bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 250: Sulindac delayed and suppressed the tumor progression, was not effective on inhibition of tumor initiation in a human colorectal cancer mouse model (CPC;Apc mouse)
Authors: Adachi Tomohiro , Hinoi Takao , Sasaki Yuu , Shimomura Manabu , Saito Yasufumi , Miguchi Masashi , Niitsu Hiroaki , Sotomaru Yuusuke , Oue Naohide , Yasui Wataru , Ohdan Hideki 
Published: May 2015

Abstract
Purpose
Non-steroidal anti-inflammatory drugs (NSAIDs) have shown potential as chemopreventive agents against cancer formation, especially colorectal cancers. However, the mechanisms by which these drugs act are not fully understood. In this study, CPC;Apc mice, a human colorectal cancer mouse model treated with sulindac, were evaluated according to tumor initiation and prognosis and gene expression profile of the tumors were analyzed.
Methods
CPC;Apc mice, originating from ApcFlox/wt mice harbor a Cdx2-Cre transgene in which colorectal tumorigenesis was driven by Apc allelic loss and represent a genetic model of human colorectal cancer (CRC) were treated with control (n=20) or sulindac (160ppm, n=22) for 12 weeks and their colorectal tumors were evaluated. Gene expression analysis was performed to identify genes differentially expressed in tumor cells from sulindac-treated mice. The gene expression was validated through quantitative real-time polymerase chain reaction in vivo.
Results
Body weight of mice with control or sulindac was no significantly difference ( P = 0.801). However, we observed that sulindac significantly suppressed the tumor progression relative to untreated controls (the colon tumors size per mouse: median of 4.2mm, range 2.3-5.9 versus 5.0mm, range 3.1-8.7, respectively ; P = 0.007 ), but not the initiation (the colon tumor numbers per mouse: median of 1.5, range 0-5 versus 1.0 tumors, range 0-8 respectively ; P = 0.979) in CPC;Apc mice. We identified some upregulated (n = 6, &gt;1.4 fold ) and downregulated (n = 5, &gt;1.4 fold) target genes by microarray assay. We validated expression of these candidate genes in human colorectal cancer.
Conclusion
We have identified for the first time that sulindac affected tumor progression by delayed and suppressing it, but had no effect on the initiation of tumor in CRC mice model.
Citation Format: Tomohiro Adachi, Takao Hinoi, Yuu Sasaki, Manabu Shimomura, Yasufumi Saito, Masashi Miguchi, Hiroaki Niitsu, Yuusuke Sotomaru, Naohide Oue, Wataru Yasui, Hideki Ohdan. Sulindac delayed and suppressed the tumor progression, was not effective on inhibition of tumor initiation in a human colorectal cancer mouse model (CPC;Apc mouse). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 250. doi:10.1158/1538-7445.AM2014-250
Abstract 2501: Proteomics signature of lack of retinoic acid signal surveillance at early breast cancer stages
Authors: Rossetti Stefano , Bshara Wiam , Sacchi Nicoletta 
Published: May 2015

Abstract
Endogenous retinoic acid (RA), the bioactive derivative of Vitamin A, is necessary for breast acinar morphogenesis. One of the hallmarks of early stage breast cancer, such as ductal carcinoma in situ (DCIS), is the inability to respond to RA morphogenetic action, which results in the uncontrolled growth of the mammary duct luminal cells. By imaging endogenous RA signaling during normal and aberrant breast acinar development in three dimensional (3D) culture, we found that the inability to form the acinar lumen can be traced to lack of activation of the RA receptor alpha (RARA) genomic function by endogenous RA variation. We further found that aberrant acinar morphogenesis, regardless of the causing factors, is marked by a distinct protein signature, which includes the upregulation of Annexin A8 (ANXA8). Forced expression of ANXA8 in breast epithelial cells was sufficient to disrupt 3D acinar architecture. Moreover, by screening DCIS tissue microarrays (TMAs), we found that ANXA8 expression correlates with tumor grade and stage. Thus, further development of this proteomics signature indicative of lack RA signal surveillance is expected to assist in the early detection of initial breast cancer stages.
This work was funded by R01 CA127614, the Friends for an Earlier Breast Cancer Test Foundation, and the Terri Brodeur Breast Cancer Foundation.
Citation Format: Stefano Rossetti, Wiam Bshara, Nicoletta Sacchi. Proteomics signature of lack of retinoic acid signal surveillance at early breast cancer stages. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2501. doi:10.1158/1538-7445.AM2014-2501
Abstract 2505: Exposure to a therapeutically relevant dose of ionizing radiation reveals colorectal cancer biomarker and associated receptor alterations
Authors: Suman Shubhankar , Fornace Albert J. , Datta Kamal 
Published: May 2015

