bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1101: Examining the role of the mechanical microenvironment in pancreatic cancer: microrheology studies in 3D tumor models.
Authors: Celli Jonathan P. , Rizvi Imran , Jones Dustin , Hanna William , Hasan Tayyaba 
Published: August 2014

Abstract
A growing body of literature points to the importance of the mechanical microenvironment, including rheology (rigidity, viscoelastic properties) of the surrounding extracellular matrix (ECM), as a regulator tumor growth behavior. This is particularly provocative for tumors of the pancreas, which are noted for profound desomplasia characterized by exceptionally dense, collagen-rich, hypovascular, fibrous stroma. While this property of pancreatic tumor stroma has been implicated in drug resistance, and even explored as a therapeutic target (stromal depletion), key questions about the role of the mechanical microenvironment remain unanswered. For example, it is unclear the extent to which this extreme matrix rigidity is driven by the tumorigenic program or what its role is in contributing to the notorious treatment-resistance of these tumors, beyond serving as a physical barrier to drug penetration. In this study we leverage in vitro 3D pancreatic tumor-fibroblast co-culture models combined with particle tracking microrheolgy as a tool to longitudinally probe the mechanical properties of the surrounding ECM during growth and in response to exogenous stimuli. Cultures are prepared by embedding pancreatic cancer cells (PANC-1, AsPC-1 or Capan-1) along with normal human fibroblasts (MRC-5) and (biologically-inert) fluorescent tracer probes in a collagen matrix. The Brownian motion of tracer probes obtained by high-speed digital video microscopy and subsequent offline particle tracking analysis, is used as a reporter of spatio-temporal changes in the viscoelastic properties of ECM. This, combined with our previously introduced high-content quantitative imaging approach for assessment of growth and treatment response in 3D tumor models comprises a platform for mapping of interdependent changes in the matrix mechanics and tumor growth behavior. In this study we correlate changes in matrix stiffness under normal growth, with and without stromal fibroblasts present as signaling partners and TGF-β stimulation. We further explore local mechanical effects by comparing groupings of trajectories of probes proximal and distant from tumor nodules. In ongoing studies we are examining the impact of traditional chemotherapeutics and photodynamic therapy (PDT) on modulation of the mechanical microenvironment and conversely, the impact of ECM rigidity on treatment sensitivity.
Citation Format: Jonathan P. Celli, Imran Rizvi, Dustin Jones, William Hanna, Tayyaba Hasan. Examining the role of the mechanical microenvironment in pancreatic cancer: microrheology studies in 3D tumor models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1101. doi:10.1158/1538-7445.AM2013-1101
Abstract 1106: Mechanism for activation of mutated EGF receptors in lung cancer.
Authors: Red Brewer Monica L. , Lai Darson , Lemmon Mark A. , Pao William 
Published: August 2014

Abstract
Previous studies have demonstrated that wild-type (WT) EGFRs are activated by an allosteric mechanism in which a ‘donor’ tyrosine kinase domain (TKD) monomer contacts an ‘acceptor’ TKD monomer, leading to its activation. Here, we present biochemical reconstitution data demonstrating that receptor activation by the most frequently occurring EGFR mutations found in lung cancer does not adhere to this mechanism. Mutated EGFRs hyperphosphorylate their WT counterparts and appear to adopt a conformation that allows them to function as acceptors but not as donors to WT EGFR. As acceptors, the mutated EGFRs also show enhanced association with WT EGFR. We suggest the term “superacceptor activity” to describe this directionally-limited mutant-specific mechanism of EGFR transactivation. Mutated EGFRs also hyperphosphorylate the related ErbB family member, ErbB-2, in a similar manner. Collectively, these data provide insights into a mechanism for activation of lung cancer-associated mutant EGFRs. Since WT EGFRs are usually present in EGFR mutant tumor cells, our studies additionally argue that WT EGFRs contribute to tumorigenesis and may alter sensitivity to EGFR-targeted therapy.
Citation Format: Monica L. Red Brewer, Darson Lai, Mark A. Lemmon, William Pao. Mechanism for activation of mutated EGF receptors in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1106. doi:10.1158/1538-7445.AM2013-1106
Abstract 1116: Sleeping Beauty mutagenesis identifies genes and pathways that cooperate with BrafV600E in melanoma initiation and progression.
Authors: Mann Michael B. , Black Michael A. , Ward Jerrold M. , Bosenberg Marcus W. , McMahon Martin , Print Cristin G. , Adams David J. , Copeland Neal G. , Jenkins Nancy A. 
Published: August 2014

