel and potent HDM2 antagonist SCH 1450206
Authors: Wang Yaolin , Wang Xiaoying , Lipari Philip , Ponery Abdul-Samad , Liu Suxing , Mirza Asra , Liu Yinghui , Bogen Stephane , Ma Yao , Doll Ronald , Shipps Gerald , Liu Ming , Seidel-Dugan Cynthia , Hicklin Daniel J. , Bishop Walter Robert 
Published: February 2011

Abstract
The HDM2-p53 protein-protein interaction is well characterized through X-ray crystallography. Disrupting this HDM2-p53 protein-protein interaction by a small molecule would therefore release the p53 from the negative inhibition of HDM2 and restore its anti-tumor activities. Peptides, antisense oligonucleotides and small molecules have been identified which disrupt this interaction and result in the stabilization of p53 protein and activation of its downstream targets. We have recently discovered a novel, potent HDM2 antagonist (SCH 1450206) with mechanism-based activity both in vitro and in vivo. Oral administration of SCH 1450206 as a single agent resulted in tumor regression in the SJSA-1 osteosarcoma xenograft model without any observable toxicity. Analysis of the pharmacodynamic markers demonstrated that the anti-tumor activity of SCH 1450206 correlated with the robust activation of p53 pathway in vivo. In addition to its single agent anti-tumor activity, combination of HDM2 antagonist SCH 1450206 with various cytotoxics resulted in further tumor growth inhibition in various human cancer xenograft models. The activation of p53 pathway in vivo targets preferentially to tumor tissues compared to high proliferating and radio sensitive organs of the mouse at the efficacious dose. The lack of single agent toxicity at the efficacious dose and schedule would potentially allow the combination of this type of HDM2 antagonist with other anti-cancer agents at full dose in the clinic.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4533.
Abstract 4535: MDM2 inhibitor MI-319 in combination with cisplatin/oxaliplatin is an effective treatment for pancreatic cancer independent of p53 function
Authors: Azmi Asfar S. , Philip Philip A. , Aboukameel Amro , Banerjee Sanjeev , Wang Zhiwei , Wang Shaomeng , Yang Dajun , Sarkar Fazlul H. , Mohammad Ramzi M. 
Published: February 2011

Abstract
Pancreatic cancer (PC) is considered to be among the most intractable malignancies as it is refractory to chemotherapy and radiation. Among the various genetic alterations in PC, mutation in the tumor suppressor p53 (mut-p53) gene has been reported to be about 50%. In the remaining 50%, the p53 is normal, but its function is inhibited by MDM2 protein which plays a key role in promoting ubiquitination and proteasomal-dependent degradation of p53. An attractive approach to p53 activation is the use of MDM2 inhibitors that disrupt the MDM2-p53 interaction and restore the p53 function. However, these small molecule inhibitors (SMIs) are not effective against tumors with mut-p53. Our group has designed a new class of SMI of MDM2 that is different from Nutlin-3. Here we are reporting, for the first time, that MI-319 can induce cell growth inhibition and apoptosis in PC irrespective of p53 mutational status when combined with cisplatin/oxaliplatin. MI-319-cisplatin or oxaliplatin combination synergistically suppressed cell growth (MTT CI&lt;1), colony formation (clonogenic assay) and induced apoptosis in both mut-p53 Colo-357, BxPC-3 and Panc-28 or wt-p53 Capan-2 cells. Western blot analysis and siRNA silencing studies in mutant as well as p53 null cells highlighted a mechanism involving p73 which is under the regulation of MDM2, and unlike p53, it is rarely mutated in PC. In order to substantiate its in vivo relevance we tested this potent combination in mice xenograft models carrying Capan-2 and BxPC-3 tumors. 4 groups, each containing 8 animals were treated either with; Control (Vehicle only), MI-319 treated 200mg/Kg orally twice a day for three weeks, Cisplatin treated 4 mg/kg (i.v.) twice a week for two weeks and combination treated (MI-319 200 mg/Kg orally + Cisplatin 4 mg/kg). The combination effectively reduced tumor growth in both wt-p53 and mut-p53 tumor xenograft models (50% Capan-2 animals were tumor free). Consistent with our in vitro results, remnant tumor tissue analysis showed up-regulation of p73 and the cell cycle regulator p21. In conclusion, this study highlights a new role of MDM2 inhibitors in combination with cisplatin or oxaliplatin, and thus warrants further clinical investigation in human pancreatic tumors containing both wt-p53 and mut-p53.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4535.
Abstract 4537: SHLP6: A novel, naturally occurring, mitochondrial peptide has therapeutic and prognostic potential in prostate cancer
Authors: Cobb Laura , Nakamura Hiromi , Cohen Pinchas 
Published: February 2011