Abstract
Purpose: Diagnostic and therapeutic radiation exposure to humans is inevitable, and radiation exposure is known to enhance risks of colorectal cancer (CRC) and inflammatory bowel diseases. Radiation exposure has also been observed to promote obesity in humans as well as in rodents. While altered levels of insulin like growth factor 1 (IGF1), leptin, and adiponectin have been reported as potential markers of obesity-related CRC risk, there is a paucity of long-term radiation-risk-markers for intestinal pathologies. The goal of the current study was to evaluate in mice whether obesity-related CRC risk markers have the potential to serve as radiation-associated CRC risk markers after exposure to a clinically relevant γ radiation dose.
Methods and materials: Mice (C57BL/6J, 6-8 week old, female; n= 8 per group) were exposed to a γ radiation dose of 2 Gy, commonly used in fractionated radiotherapy. Serum and intestinal tissues were collected two and twelve months after radiation. Serum levels of IGF-1, IGF binding protein 3 (IGFBP3), leptin, and adiponectin were analyzed by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was performed on small intestine and colon sections for IGF1 receptor (IGF1R), obesity receptor (OB-R), adiponectin receptor 1 (AdipoR1), adiponectin receptor 2 (AdipoR2) and proliferative marker Ki-67.
Results: The levels of free IGF1 and free leptin measured by calculating IGF1/IGFBP3 and leptin/adiponectin ratio showed a distinct pattern. While significantly higher free IGF1 was observed twelve months post-radiation, higher free leptin was observed two months after radiation exposure. Immunohistochemical analysis demonstrated increased IGF1R and OB-R, decreased AdipoR1 and R2, and increased Ki67 in intestinal as well as in colonic sections at both the time points.
Conclusions: Considering that one fraction of 2 Gy showed significant alterations in risk markers, we believe exposure to a higher total dose using more fractions will show more pronounced effects. Taken together, this study demonstrates that adipogenic risk markers of CRC could be effective tools to assess CRC risks after therapeutic γ radiation exposures.
Note: This abstract was not presented at the meeting.
Citation Format: Shubhankar Suman, Albert J. Fornace, Kamal Datta. Exposure to a therapeutically relevant dose of ionizing radiation reveals colorectal cancer biomarker and associated receptor alterations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2505. doi:10.1158/1538-7445.AM2014-2505
Abstract 2507: Circulating proteolytic products of carboxypeptidase N for early detection of breast cancer
Authors: Hu Ye 
Published: May 2015