Abstract
Malignant melanoma is a devastating disease the prevalence of which is on the rise. In humans, somatic mutation of BRAF, to encode the BRAFV600E oncoprotein, is an early predisposing event in melanoma initiation, but is insufficient to drive malignant melanomagenesis in the absence of additional cooperating events. We describe a genome-wide, forward genetic screen in mice restricted to pigment producing melanocytes as an unbiased approach to identify new candidate melanoma progression genes. By combining Sleeping Beauty (SB) with a Cre-activated BRafCA allele we observed frank melanomas with average latency of 36 weeks. By contrast, melanocyte specific expression of BRAFV600E elicited benign melanocytic nevi that failed to progress to malignant melanoma by one year of age. These findings confirm that SB mobilization altered genes that cooperate with BRAFV600E to promote melanoma progression. A discovery set of 1,200 statistically-defined candidate melanoma genes was identified from 70 SB|BRAFV600E tumors. Importantly, our screen identified seven SB mutated genes with human orthologs that are well established human melanoma drivers including: Cdkn2a, Pten, Gnaq, Mitf, Nf1, Rac1 and Ppp6c. Many biological signaling pathways and cellular processes were enriched for candidate melanoma genes altered in SB|BRAFV600E melanomas, including Wnt/Beta-catenin, TGFβ, PI3’-kinase and MAPK signaling pathways and biological processes regulating ubiquitin mediated proteolysis, tight junctions, cell cycle and axonal guidance. Integrated comparative oncogenomic analysis with human melanoma data sets provided a data-driven method to filter and prioritize candidate melanoma genes. The genes identified using the SB|BRAFV600E model may represent new human melanoma candidate cancer genes with potential clinical relevance to the progression and maintenance of human BRAF mutated melanoma.
Citation Format: Michael B. Mann, Michael A. Black, Jerrold M. Ward, Marcus W. Bosenberg, Martin McMahon, Cristin G. Print, David J. Adams, Neal G. Copeland, Nancy A. Jenkins. Sleeping Beauty mutagenesis identifies genes and pathways that cooperate with BrafV600E in melanoma initiation and progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1116. doi:10.1158/1538-7445.AM2013-1116
Abstract 1126: Efficacy of BET bromodomain inhibition in Kras-positive non-small cell lung cancer.
Authors: Shimamura Takeshi , Chen Zhao , Soucheray Margaret , Carretero Julian , Kikuchi Eiki , Tchaicha Jeremy H. , Gao Yandhi , Cheng Katherine A. , Cohoon Travis J. , Qi Jun , Akbay Esra A. , Kimmelman Alec C. , Kung Andrew L. , Bradner James E. , Wong Kwok Kin 
Published: August 2014

Abstract
Amplification of MYC is one of the most common genetic alterations in lung cancer, contributing to a myriad of phenotypes associated with growth, invasion and drug resistance. Murine genetics has established both the centrality of somatic alterations of Kras in lung cancer, as well as dependency of Kras-dependent tumors on c-Myc function. Unfortunately, drug-like small-molecule inhibitors of KRAS and c-Myc have yet to be realized. The recent discovery in hematologic malignancies that bromodomain inhibition impairs MYC expression and MYC-dependent transcriptional function prompted the possibility of targeting KRAS-driven NSCLC with a potent, prototypical BET bromodomain inhibitor, JQ1. Here, we report that NSCLC cells harboring the KRAS mutation are sensitive to JQ1 while NSCLC cells with concurrent mutant KRAS and LKB1 mutations are resistant to JQ1. In sensitive NSCLC models, JQ1 treatment results in the coordinate downregulation of the MYC-dependent transcriptional program. Furthermore, we evaluated JQ1 in transgenic mouse lung cancer models expressing mutant kras or concurrent mutant kras and lkb1. We found that JQ1 treatment produces significant tumor regression in mutant kras mice. As predicted, tumors from mutant kras and lkb1 mice did not respond to JQ1. Together, these data provide a compelling rationale for the study of BET bromodomain inhibitors in a common, genetically-defined population of patients with aggressive NSCLC.
Citation Format: Takeshi Shimamura, Zhao Chen, Margaret Soucheray, Julian Carretero, Eiki Kikuchi, Jeremy H. Tchaicha, Yandhi Gao, Katherine A. Cheng, Travis J. Cohoon, Jun Qi, Esra A. Akbay, Alec C. Kimmelman, Andrew L. Kung, James E. Bradner, Kwok Kin Wong. Efficacy of BET bromodomain inhibition in Kras-positive non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1126. doi:10.1158/1538-7445.AM2013-1126
Abstract 1130: Antitumor activity of a pyrrole-imidazole polyamide in three tumor xenograft models.
Authors: Nickols Nicholas G. , Yang Fei , Li Benjamin C. , Marinov Georgi K. , Said Jonathan W. , Dervan Peter B. 
Published: August 2014