Abstract
Mitochondrial DNA (mtDNA) mutations have been demonstrated in prostate cancer, particularly at the 16S rRNA region; and abnormal mRNA transcripts from that locus have been described. We and others showed that a novel open reading frame (ORF) within the mitochondrial 16S rRNA region, encoding for a 24 AA peptide called humanin, is a potent cell-survival and metabolic factor (PNAS 2003, PLoS-ONE 2009).
Hypothesizing that additional bioactive peptides may be encoded from this region we have identified an additional six ORFs that encode peptides transcribed from within the 16s rRNA gene in the mtDNA, which we have named small humanin-like peptides, or SHLPs. SHLP1-5 are functionally analogous to humanin, and act as potent survival factors.
Intriguingly an additional peptide, SHLP6, functions in a completely opposing manner. We demonstrate that endogenous SHLP6 is expressed in serum and in multiple tissues, including the prostate, and that its expression declines with age. In addition, the addition of exogenous SHLP6 promotes apoptosis in prostate cancer cell lines including 22RV1, LNCaP and DU145. Analysis of gene and protein expression of SHLP6 treated cells reveals modulation of cell cycle and apoptosis genes and a dramatic inhibition of VEGF expression.
To assess the in vivo potency of SHLP6, we treated 22RV1 xenografts in SCID mice with SHLP6 for 1 week, and observed a potent inhibition of CaP xenograft growth and angiogenesis in vivo. In addition, we show that SHLP6 expression is decreased in preliminary staining of human prostate cancer, compared with normal prostate tissue.
Thus, our findings not only introduce the revolutionary concept that a previously unrecognized family of peptides is produced from the mitochondria, challenging existing paradigms about mitochondrial function, but also demonstrate that SHLP6 is altered in prostate cancer, and may serve as a novel therapeutic and diagnostic agent in this disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4537.
Abstract 455: Hypoxia induced carbonic anhydrase IX is essential for the growth and metastasis of breast tumors
Authors: Lou Yuanmei , McDonald Paul C. , Oloumi Arusha , Chia Stephen , Kyle Alastair , dem Keller Ulrich auf , Fotovati Abbas , Gray Virginia , Leung Samuel , Huntsman David , Clarke Blaise , Waterhouse Dawn , Bally Marcel , Roskelley Calvin , Overall Christopher , Minchinton Andrew , Supuran Claudiu T. , Dedhar Shoukat 
Published: February 2011

Abstract
Metastasis of primary malignancies is a multi-step process and remains the principal cause of cancer deaths. Carbonic anhydrase IX (CAIX) is a hypoxia inducible protein and a poor prognostic marker for several types of cancer, including breast cancer. However, the functional role of CAIX in the metastatic progression of breast cancer is unclear. Here, we have investigated its role in the growth and metastasis of breast tumors. Orthotopic mouse mammary tumors derived from metastatic 4T1 and 66cl4 cells or non-metastatic 67NR cells were examined for levels of proliferation (BrdU), hypoxia, (pimonidazole), perfusion (DiOC7), vasculature (CD31), apoptosis (TUNEL) and lymphangiogenesis (LYVE-1). Metastatic 4T1 and 66cl4 tumors expressed a hypoxia gene signature and were characterized as being poorly vascularized, with high levels of hypoxia. Large numbers of apoptotic cells and well developed intratumoral lymphatic vessels were also evident. Inhibition of expression of CAIX in the metastatic 4T1 cells by stable expression of short hairpin RNA (shRNA) resulted in cell death and reversal of extracellular acidosis in hypoxia in vitro, dramatic regression of tumors in vivo, and inhibition of metastasis. These properties were rescued by constitutive expression of human CAIX. Treatment of mice harboring 4T1 tumors with a novel CAIX-specific inhibitor resulted in significant inhibition of tumor growth. Interrogation by immunohistochemistry of a large (3992 patient samples) primary breast tumor tissue microarray showed that CAIX expression was significantly associated with worse distant relapse free survival (p&lt;10−16) and was most prominent in the basal breast cancers (51%). Our data show that CAIX-mediated function is required for the survival and metastasis of hypoxic breast tumors, and suggest that CAIX is a promising therapeutic target for metastatic breast cancer.
This work was supported by the Canadian Breast Cancer Research Alliance, with special funding from the Canadian Breast Cancer Foundation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 455.
Abstract 4551: 111In-NLS-Nimotuzumab: A potent auger electron-emitting radiotherapeutic agent for EGFR-overexpressing breast cancer
Authors: Fasih Aisha , Reilly Ray , Tikhomirov Ilia 
Published: February 2011