Abstract
Background: Carboxypeptidase N (CPN) plays an important role in regulating vasoactive peptide hormones, growth factors, and cytokines by specifically cleaving their C-terminal basic residues. Herein we demonstrated that the circulating peptides specifically cleaved by CPN in the tumor microenvironment can indeed be stage-specific indicators of breast cancer.
Methods: The activity of CPN was evaluated using an ex-vivo peptide cleavage assay, in which synthesized C3f peptide (His6-C3f_S1304-R1320-His6) is incubated in interstitial fluids of breast tumor and adjacent normal breast tissues in mice with orthotopic implantation of the human cell line MDA-MB-231. Fragment profiling, by an approach combining nanopore fractionation and mass spectrometry, revealed the nature and extent of cleavage by CPN. These results correlated with the level of CPN-catalyzed peptides in blood specimens taken from the tumor-bearing mice, healthy women and breast cancer patients. CPN expression in the same set of samples was further examined by immunohistochemistry and immunoblotting.
Results: We showed that generation of C3f_R1310-L1319 specifically correlated with the CPN expression level. In both the mouse and clinical patient samples, the amount of CPN was clearly increased in tumor tissues compared to that seen in normal breast tissue, while its counterpart in blood remained constant. The amount of 6 CPN-catalyzed peptides predominantly increased in sera taken from the mice (n=8) at 2 weeks after orthotropic implantation. Six homologous peptides displayed the significantly higher expression in the patients' plasma as early as the first pathologic stage of breast cancer.
Conclusions: The amount of circulating CPN-catalyzed peptides reported here reflects the extent of this enzyme's activity in tumors, and our results clearly indicate their strong potential as biomarkers for non-invasive and early diagnosis of breast cancer. It would certainly be naïve to think that CPN-catalyzed peptides and the enzyme itself are the only biomarkers specific for breast cancer diagnosis. We do however argue that they can be used as a complementary measure for very early diagnosis of tumor growth, particularly because CPN activity within the tumor at this point is already detectable by blood sampling. Such sensitivity together with all of the features mentioned above lend well to their translation to the clinic, for breast cancer and perhaps other pathologies.
Citation Format: Ye Hu. Circulating proteolytic products of carboxypeptidase N for early detection of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2507. doi:10.1158/1538-7445.AM2014-2507
Abstract 2512: Design and antiproliferative evaluation of cell-penetrating TPM-Dox conjugates as prodrugs
Authors: Beni Yousef , Pippas Andrew W. 
Published: May 2015

Abstract
Doxorubicin (Dox) is well-known anthracycline widely used anticancer agent for the treatment of a wide variety of cancers. The major limitations of cancer chemotherapy treatment are low cellular uptake, high efflux rate and the development of resistance to a certain dose of anticancer drugs, such as Dox. Improving of cellular uptake and duration of action of Dox is very demanding. This will improve its therapeutic index and decrease its side effects. The biological activity of Dox can potentially be enhanced by increasing and optimizing its hydrophobicity using appropriate hydrophobic linker attachment to the Dox using triphenylmethanol (TPM) which led to higher cellular uptake. In this regard, TPM-Dox prodrugs were designed to deliver and release Dox into cells. The attachment of TPM analogs along with fatty alcohol significantly enhanced the lipophilicity and thus the cellular uptake of these multifunctional conjugates. In this study, a number of TPM derivatives of Dox were synthesized by the reaction of 2-substituted methoxy benzenes and 1,3,5-trioxane in glacial acetic acid in 72-87% yield. The reaction of TPM derivatives with tosylated fatty diol continued with conjugation to Dox to afford eight TPM-Dox conjugates with different hydrophobicity in 44-67% overall yield. Comparative antiproliferative assays between TPM-Dox conjugates and the corresponding noncovalent physical mixtures of the TPM derivatives and Dox were performed. TPM-Dox conjugates inhibited the cell proliferation of human leukemia (CCRF- CEM), ovarian adenocarcinoma (SK-OV-3), colorectal carcinoma (HCT-116), and breast carcinoma (MDA-MB-468) cells by 63-94% at a concentration of 1 µM after 72-120 h of incubation. These data suggest that TPM-Dox derivatives can be used as a potential prodrug for improving the cellular delivery and retention of Dox.
Citation Format: Yousef Beni, Andrew W. Pippas. Design and antiproliferative evaluation of cell-penetrating TPM-Dox conjugates as prodrugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2512. doi:10.1158/1538-7445.AM2014-2512
Abstract 2518: Development of a non-hydrolysable phosphotyrosine mimetic peptide based on a high affinity SHP2 substrate
Authors: Lawrence Harshani R. , Ge Yiyu , Becker Andreas , Ren Yuan , Luo Yunting , Wu Jie , Lawrence Nicholas J. 
Published: May 2015