Abstract
Background: Pyrrole-imidazole polyamides are synthetic minor groove binders with modular sequence recognition. We developed a polyamide that targets the DNA sequence 5’-WGWWCW-3’ (W=A/T). This molecule is cytotoxic in a number of cancer cell lines including LNCaP (prostate cancer), DU145 (prostate cancer), and A549 (lung cancer). Data in cell culture suggests that this molecule interferes with RNA polymerase 2 activity resulting in proteasome-mediated degradation of the RNA Polymerase 2 large subunit, activation of p53 and induction of p53 target genes, and apoptosis. This polyamide demonstrates no detectable DNA damage by alkaline comet assay nor does it induce detectable phosphorylation of γH2A.X, ATM, DNA-PKcs, p53, or Chk2. This polyamide circulates in mice after intravenous and subcutaneous injection in saline vehicle.
Methods: Male immune compromised mice were implanted with LNCaP, DU145, or A549 tumors. Tumors were allowed to grow until approximately 100 mm3 and then stratified into vehicle (5% DMSO/PBS) and treatment arms (1 mg/kg polyamide, in vehicle). Treatment was administered via subcutaneous injection every three days, for a total of three cycles (LNCaP), eight cycles (DU145), or six cycles (A549). At the experimental endpoint, tumors were resected and weighed immediately. For LNCaP xenografts, serum PSA pre- and post-treatment were also measured. In parallel, a group of immune compromised mice without xenografts were treated with an identical regimen for eight cycles and subsequently observed for three months.
Results: Tumors resected from polyamide-treated mice were statistically smaller than those of vehicle-treated mice. The effect was greatest on LNCaP tumors (n=12, Treated (T)/Control (C): 32%, p=1.6E-5). DU145 tumors (n=6, T/C: 34%, p=0.013), and A549 tumors (n=8, T/C: 62%, p=0.047) were also affected. Post-treatment serum PSA in the polyamide-treated mice with LNCaP xenografts were lower than for the vehicle treated mice (p = 0.024). Statistical differences between treated and control groups were determined using two-tailed t-tests. Polyamide treatment resulted in no significant weight loss or observable distress in tumor-free mice and these mice appeared healthy for at least three months after treatment was complete.
Conclusions: The polyamide demonstrated in vivo antitumor activity in this panel of tumor xenografts with limited host toxicity.
Citation Format: Nicholas G. Nickols, Fei Yang, Benjamin C. Li, Georgi K. Marinov, Jonathan W. Said, Peter B. Dervan. Antitumor activity of a pyrrole-imidazole polyamide in three tumor xenograft models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1130. doi:10.1158/1538-7445.AM2013-1130
Abstract 1133: Synthetic lethal screen identifies candidates that modulate cancer cell sensitivity in response to HSP90 inhibition.
Authors: Howes Jennifer , Lu Bing-Feng , Powers Marissa , Clarke Paul , Workman Paul 
Published: August 2014

