bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4437: Fbxw8 targets hematopoietic progenitor kinase 1 for proteasomal degradation
Authors: Wang Hua , Chen Yue , Lin Ping , Li Lei , Zhou Guisheng , Liu Guangchao , Logsdon Craig , Jin Jianping , Abbruzzese James L. , Tan Tse-Hua , Wang Huamin 
Published: May 2015

Abstract
HPK1, a member of mammalian Ste20-like serine/threonine kinases, is lost in &gt;95% pancreatic cancer through proteasomemediated degradation. However, the mechanism of HPK1 loss has not been defined. The aims of this study are to identify the ubiquitin ligase and to examine the mechanisms that targets HPK1 degradation. We found that the CUL7 ubiquitin ligase targeted HPK1 for degradation via the 26S proteasome. The ubiquitination of HPK1 required its kinase activity and autophosphorylation. Wild-type protein phosphatase 4 (PP4), but not the phosphatase-dead PP4 mutant, PP4-RL, inhibits the interaction of Fbxw8 with HPK1 and Fbxw8-mediated ubiquitination of HPK1.
In addition, we showed that Thr355 of HPK1 is a key PP4 dephosphorylation site, through which Fbxw8 and PP4 regulates HPK1 stability. Our study demonstrated that CUL7 ubiquitin ligase targets HPK1 for degradation which requires HPK1 kinase activity and autophosphorylation. Fbxw8-mediated HPK1 degradation revealed a direct link and novel role of CUL7 ubiquitin ligase in the MAPK pathway, which plays a critical role in cell proliferation and differentiation.
Citation Format: Hua Wang, Yue Chen, Ping Lin, Lei Li, Guisheng Zhou, Guangchao Liu, Craig Logsdon, Jianping Jin, James L. Abbruzzese, Tse-Hua Tan, Huamin Wang. Fbxw8 targets hematopoietic progenitor kinase 1 for proteasomal degradation. [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 4437. doi:10.1158/1538-7445.AM2014-4437
Abstract 444: BRM/SMARCA2 is a critical synthetic lethal target in BRG1-deficient cancers
Authors: Jaskelioff Mariela , Hoffman Gregory , Rahal Rami , Xiang Kay , Haas Kristy , Saenz-Vash Veronica , Zhai Huili , Keen Nicholas , Stegmeier Frank , Jagani Zainab 
Published: May 2015

Abstract
The mammalian SWI/SNF complexes (mSWI/SNF) regulate chromatin structure through ATP-dependent nucleosome remodeling and thereby control key cellular processes. Recent cancer genome studies have revealed a significant frequency of mutations in several components of the mSWI/SNF complexes including the catalytic subunit BRG1. Emerging evidence is supportive of tumor suppressor roles for mSWI/SNF subunits, yet the inactivating nature of these mutations presents a challenge for devising targeted therapeutic strategies against cancers harboring such mutations. In this study, we interrogated epigenetic cancer dependencies by screening a deep-coverage design (DeCoDe) shRNA library targeting the epigenome across a broad range of 50+ cancer cell lines. Strikingly, this unbiased screen revealed that silencing of the SWI/SNF ATPase subunit BRM/SMARCA2, selectively inhibits the proliferation of BRG1-deficient cancer cells. BRM knockdown selectively induced cell cycle arrest in BRG1-mutant cancer cells and significantly impaired the growth of BRG1-mutant lung tumor xenografts. BRM is the paralog of BRG1, suggesting a model in which mSWI/SNF mutations lead to a hypomorphic complex that promotes tumorigenesis but cannot tolerate complete inactivation. Thus, targeting mSWI/SNF subunits that exhibit redundant activities to the residual mutated complexes may present a general strategy for SWI/SNF mutated cancers.
Citation Format: Mariela Jaskelioff, Gregory Hoffman, Rami Rahal, Kay Xiang, Kristy Haas, Veronica Saenz-Vash, Huili Zhai, Nicholas Keen, Frank Stegmeier, Zainab Jagani. BRM/SMARCA2 is a critical synthetic lethal target in BRG1-deficient cancers. [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 444. doi:10.1158/1538-7445.AM2014-444
Abstract 4448: Overexpression of ECT2 promotes proliferation and metastasis of UPSC
Authors: Mach Claire M. , Magliaro Thomas J. , Anderson Matthew L. 
Published: May 2015