Abstract
The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is a transducer of growth factor, cytokine, integrin, and hormone signaling pathways that regulate processes such as cell proliferation, differentiation, adhesion, migration, and apoptosis and plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with several types of leukemias, and solid tumors. This makes SHP2 an attractive target for developing new anticancer therapy. Several small molecules have been developed for inhibition of this important phosphatase, which serve as chemical tools to probe the role of SHP2 in disease and lead compounds for optimization. Nevertheless improvements are required to improve these lead compounds with better potency, selectivity and cell permeability. To gain structural insights for development of potent and selective Shp2 inhibitors, we synthesized a non-hydrolysable phosphotyrosine peptide mimetic, based on reported Shp2 substrate peptide sequences. The non-hydrolyzable phosphopeptide, containing the phosphotyrosyl surrogate difluoromethylphosphonate, was prepared by solid phase peptide synthesis methods from the known building block N-FMOCF2Pmp. We will present the synthesis of the peptide, analysis of Shp2 phosphatase inhibition, and binding of the phosphopeptide mimic to SHP2 by micro isothermal calorimetry. We will present a model for the binding mode of the peptide and its implications for the design of selective Shp2 inhibitors.
Citation Format: Harshani R. Lawrence, Yiyu Ge, Andreas Becker, Yuan Ren, Yunting Luo, Jie Wu and Nicholas J. Lawrence. Development of a non-hydrolysable phosphotyrosine mimetic peptide based on a high affinity SHP2 substrate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2518. doi:10.1158/1538-7445.AM2014-2518
Abstract 2519: A small molecule that binds and inhibits the ETV1 transcription factor oncoprotein
Authors: Pop Marius , Stransky Nicolas , Garvie Colin , Theurillat Jean-Philippe , Lewis Timothy , Zhong Cheng , Culyba Elizabeth , Lin Fallon , Daniels Douglas , Pagliarini Raymond , Ronco Lucienne , Koehler Angela , Garraway Levi 
Published: May 2015

Abstract
Members of the ETS transcription factor family have been implicated in several cancers, where they are often dysregulated by genomic derangement. ETS variant 1 (ETV1) is an ETS factor gene that undergoes chromosomal translocation in prostate cancers and Ewing's sarcomas, amplification in melanomas, and lineage dysregulation in gastrointestinal stromal tumors. Pharmacologic perturbation of ETV1 would be appealing in these cancers; however, oncogenic transcription factors are often deemed “undruggable” by conventional methods. Here, we used small-molecule microarray (SMM) screens to identify and characterize drug-like compounds that modulate the biological function of ETV1. We identified the 1,3,5-triazine small molecule BRD32048 as a top candidate ETV1 perturbagen. BRD32048 binds ETV1 directly, modulating both ETV1-mediated transcriptional activity and invasion of ETV1-driven cancer cells. Moreover, BRD32048 inhibits p300-dependent acetylation of ETV1, thereby promoting its degradation. These results point to a new avenue for pharmacological ETV1 inhibition and may inform a general means to discover small molecule perturbagens of transcription factor oncoproteins.
Note: This abstract was not presented at the meeting.
Citation Format: Marius Pop, Nicolas Stransky, Colin Garvie, Jean-Philippe Theurillat, Timothy Lewis, Cheng Zhong, Elizabeth Culyba, Fallon Lin, Douglas Daniels, Raymond Pagliarini, Lucienne Ronco, Angela Koehler, Levi Garraway. A small molecule that binds and inhibits the ETV1 transcription factor oncoprotein. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2519. doi:10.1158/1538-7445.AM2014-2519
Abstract 2520: Novel inhibitors of β-catenin
Authors: Nurmemmedov Elmar , Cheltsov Anton , Vogt Peter K. 
Published: May 2015

Abstract
β-catenin is a key player of the WNT pathway; its aberrant regulation is associated with the onset and progression of numerous types of cancer. β-catenin is therefore an attractive drug target but direct inhibition of β-catenin is a challenging approach toward suppression of β-catenin-driven tumorigenesis. Ideal drug candidates should specifically target nuclear β-catenin, leaving its cytoplasmic and cell junctional functions intact. We have identified several drug-like candidate β-catenin inhibitors using a robust screening method against four allosteric binding sites of β-catenin (TCF4, BCL9 and two novel sites). We show that these inhibitors significantly reduce proliferation of a panel of human β-catenin-driven cancer cell lines, and repress the expression of β-catenin-induced target genes. They cause a shift in the melting temperature of the purified β-catenin protein. We also show that the candidate compounds reduce levels of β-catenin in the nucleus and block β-catenin-driven oncogenic transformation in cell culture. We consider these novel β-catenin inhibitors promising leads that should be further investigated for their molecular mechanism of action and for their potential development as therapeutic drugs.
Key words: β-catenin, oncogene, therapeutic, target, small molecule, protein-protein interaction
This work was supported by NIH Grant R01 CA078230. This is abstract 26043 of The Scripps Research Institute.
Citation Format: Elmar Nurmemmedov, Anton Cheltsov, Peter K. Vogt. Novel inhibitors of β-catenin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2520. doi:10.1158/1538-7445.AM2014-2520
Abstract 2523: Mechanism-based inhibitors of HGFA, matriptase and hepsin for breast cancer treatment
Authors: Janetka James , Han Zhenfu , Harris Peter , Wildman Scott 
Published: May 2015

