bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4689: Pre-clinical investigation of the wee1 inhibitor MK-1775 using pharmacodynamic and mechanistic markers in diverse cancer models in vivo
Authors: Wilsker Deborah F. , Marrero Allison M. , Hollingshead Melinda , Lawrence Scott M. , Chen Alice , Kummar Shivaani , Covey Joseph M. , Parchment Ralph E. , Kinders Robert J. , Tomaszewski Joseph E. , Doroshow James H. 
Published: May 2015

Abstract
Wee1 kinase is a critical regulator of the G2/M checkpoint by initiating inhibitory phosphorylation of the conserved tyrosine-15 residue of cdk1/cdc2. Wee1 also phosphorylates tyrosine 15 of cdk2 and plays a crucial role in maintaining genome integrity during S-phase. MK1775 (NSC 754352) is a small molecule selective inhibitor of Wee1 kinase that is currently under clinical evaluation. We have developed a quantitative immunofluorescence assay to measure inhibition of Wee1 by detection of pY15 of cyclin-dependent kinases. A full analysis of the pharmacodynamic (PD) effects of Wee1 inhibition by MK1775, as well as the downstream mechanistic consequences of Wee1 inhibition on DNA repair, apoptosis, and premature mitotic entry markers was performed using two xenograft models: A673 Ewing sarcoma and U87-MG glioblastoma. Four DNA repair markers (pNbs1, γH2AX, Rad51, and pATR) were examined as well as the mitotic marker pHistone H3. Advanced quantitative image analysis was performed using Definiens software to measure changes in PD markers by two approaches: total nuclear area measurements and foci per nucleus. Definiens software enables enhanced analysis of the markers by enumeration of the nuclei in the imaged xenograft tissues over an entire data set with high-content capacity. Our data demonstrate greater than 80% inhibition of pY15-cdk in vivo at the clinically relevant dose of 60 mg/kg (180 mg/m2) MK1775 in two xenograft models. In addition, γH2AX induction was observed after multiple doses of MK1775 as a single agent. A PD biomarker time course was determined for MK1775 and gemcitabine (NSC 750927) as single agents to develop a drug administration schedule for combination studies in a Ewing sarcoma model. The time point at which the DNA damage response peaked following administration of the maximum tolerated dose of gemcitabine in the mouse was determined. This study elucidates a broad profile of PD marker response, as well as the corresponding levels of MK1775 in the xenografts. Funded by NCI Contract No. HHSN261200800001E.
Citation Format: Deborah F. Wilsker, Allison M. Marrero, Melinda Hollingshead, Scott M. Lawrence, Alice Chen, Shivaani Kummar, Joseph M. Covey, Ralph E. Parchment, Robert J. Kinders, Joseph E. Tomaszewski, James H. Doroshow. Pre-clinical investigation of the wee1 inhibitor MK-1775 using pharmacodynamic and mechanistic markers in diverse cancer models in vivo. [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 4689. doi:10.1158/1538-7445.AM2014-4689
Abstract 4693: Inhibition of BET bromodomain targets PTEN positive endometrioid endometrial cancers
Authors: Qiu Haifeng , Jackson Amanda , Kilgore Joshua , Zhou Chunxiao , Bae-Jump Victoria Lin 
Published: May 2015