Abstract
Objective: To evaluate the cytotoxicity of nimotuzumab (Nmab), a monoclonal antibody specific for EGFR labeled with 111In and modified with nuclear localization sequence (NLS) peptides for importation into the nucleus of human breast cancer (BC) cells, where the emitted Auger electrons are most damaging to DNA and lethal.
Methods: NMab was derivatized with sulfo-SMCC to introduce maleimide groups for reaction with NLS-peptides (CGYGPKKKRKVGG) and benzyl-DTPA (bn-DTPA) for complexing 111In. NLS substitution was quantified by a band shift on SDS-PAGE and bnDTPA substitution by an 111In-binding assay. The immunoreactivity (Kd) of NLS-Nmab was determined by the displacement of binding of 111In-Nmab to MDA-MB-468 BC cells (106 EGFR/cell). Internalization and nuclear importation were determined in MDA-MB-468 and MCF-7 (104 EGFR/cell) BC cells by subcellular fractionation at 37 oC and 4 oC up to 3 h. Clonogenic survival (CS) was measured in MDA-MB-468 and MCF-7 cells exposed to 2 to 40 nM (450-900 KBq/mL) of 111In-NLS-Nmab for 3 days.
Results: Nmab was modified with 8.5±0.2 NLS and 2.1±2.1 bn-DTPA groups. The Kd for binding of 111In-NLS-Mab to MDA-MB-468 cells was 9.8±0.9 nM. NLS-Nmab was labeled with 111In to a radiochemical purity of 99.2±0.1% (specific activity 350±9 MBq/mg). The proportion of cell-bound 111In internalized into MDA-MB-468 cells at 3 h was 27.8±0.8% at 37 oC and 4.4±0.2 at 4 oC. Nuclear uptake was 31.2±2.6% for 111In-NLS-Nmab and 16.0±0.6% for 111In-Nmab (P&lt;0.001). Binding and nuclear uptake were 20-fold and 6-fold lower, respectively for MCF-7 cells. The CS of MDA-MB-468 cells exposed to 111In-NLS-Nmab (20 nM) was 2.8±0.2% compared to 21.0±5.3% for 111In-Nmab (P=0.004) and 60.0±7.0% for Nmab (P=0.001). The CS of MCF-7 cells exposed to 111In-NLS-Nmab (40 nM) was 82.6±6.4% vs. 80.0±1.6% for 111In-Nmab (p&gt;0.05) and 95±19.4% for Nmab (p&gt;0.05).
Conclusion: 111In-NLS-Nmab is a promising targeted radiotherapeutic agent for EGFR-overexpressing BC as evidenced by a 20-fold increased toxicity towards MDA-MB-468 cells compared to Nmab but lack of toxicity towards MCF-7 cells with 10-fold lower EGFR expression similar to that on most normal epithelial cells. Supported by the Canadian Breast Cancer Research Alliance (Grant 019513).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4551.
Abstract 4553: Novel bispecific 111In-labeled immunoconjugates (bsICs) for imaging HER2/HER3 heterodimerization in breast cancer
Authors: Eva Razumienko J. , Reilly Raymond M. 
Published: February 2011