Abstract
Hepatocyte Growth Factor Activator (HGFA) is a member of the S1 family of trypsin-like serine proteases. Its biological function is to proteolytically process the inactive single-chain zymogen precursors of the receptor tyrosine kinase ligands HGF (hepatocyte growth factor) and MSP (macrophage stimulating protein) resulting in formation of their active heterodimeric forms which initiate ligand-dependent c-MET and RON kinase cell signaling, respectively. We have discovered the first small molecular weight mechanism-based ketothiazole inhibitors of HGFA. The compounds were evaluated for HGFA, matriptase and hepsin inhibition in a protease competition assay using a chromogenic peptide substrate. We have identified several sub-micromolar inhibitors of HGFA and demonstrate they inhibit conversion of the native pro-HGF and pro-MSP substrates into active heterodimers. Finally, we show that HGFA inhibitors cause a dose-dependent decrease c-MET phosphorylation in invasive MDA-MB-231 breast cancer cells. This investigation provides preliminary validation of HGFA as a novel therapeutic target for breast cancer. These initial peptides serve as templates for lead optimization and the structure-based design of other small-molecule inhibitors. Optimized inhibitors will be used to study the role of HGFA in the regulation of growth factors, kinase receptor activation, cell signaling, invasion, and breast cancer metastasis.
Citation Format: James Janetka, Zhenfu Han, Peter Harris, Scott Wildman. Mechanism-based inhibitors of HGFA, matriptase and hepsin for breast cancer treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2523. doi:10.1158/1538-7445.AM2014-2523
Abstract 2525: Identification and characterization of class I HDAC-specific small-molecule inhibitors with a novel pharmacophore
Authors: Wang Yunfei , Stowe Ryan , Pinello Christie E. , Zhao Lisa Y. , Tian Guimei , Hodder Peter , Roush William R. , Liao Daiqing 
Published: May 2015

Abstract
Small-molecule inhibitors of HDACs (HDIs) have therapeutic potentials for treating cancer, metabolic disorders, cardiovascular diseases and neurodegenerative maladies. Two FDA-approved HDIs (vorinostat and romidepsin) are in clinical use for cancer therapy and a variety of other HDIs have been actively tested in clinical trials. Current challenges facing drug development of HDIs include the lack of isoform specificity, undesirable toxicity and suboptimal therapeutic efficacy against solid tumors. Most HDIs in preclinical or clinical evaluations belong to the hydroxamic acid or aminobenzamide classes. The former class lacks isoform specificity and the latter has not yet been approved for clinical use. Thus, the identification of HDIs with novel chemical properties and isoform-specificity may unleash the considerable therapeutic potential of targeting HDACs. We have conducted a high-throughput screening of &gt;620,000 compounds and identified a lead with a hitherto undescribed pharmacophore with an inhibitory specificity against the class I HDACs, and a low two-digit nanomolar potency. An array of synthetic analogs established the structure-activity relationship. These novel inhibitors induced histone hyperacetylation, suppressed cancer cell proliferation of diverse cancer cell lines including the NCI-60 panel, and malignant cell-biological features associated with tumor metastasis. These compounds are under active preclinical development for cancer therapy.
Citation Format: Yunfei Wang, Ryan Stowe, Christie E. Pinello, Lisa Y. Zhao, Guimei Tian, Peter Hodder, William R. Roush, Daiqing Liao. Identification and characterization of class I HDAC-specific small-molecule inhibitors with a novel pharmacophore. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2525. doi:10.1158/1538-7445.AM2014-2525