Abstract
Heat shock protein 90 (HSP90) is an important cancer therapeutic target. HSP90 chaperone activity maintains the conformation, stability and function of mutated variants and over-expressed oncogenic client proteins responsible for driving the proliferation of human cancer. To further increase the efficacy and specificity of HSP90 inhibitor treatment, cancer cell response to HSP90 inhibition can be modulated through the use of combinatorial therapeutics. An siRNA screen targeting 7,593 genes encoding proteins considered to be druggable was used to identify candidates that modulate the cellular response to HSP90 inhibition by 17-AAG. This approach may provide information on the potential mechanisms of cancer cell resistance, allow selection of responsive patient populations based on the identification of novel biomarkers, and potentially provide targets for combinatorial therapy. Screening produced robust data with an average plate z-factor of 0.6 and results were validated with an alternative chemotype of HSP90 inhibitor. As anticipated, significant sensitisation to HSP90 inhibition was observed with HSF1 depletion, and conversely resistance was observed with NQO1 depletion. Sensitisation candidates were the main focus of analysis as they potentially represent the more amenable drug targets. There was an enrichment of mitochondrial constituents, cell cycle regulators and post-translational protein modifiers that when depleted produced significant sensitisation to HSP90 inhibitors in human carcinoma cells. Future work aims to reveal the molecular mechanisms underpinning the sensitisation phenotypes observed and to identify points of intervention for clinical combinatorial therapy with HSP90 inhibitors.
Citation Format: Jennifer Howes, Bing-Feng Lu, Marissa Powers, Paul Clarke, Paul Workman. Synthetic lethal screen identifies candidates that modulate cancer cell sensitivity in response to HSP90 inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1133. doi:10.1158/1538-7445.AM2013-1133
Abstract 1137: Expression of specific apoptotic mediators predicts sensitivity to combined MEK and PI3K inhibition in KRAS mutant non-small cell lung cancer according to TP53 mutational status.
Authors: Hata Aaron , Faber Anthony , Yeo Alan , Chen Zhao , Wong Kwok-Kin , Engelman Jeffrey 
Published: August 2014

Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death world-wide. Though targeted therapies have been developed for NSCLC with activating EGFR mutations or the EML4-ALK translocation, no highly effective targeted therapies exist for cancers harboring activating KRAS mutations. We previously observed that concomitant use of MEK and PI3K inhibitors (MEKi/PI3Ki) led to tumor regressions in a mouse model of KRAS mutant NSCLC, and clinical trials investigating this strategy are underway. However, KRAS mutant NSCLCs are a heterogeneous group of cancers, and the molecular determinants of sensitivity to MEKi/PI3Ki are unknown. Here we report that human KRAS mutant NSCLC cell lines exhibit variability in responsiveness to MEKi/PI3Ki resulting from differential apoptotic responses. We identified key pro- and anti-apoptotic regulators regulators of the apoptotic response induced by MEKi/PI3Ki. Loss of the apoptotic response due to down-regulation of pro-apoptotic mediators was associated with acquired resistance to MEKi/PI3Ki. The responsiveness of KRAS mutant NSCLCs to combined MEKi/PI3Ki could be predicted by the relative expression levels of specific apoptotic regulators, depending on TP53 mutational status. These results reveal genotype-specific mechanisms of apoptosis necessary for responsiveness to targeted therapies and suggest biomarkers for predicting responsiveness of KRAS mutant NSCLC to MEKi/PI3Ki.
Citation Format: Aaron Hata, Anthony Faber, Alan Yeo, Zhao Chen, Kwok-Kin Wong, Jeffrey Engelman. Expression of specific apoptotic mediators predicts sensitivity to combined MEK and PI3K inhibition in KRAS mutant non-small cell lung cancer according to TP53 mutational status. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1137. doi:10.1158/1538-7445.AM2013-1137
Abstract 1140: Novel single-nucleotide polymorphism markers predictive of pathologic response to preoperative chemoradiotherapy in rectal cancer patients.
Authors: Kim Jin Cheon , Roh Seon Ae , Cho Dong Hyung , Choi Eun Young , Ha Ye Jin , Kim Tae Won , Kim Jong Hoon , Kang Tae Wook , Kim Seon Young , Kim Yong Sung 
Published: August 2014