Abstract
Objective: Our objective was to construct novel bsICs capable of binding HER2 and HER3 labeled with 111In for imaging HER2-HER3 heterodimerization in breast cancer (BC) possibly through higher avidity for dimeric vs. monomeric complexes.
Methods: bsICs were composed of trastuzumab Fab recognizing HER2 linked to a 7.5 kDa HER3-binding peptide of heregulin-β1 (pHRG). Fab were produced by digestion of trastuzumab IgG with papain. Fab were modified with Sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-SMCC) or related analogues with polyethyleneglycol (PEG) spacers (SM-PEG12-NHS and SM-PEG24-NHS) to introduce maleimide groups for cross-linking to pHRG thiolated with Traut's reagent. bsICs were derivatized with diethylenetriaminepentaacetic acid (DTPA) for labeling with 111In. The ability to independently bind HER2 or HER3 was determined in competition assays using 111In-bsICs on cells expressing HER2, HER3 or both receptors competed with a 25-fold excess of Fab, pHRG or combined ligands.
Results: Conjugation of Fab to pHRG was confirmed by SDS-PAGE, Western blot and size-exclusion HPLC. bsICs were labeled with 111In to a radiochemical purity of 98.9 ± 0.2% (specific activity 375 ± 14 MBq/mg). Insertion of a PEG spacer between Fab and pHRG was required for displacement of binding of 111In-bsICs to HER3 but not HER2. For 111In-bsICs with the longest spacer (PEG24), the binding to SKBR-3 cells (HER2+/HER3+) was reduced to 32.7 ± 0.7%, 85.9 ± 1.0% or 30.4 ± 1.6%, respectively by Fab, pHRG or both ligands. The binding to SKOV-3 cells (HER2+/HER3-) was reduced to 16.7 ± 0.8%, 88.8 ± 5.3% or 13.4 ± 0.1% by Fab, pHRG or both ligands. The binding to MDA-MB-468 cells (HER2-/HER3+) was reduced to 98.5 ± 1.5%, 68.8 ± 0.3% or 64.8 ± 4.5% by Fab, pHRG or both ligands. Less efficient competition for HER3 was observed for the PEG12 spacer and no competition for 111In-bsICs without a spacer.
Conclusion: 111In-bsICs composed of trastuzumab Fab and pHRG bound specifically to HER2 and HER3 when an appropriate length PEG spacer was inserted between these two binding moieies. These 111In-bsICs may be useful for imaging HER2-HER3 heterodimerization in BC. Supported by the Ontario Institute of Cancer Research (1 mm Challenge) and the Canadian Breast Cancer Foundation (Ontario Branch).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4553.
Abstract 456: Adaptation of cancer cells to hypoxic environments for tumor progression
Authors: Mizushima Tomoko , Kawai Kenji , Nishime Chiyoko , Ohmura Mitsuyo , Hayakawa Eri , Matsuyama Masahiro , Asakura Keisuke , Izumi Yotaro , Suemizu Hiroshi , Ohnishi Yasuyuki , Nakamura Masato , Suematsu Makoto , Wakui Masatoshi 
Published: February 2011

Abstract
There have been a number of reports mentioning the significance of adaptation of cancer cells to hypoxic environments in tumor growth, invasion, and metastases. However, understanding of molecular aspects based on in vivo evidence still remains insufficient. We established an in vivo tumor progression model by transfer of human colorectal cancer HCT116 cells cultured under hypoxia to NOD/Shi-scid, IL-2Rγnull (NOG) mouse recipients. The hypoxic culture resulted in invasive proliferation of subcutaneous tumors. Immnohistochemical staining for molecular markers, such as E-cadherin, vimentin and BCRP1, demonstrated that adaptation of HCT116 cells to hypoxia was associated with increased frequencies of epithelial-mesenchymal transition and cancer stem cell-like appearance. To investigate the molecular basis of such effects of hypoxia on tumor progression, biological and molecular profiles of HCT116 cultured under hypoxia were analyzed. The hypoxic culture resulted in slowing cell cycling and increase in the side population cell frequency, suggesting induction of stemness. Capillary electrophoresis-mass spectrometric analysis revealed altered metabolism in hypoxic HCT116 cells, which appeared to be associated with adaptation to hypoxia. Gene expression profiling of the cultured cells under pharmacological inhibition of p53, which is not mutated in HCT116 cells, presented evidence for dependence of the adaptation to chronic mild but not acute severe hypoxia on p53 function. Our results provided insights into molecular basis of tumor progression critically directed by hypoxia.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 456.
Abstract 4577: Comparative proteomic biomarker screening in laser microdissected tissues from colon adenoma and cancer
Authors: Meyer Markus , Spörl Monika , Harasym Agnieszka , Spangenberg Jörg , Unger Florian , Juhl Hartmut , David Kerstin A. 
Published: February 2011