Abstract
Introduction: UPSC is a rare but aggressive malignancy that accounts for no more than 5 to 10% of uterine cancers, but more than 40% of associated uterine cancer deaths. The molecular events responsible for the poor clinical outcomes observed with UPSC are largely unknown. Epithelial cell transforming sequence 2 oncogene (ECT2) is a guanine nucleotide exchange factor (Rho-GEF) that catalyzes the exchange of GDP for GTP by Rho family GTPases. High levels of ECT2 expression have been reported in brain, lung and breast cancers, where they were shown promote metastasis. However, the role of ECT2 in UPSC has not been previously explored.
Methods: After obtaining IRB permission, ECT2 mRNA and protein expression were measured in flash frozen specimens of normal proliferative endometrium (n=8) and UPSC (n =8) by quantitative real-time PCR (qPCR) and Western blot. Established cultures of UPSC cell lines (UPSC-ARK1, UPSC-ARK2) were transfected with either an siRNA targeting ECT2 or a non-targeting control (Dharmacon) using Lipofectamine 2000 (Invitrogen). Reduced expression of ECT2 following transfections with ECT2 siRNAs was confirmed by qPCR and Western blot. Standard MTS and Caspase 3/7 assays (Promega) were utilized to measure proliferation and apoptosis. Colony formation and Boyden chamber assays were used to measure metastatic capacity, migration and invasion in vitro.
Results: Our data indicate that ECT2 is overexpressed &gt;4-fold in nearly all UPSC specimens tested (n=8, p&lt;0.001). We also found that ECT2 is robustly expressed in both the UPSC-ARK1 and UPSC-ARK2 cell lines. Utilizing these 2 cell lines, we found that knockdown of ECT2 significantly decreased proliferation (UPSC-ARK1: 0.62-fold versus control; n=3, p&lt;0.05; UPSC-ARK2: 0.34-fold versus control, p&lt;0.05) and increased rates of apoptosis (UPSC-ARK1: 1.3-fold; n=3, p&lt;0.05; UPSC-ARK2: 2.2-fold, n=3, p&lt;0.05) in both cell lines tested. Decreased ECT2 expression targeted by transfection with siRNAs led to decreased rates of colony formation in UPSC-ARK1 and UPSC-ARK2 cell lines. Knockdown of ECT2 also significantly reduced rates of migration and invasion observed in vitro with both cell lines.
Conclusions: Overexpression of ECT2 plays a critical role in promoting the growth and metastasis of UPSC. Targeting ECT2 expression may provide an effective strategy for improving outcomes for UPSC and other human cancers where hyperactivation of metastasis-promoting Rho GTPases are observed.
Citation Format: Claire M. Mach, Thomas J. Magliaro, Matthew L. Anderson. Overexpression of ECT2 promotes proliferation and metastasis of UPSC. [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 4448. doi:10.1158/1538-7445.AM2014-4448
Abstract 4449: Tissue- and isoform-specific Ras expression during development
Authors: Newlaczyl Anna U. , Coulson Judy M. , Prior Ian A. 
Published: May 2015

Abstract
Ras GTPases are proto-oncogenes that transduce intracellular signals important for diverse cellular processes, such as proliferation and differentiation. The four main Ras isoforms, H-Ras, KRas-4A, KRas-4B and N-Ras, are well conserved across the species and are often mutated in human cancers. However, distinct isoforms preferentially contribute to different cancer types, suggesting non-redundant function.
In order to study Ras isoform prevalence within different tissues and lineages, the transcript copy numbers were examined throughout development using a series of mouse embryo, postnatal and adult tissues. Quantitative RT-PCR was used to measure Ras isoforms in 16 different adult tissues and in 8 of these tissues at 10 developmental time points (n=3). The data showed that Ras abundance is both tissue-specific, with 10-60 copies of total Ras per 1pg RNA in adult tissues, and isoform-specific. KRas-4B and N-Ras were the major isoforms in all tissues. In general Ras isoform expression levels were stable through development except for KRas-4A that showed dramatic upregulation over time in stomach, intestine and kidneys. In heart, KRas-4A transcripts were detected only at and just before birth. Ongoing quantitative proteomics experiments will test whether transcript expression patterns persist at the protein level.
We are building the first complete map of developmental Ras isoform expression. Importantly, establishing baseline expression in normal tissues will give clues to questions about isoform-specific Ras coupling to different cancers.
Citation Format: Anna U. Newlaczyl, Judy M. Coulson, Ian A. Prior. Tissue- and isoform-specific Ras expression during development. [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 4449. doi:10.1158/1538-7445.AM2014-4449
Abstract 4455: Targeting a novel kras-integrin-linked kinase regulatory circuitry in pancreatic cancer
Authors: Chu Po-Chen , Yang Ming-Chen , Kulp Samuel K. , Chen Ching-Shih 
Published: May 2015