Abstract
Purpose: Studies aimed at predicting individual responsiveness to preoperative chemoradiotherapy (CRT) are urgently needed, especially considering the risks associated with poorly responsive patients, i.e., delay of curative surgery, immune suppression, and adverse effects.
Methods and Materials: A three-step strategy for the determination of CRT sensitivity is proposed that includes: 1) screening of a human genome-wide single-nucleotide polymorphism (SNP) array correlated with histopathological tumor regression grade (TRG), 2) clinical association analysis in 113 patients treated with preoperative CRT, and 3) a cell-based functional assay for biological validation. Genome-wide screening identified nine SNPs associated with preoperative CRT responses.
Results: Genome-wide screening identified nine SNPs associated with preoperative CRT responses. The patients carrying the reference allele (C) of the SNP CORO2A rs1985859 exhibited greater positive responses (TRG 1-3) than those with the substitution allele (T) (P=0.01). Down-regulation of CORO2A was associated with significantly reduced early apoptosis in RKO and COLO320DM colorectal cancer cells by 27% (P=0.048) and 39% (P=0.023), respectively, as determined by flow cytometry. Although a specific genotype associated with radiosensitivity was not detected in the clinical association analysis, down-regulation of FAM101A significantly increased the viability of RKO and COLO320DM cells by 25% (P=0.01) and 23% (P=0.023), respectively in the MTT assay. Conclusion: CRT-sensitive SNP markers were identified using a novel three-step process. The candidate marker CORO2A rs1985859 and the putative marker FAM101A rs7955740 may improve the prediction of radiosensitivity to preoperative CRT, although further validation is needed in large cohorts.
Citation Format: Jin Cheon Kim, Seon Ae Roh, Dong Hyung Cho, Eun Young Choi, Ye Jin Ha, Tae Won Kim, Jong Hoon Kim, Tae Wook Kang, Seon Young Kim, Yong Sung Kim. Novel single-nucleotide polymorphism markers predictive of pathologic response to preoperative chemoradiotherapy in rectal cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1140. doi:10.1158/1538-7445.AM2013-1140
Abstract 1152: Identification of protein tyrosine kinase 7 gene in hepatocellular carcinoma using a novel triple-combination array analysis.
Authors: Hishida Mitsuhiro , Nomoto Shuji , Inokawa Yoshikuni , Hayashi Masamichi , Yamada Suguru , Fujii Tsutomu , Sugimoto Hiroyuki , Takeda Shin , Kodera Yasuhiro 
Published: August 2014

Abstract
Background. Hepatocellular carcinoma (HCC) is one of the top five causes of cancer-related deaths worldwide. Recent developments in the treatment of HCC still have failed to prevent HCC. Genome-wide gene-expression profile analyses can now detect many candidate genes that are modified by HCC. We have developed a new technique to identify suppressor genes of HCC: triple-combination array analysis, which combines gene expression profile, single nucleotide polymorphism array and methylation array.
Methods. Triple-combination array analysis was performed on one HCC sample from a 68-year-old female patient, and one candidate of tumor suppressor gene was selected. Subsequently, we analyzed the identified gene by quantitative real-time reverse-transcriptase polymerase chain reaction (PCR) and methylation-specific PCR in samples from 48 HCC patients and in nine cell lines.
Results. Using this method, protein tyrosine kinase 7 (PTK7) was detected as a candidate of tumor suppressor gene. PTK7 gene is located on 6q21.2, and expression was reduced in HCC tissues at the high level of -2.5 compared with normal tissues. PTK7 locus did not show any deletion or amplification in the SNP array. The methylation value (0-1.0) in the tumor sample was 0.825 compared to 0.047 in normal tissues, indicating high methylation in tumor tissues in the methylation array. Of the 48 clinical samples, 30 (62.5%) showed PTK7 promoter hypermethylation. The PTK7 promoter hypermethylated cases were significantly low expressions status (P=0.035), and bad prognosis in both overall survival (P&lt;0.01) and recurrence-free survival (P=0.018) compared to hypomethylated cases. On the other hand, the cases, of which the PTK7 expressions in tumor tissues decreased by more than 20% degrees compared to those in normal tissues, were significantly worse prognosis in overall survival (P=0.0136) than the other cases, but not in recurrence-free survival (P=0.3102).
Conclusions. We suggest that the PTK7 gene acts as a tumor suppressor gene in HCC. This present study indicates that triple-combination array is an available and convenient technique for detecting the genes with altered expression in disease.
Citation Format: Mitsuhiro Hishida, Shuji Nomoto, Yoshikuni Inokawa, Masamichi Hayashi, Suguru Yamada, Tsutomu Fujii, Hiroyuki Sugimoto, Shin Takeda, Yasuhiro Kodera. Identification of protein tyrosine kinase 7 gene in hepatocellular carcinoma using a novel triple-combination array analysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1152. doi:10.1158/1538-7445.AM2013-1152