Abstract
Colorectal (CRC) malignancies rank world wide at the third place for tumor diseases and account for an annual mortality rate of 492 000 cases. Although several molecular events are known to be involved in the transition from normal tissue to adenoma and finally to undifferentiated carcinoma it remains a challenge to discover new and more reliable biomarkers for diagnosis, prognosis and prediction of outcome. Towards this end a study was designed to identify potential biomarkers which are associated with the molecular events leading from epithelial adenoma to the early stages of carcinoma.
A new biomarker discovery strategy was developed to combine the cell specificity and selectivity of laser capture microdissection (LCM) with the resolution power and sensitivity of liquid-chromatography (LC)-matrix-assisted-laser-desorption/ionization mass spectrometry (LC-MALDI-MS). We carefully selected a group of closely matched patients (n = 10 for each group) afflicted with epithelial adenoma (high dysplasia) or early stages of carcinoma (stage I) and used the derived normal as well as the matched tumor tissue samples to reveal protein expression differences. According to this LC-MALDI-MS strategy microdissected cells (around 10 000 cells) were lysed and extracted proteins were digested with Trypsin. Obtained peptides were separated by capillary reversed phase HPLC (Agilent). The resulting LC-fractions (300) were spotted on prespotted AnchorChip targets (PAC, Bruker) and tryptic fragments subsequently detected by reflector MALDI-MS (ultraflex III, Bruker) measurements. This generated between 5000-7000 ion signals ranging from m/z 800 to 4000.
Differential peptide analysis was then performed with the goal to discover robust and significant expression differences between patient groups. Therefore, only m/z ions displaying a minimum twofold difference and a p-value of 0.01 between the tissue samples were considered for further analysis. The selected peptides were subsequently fragmented by MS/MS experiments to reveal their primary sequence and protein identity. Our targeted biomarker discovery approach resulted in the identification of more than 30 biomarker candidates which act in diverse cellular functions and can now be linked to early events (e.g. adenoma vs. normal tissue) or later events (e.g. carcinoma vs. normal) of tumor progression. Currently these biomarkers are validated using antibody based assays to further analyze their potential as markers in a clinical setting.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4577.
Abstract 4578: Comparative subcellular proteomics study of hepatocellular carcinoma cell lines differentially expressed alpha fetoprotein: Annexin A2 could serve as a potential histological and serological biomarker
Authors: Zhao Xiaohang , Sun Yulin , Cai Jianqiang , Qiao Yuanyuan , Zhou Lanping , Bi Xinyu , Liu Fang , Bai Xiaofeng 
Published: February 2011

Abstract
Hepatocellular carcinoma (HCC) is a common tumor worldwide with an extremely poor prognosis. Alpha-fetoprotein (AFP) is the only available HCC serological biomarker and has limited effect at early stages. Previous work has proven that AFP-producing and -nonproducing HCC cells have different gene/protein expression profiles. To identify additional candidates that might aid in HCC diagnosis, in addition to giving a better understanding of the mechanisms underlying hepatocarcinogenesis, subcellular fraction proteins from multiple liver cancer (HepG2, Hep3B and SK-HEP-1) and normal cells (HL-7702) were separated and identified using a 2-DE/MALDI-TOF-TOF approach. In total, 50 differentially-expressed proteins between liver cancer and normal liver cells were identified from different fractions including the cytosol, membrane/organelles and nuclear proteins. Among them, the tumor-related protein Annexin A2, was verified to be significantly upregulated in HCC tissues (63.5%, 80/126) especially in AFP-normal cases based on large-scale clinical specimens. Serum levels of Annexin A2 measured by an established ELISA assay were found to be significantly elevated in HCC patients compared with healthy individuals. The serum concentration was also correlated with histological grade. Combined use of AFP and Annexin A2 could increase the diagnostic performance of HCC. These data suggest that Annexin A2 may serve as a novel serological/histological candidate involved in HCC, especially among individuals with normal levels of serum AFP.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4578.