Abstract
Activating KRAS mutations are the most frequent genetic abnormality in over 90% of pancreatic cancers. Evidence indicates that these mutations not only play a crucial role in initiating pancreas carcinogenesis, but also are required for pancreatic tumor maintenance. From a clinical perspective, oncogenic KRAS represents a therapeutically relevant target in pancreatic cancer, of which the proof-of-concept was demonstrated by the effectiveness of siRNA-mediated silencing of KRAS to suppress pancreatic tumor growth in vivo. Nonetheless, attempts to develop small-molecule agents to inhibit oncogenic KRAS activity have proven futile to date. Consequently, recent strategies have focused on targeting downstream effectors of KRAS signaling, including Raf, MEK, and PI3K kinase, each of which, however, shows limited clinical benefit as single agent. In this study, we have identified a novel KRAS-E2F1-ILK-hnRNP A1 regulatory circuitry that governs the expression of oncogenic KRAS. Integrin-linked kinase (ILK) is a serine/threonine kinase that mediates a diversity of cellular functions including cell survival, cell-matrix interactions, angiogenesis and also plays a role in epithelial to mesenchymal transition (EMT) in cancer cells. Dysregulation of ILK expression has been observed in several tumors including breast, ovary, melanoma, lung, prostate and pancreas and reported to be correlated with tumor progression, metastasis and chemoresistance to gemcitabine in pancreatic adenocarcinoma cells, but the mechanisms by which ILK is required for the tumorogenesis in pancreatic cancer are yet to be understood. In this circuitry, KRAS induces ILK expression via an E2F1-dependent mechanism, which, in turn, stimulates KRAS expression through hnRNP A1 upregulation. Mechanistically, hnRNP A1 binds and relaxes the G-quadruplex structure at the KRAS promoter, thereby enhancing the transcription initiation of the KRAS gene. As a result, disruption of this circuitry via siRNA-mediated knockdown of any of these intermediary effectors (E2F1, ILK, or hnRNP A1), or pharmacological inhibition of ILK by T315, a novel ILK inhibitor developed in our laboratory, led to suppression of KRAS expression and reversal of the mesenchymal phenotype of pancreatic cancer cells. The therapeutic relevance of ILK in regulating this regulatory circuitry is also evident in the suppressive effect of ILK knockdown on epidermal growth factor (EGF)-induced KRAS expression. Together, these findings provide a rationale for targeting ILK as a novel strategy to suppress oncogenic KRAS signaling.
Citation Format: Po-Chen Chu, Ming-Chen Yang, Samuel K. Kulp, Ching-Shih Chen. Targeting a novel kras-integrin-linked kinase regulatory circuitry in pancreatic 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 4455. doi:10.1158/1538-7445.AM2014-4455
Abstract 4465: Differential MMAE delivery from ADCs utilizing the valine-citrulline-PAB and β-glucuronide cleavable linker systems
Authors: Okeley Nicole M. , VanEpps Heather A. , Zhang Xinqun , Setter Jocelyn R. , Burke Patrick J. , Hamilton Joseph Z. , Lyon Robert P. 
Published: May 2015

Abstract
The previously described β-glucuronide linker system (Jeffrey S.C. et al, Bioconj. Chem. 17, 831-840, 2006) was designed to release the toxic payload from an antibody-drug conjugate via the activity of β-glucuronidase, a known lysosomal enzyme. This linker system was shown to be suitable for the generation of potent ADCs utilizing the microtubule disrupting agent monomethylauristatin E (MMAE) as the delivered payload, and is thus an alternative to the protease-cleavable linker valine-citrulline-p-amino benzyl alcohol (vc-PAB). We have recently observed that ADCs utilizing the β-glucuronide linker system to deliver an MMAE payload exhibit potent cytotoxic activity in some cell lines that are resistant to conjugates utilizing the vc-PAB linker to deliver the same drug. To better understand this phenomenon, we have used mass spectrometry to compare the concentration and distribution of MMAE released from both glucuronide and vc-PAB linked ADCs in cell culture. Our data demonstrate that cellular accumulation of released MMAE is considerably greater when delivered by a glucuronide ADC relative to a vc-PAB ADC. We have also employed live-cell fluorescence microscopy to monitor the process of enzymatic cleavage of glucuronide and vc-PAB conjugates. The results of these studies suggest that the two linker systems deliver drug via distinct cellular mechanisms, possibly due to unique intracellular locations of drug release. We propose a model for how these unique linker systems can lead to differences in cellular accumulation of free drug and ultimately increased cytotoxicity.
Citation Format: Nicole M. Okeley, Heather A. VanEpps, Xinqun Zhang, Jocelyn R. Setter, Patrick J. Burke, Joseph Z. Hamilton, Robert P. Lyon. Differential MMAE delivery from ADCs utilizing the valine-citrulline-PAB and β-glucuronide cleavable linker systems. [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 4465. doi:10.1158/1538-7445.AM2014-4465
Abstract 4470: Elucidating the role of drug-linker hydrophobicity in the disposition of antibody-drug conjugates
Authors: Doronina Svetlana O. , Setter Jocelyn R. , Bovee Tim D. , Anderson Martha E. , Jonas Mechtild , Daniho Steven , Kostner Heather , Senter Peter D. , Lyon Robert P. 
Published: May 2015

Abstract
The in vitro potency of antibody-drug conjugates (ADCs) is generally proportional to the level of drug loading, with higher drug per antibody levels producing more potent ADCs. However, this intuitive relationship often fails to translate in vivo, presumably because plasma clearance of the ADC also increases with drug loading, resulting in substantially reduced exposure to highly loaded ADCs (Hamblett, KJ et al, Clin. Cancer Res. 2004, 10: 7063-7070). We postulated that this accelerated clearance effect is not purely a function of the number of drugs per antibody, but also of the intrinsic hydrophobicity of each drug-linker. Collectively, drug-linker hydrophobicity and number of drugs per antibody determine the overall hydrophobicity of the ADC. To test this hypothesis, we designed and prepared a series of drug-linkers within the auristatin class that varied in hydrophobicity, and used them to produce a corresponding series of homogeneous 8-loaded ADCs. The pharmacokinetic profiles of these ADCs were determined and found to correlate well with their relative retention times by hydrophobic interaction chromatography. We further postulated that hydrophobicity-driven clearance is likely to be mediated by cells of the mononuclear phagocytic system (MPS). To identify the specific cell populations responsible for accelerated ADC clearance, we performed an immunohistochemistry-based biodistribution study which has provided clear evidence for the cellular sites of hydrophobic ADC clearance which are not operative on native antibodies or hydrophilic ADCs. Using the information gained from these studies, we have successfully prepared a hydrophilic auristatin drug-linker which enables the preparation of ADCs uniformly loaded with 8 drugs per antibody at defined cysteine sites. These ADCs evade clearance by the MPS, maintain native antibody pharmacokinetics, and translate their high in vitro potency into the in vivo setting.
Citation Format: Svetlana O. Doronina, Jocelyn R. Setter, Tim D. Bovee, Martha E. Anderson, Mechtild Jonas, Steven Daniho, Heather Kostner, Peter D. Senter, Robert P. Lyon. Elucidating the role of drug-linker hydrophobicity in the disposition of antibody-drug conjugates. [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 4470. doi:10.1158/1538-7445.AM2014-4470
Abstract 4474: Protein-photosensitizer nanoparticles for the treatment of cancer
Authors: Benitez Marimar , Molina Anna M. , Griebenow Kai 
Published: May 2015

Abstract
Photodynamic therapy is a treatment that uses photosensitizer drugs to produce reactive oxidative species that kill cells when exposed to light of a specific wavelength. Our research project focuses on the development of protein nanoparticles as delivery systems for photosensitizers in cancer treatments, with the objective to overcome the lack of target specificity resulting in inappropriate drug retention by non-target tissues. The main goal is to produce nanoparticles that selectively accumulate in the target tissue due to their size, are effectively internalized into the cells via receptor-mediated endocytosis and disintegrate in the reducing environment of the cell, resulting in the activation of the drug. The synthesis method has been optimized to obtain nanoparticles of the desired size that disintegrate rapidly in the intracellular space. The photosensitizer is covalently bound to prevent non-specific release, and folate has been immobilized on the nanoparticle surface. The reversible activation of the drug was confirmed by fluorescence experiments and the therapeutic efficiency of the system was evaluated in HeLa cells. The system dark toxicity and phototoxicity was evaluated in vitro, as well as the internalization, the intracellular localization, and the mechanism of cell death.
Note: This abstract was not presented at the meeting.
Citation Format: Marimar Benitez, Anna M. Molina, Kai Griebenow. Protein-photosensitizer nanoparticles for the treatment of 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 4474. doi:10.1158/1538-7445.AM2014-4474
Abstract 4476: Targeted delivery of curcumin to improve therapeutic outcome in breast cancer
Authors: Singh Rajesh , Lillard James W. 
Published: May 2015

Abstract
Conventional chemotherapeutics offered to treat breast cancer (BrCa) are not selectively targeted. Due to this fact, they are toxic to the normal cells. It is imperative to identify new anti-cancer agents and/or methods to selectively target BrCa cells without affecting normal cells. In this regard, Curcumin, a plant polyphenol, has shown very promising results. Despite the proven anti-tumor effects of curcumin, clinical use of this compound is restricted due to its poor bioavailability. To surmount these problems, we developed nanoparticles, loaded with curcumin, using a planetary-balled milling (PBM) technique with particles tagged with folate for selective targeting to BrCa cells, which express high affinity folate receptors. Multispectral imaging, using an Amnis ImageStream system, was used to measure the response of curcumin-loaded PBM nanoparticles, and free curcumin on various BrCa cell lines. Curcumin-loaded folic acid-coated PBM nanoparticles selectively targeted and were taken-up by BrCa cells and induced apoptosis. Furthermore, our results indicate that targeted delivery of curcumin using PBM nanoparticles was 60 % more effective in killing BrCa cells at concentrations lower than the IC50 of free curcumin.
Citation Format: Rajesh Singh, James W. Lillard. Targeted delivery of curcumin to improve therapeutic outcome in 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 4476. doi:10.1158/1538-7445.AM2014-4476
Abstract 4492: Blockade of angiopoietin-2 or Tie2 is equally effective at inhibiting tumor growth and reducing tumor vessel density in most human tumor xenograft models
Authors: Adler Alexander P. , Daly Christopher , Parveen Asma A. , Nevins Thomas , Shan Jing , Fairhurst Jeanette , Huang Tammy , Martin Joel , Papadopoulos Nicholas , Yancopoulos George D. , Thurston Gavin , Thurston Gavin , Eichten Alexandra 
Published: May 2015

Abstract
Angiopoietin-1 (Ang1) and -2 (Ang2) regulate angiogenesis via the endothelial cell-specific receptor tyrosine kinase Tie2. Blocking Ang2 binding to Tie2 decreases vessel density and inhibits tumor growth in various human xenograft models. However, not all tumors respond to Ang2 blockade, which could be due to high Ang1 levels acting as another ligand for Tie2, to Ang2 activities independent of Tie2, or to a weak role for Ang-2/Tie2 signaling in these tumors. To elucidate if Ang1 plays an integral role in tumor angiogenesis and growth, we compared the effects of blocking Ang2 or Tie2 in various tumor xenografts with differing levels of Ang1 expression. We found that in six out of seven tumor models, antibodies that specifically bind Ang2 (REGN910, 10 mg/kg 2x/wk) or that bind Tie2 and block binding of both Ang1 and Ang2 (REGN1376, 10 mg/kg 2x/wk) were equally efficacious at inhibiting tumor growth and decreasing vessel density. In only one tumor model (Calu-6), blockade of Tie2 with REGN1376 was more effective than blockade of Ang2 (REGN910) at reducing tumor growth and decreasing tumor vessel density. Although Calu-6 tumors express high Ang1 levels, other tumors tested (Lox, LS174T) have comparable or higher Ang1 levels and respond similarly to Ang2 and Tie2 blockade, thus the levels of Ang1 do not account for the differential response of Calu-6 tumors. Taken together, our data suggest that Ang2 is the dominant ligand for Tie2 in the microenvironment of most tumors, and further, that the effects of Ang2 are mediated primarily via Tie2. These findings support the approach to specifically block the binding of Ang2 to Tie2 as an anti-angiogenic therapy.
Citation Format: Alexander P. Adler, Christopher Daly, Asma A. Parveen, Thomas Nevins, Jing Shan, Jeanette Fairhurst, Tammy Huang, Joel Martin, Nicholas Papadopoulos, George D. Yancopoulos, Gavin Thurston, Gavin Thurston, Alexandra Eichten. Blockade of angiopoietin-2 or Tie2 is equally effective at inhibiting tumor growth and reducing tumor vessel density in most human tumor xenograft models. [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 4492. doi:10.1158/1538-7445.AM2014-4492