Abstract
Introduction: Endometrioid endometrial cancers (EEC) are commonly characterized by PTEN mutations and loss of function. JQ-1 is a selective small-molecule BET bromodomain inhibitor, and BET inhibition by JQ-1 leads to the downregulation of c-Myc transcription. Thus, JQ-1 functions as a novel c-Myc inhibitor and has been found to potently suppress tumor growth in many human cancers. Given the known interactions between c-Myc and the PI3K/Akt/mTOR pathway, we aim to assess the impact of JQ-1 on human EEC cell lines and further explore the mechanism underlying cellular resistance to JQ-1 treatment.
Methods: Six EEC cancer cell lines were used in this study. Cell proliferation was assessed by MTT assay and colony formation assay after exposure to JQ-1. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by Annexin V-FITC assay. Expression of c-Myc, PTEN, phosphorylated-Akt, phosphorylated-S6, cyclins and cyclin-dependent kinases (CDKs) was detected by Western blotting analysis. Up- or down-regulation of PTEN was achieved by stable transfection with pcDNA3.1-PTEN or shRNA-PTEN, respectively.
Results: JQ-1 significantly suppressed proliferation in the EEC cell lines that were PTEN positive (IC50=75 nM for HEC-1A, 550 nM for KLE and 1000 nM for ECC-1), but not in those that were PTEN negative (IC50&gt;10000 nM for Ishikawa, AN3CA and RL 95-2). JQ-1 induced G1 cell cycle arrest in the PTEN positive HEC-1A and KLE cell lines, but had minimal effects on cell cycle progression in the PTEN negative Ishikawa and AN3CA cell lines. Western blotting analysis demonstrated that JQ-1 suppressed the expression of c-Myc, cyclins and CDKs. JQ-1 up-regulated PTEN expression and decreased phosphorylation of downstream targets of the PI3K/Akt/mTOR signaling pathway, including Akt and S6. Knock-down of PTEN led to cellular resistance to JQ-1 in the HEC-1A and KLE cells, while over-expression of PTEN sensitized Ishikawa and AN3CA cells to JQ-1 treatment.
Conclusions: We find that JQ-1 significantly suppressed cellular proliferation through G1 cell cycle arrest in the EEC cell lines with abundant PTEN expression. Knock-down of PTEN caused cellular resistance while over-expression of PTEN sensitized EEC cells to JQ-1. This evidence suggests that JQ-1 may be a promising targeted therapy for EEC patients with PTEN positive tumors.
Note: This abstract was not presented at the meeting.
Citation Format: Haifeng Qiu, Amanda Jackson, Joshua Kilgore, Chunxiao Zhou, Victoria Lin Bae-Jump. Inhibition of BET bromodomain targets PTEN positive endometrioid endometrial 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 4693. doi:10.1158/1538-7445.AM2014-4693
Abstract 4696: Identification of driver mutations and gene amplifications in resected asophageal adenocarcinoma: Impact on clinical care
Authors: Zhou Haiyu , Vargas Luis Tapias , Elliot Justin , Mathisen Douglas J. , Lanuti Michael 
Published: May 2015

Abstract
BACKGROUND:
Adenocarcinoma of the distal esophagus and esophagogastric junction (EGJ) have received much attention because of increasing frequency and poor outcome despite multimodality therapy. Driver mutations and gene amplifications in resected esophageal adenocarcinoma are not widely investigated. Opportunity exists to discover actionable mutations in resected esophageal adenocarcinoma.
METHODS:
We analyzed driver mutations harbored in coding regions of 25 selected genes (∼95 point mutations) using a multiplex PCR-based assay. EGFR, HER2, MET, and PI3K amplifications were tested using fluorescent in situ hybridization in patients who underwent esophagectomy for distal esophagus and EGJ adenocarcinoma from 2009 to 2013. Disease free survival (DFS) and overall survival (OS) were compared between patients with TP53, KRAS, PI3K, BRAF, APC mutant and wild-type tumors using Kaplan-Meier methods and Cox regression models. The impact of HER2 expression and outcomes were also analyzed.
RESULTS:
Of 54 distal esophagus and EGJ adenocarcinoma patients, 5 different driver mutations were observed in 39 patients, including TP53 (11/39, 28.2%), KRAS (6/39,15.4%), PI3K (2/11,5.1%), BRAF(1/39, 2.6%) and APC (2/39,5.1%). Double driver mutations (3/39, 7.9%) were shared in 3 patients with TP53 and KRAS (1/39, 2.6%), TP53 and PI3K (1/39, 2.6%), KRAS and PI3K (1/39, 2.6%), respectively. Amplifications in HER2 (10/45, 22.2%), MET (1/34, 2.9%) and EGFR (2/17, 11.8%) were observed where directed therapy was altered in 5 patients (1 patient received induction herceptin and 4 patients received adjuvant herceptin). In the targeted patients with HER2 amplification who received herceptin, mean progression-free survival was 18.8 (range 7-41 months) vs. 8.9 (1-28 months) [p=0.089] and OS was 35.7 (range 26-46 months) vs. 24.2 (range 20-29 months) [p=0.053], compared to herceptin naive patients. We did not identify any significant difference in DFS and OS (inclusive of all stages) between TP53, KRAS or any mutation compared to wild type patients.
DISCUSSION:
Oncogenic driver mutations are under-investigated in resected distal esophageal and EGJ adenocarcinoma. Different therapeutic opportunities may become available if routine tumor genotyping is employed in the treatment of esophageal adenocarcinoma. We recommend the routine use of driver mutation and gene amplification analysis for esophageal cancer.
Citation Format: Haiyu Zhou, Luis Tapias Vargas, Justin Elliot, Douglas J. Mathisen, Michael Lanuti. Identification of driver mutations and gene amplifications in resected asophageal adenocarcinoma: Impact on clinical care. [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 4696. doi:10.1158/1538-7445.AM2014-4696
Abstract 4697: Quantitation of BRAF V600E alleles predicts papillary thyroid cancer progression
Authors: Jung Chan Kwon , Kim Min Hee , Bae Ja Seong , Lim Dong Jun , Lee Hyoungnam , Jeon So Ra , Park Gyeong Sin 
Published: May 2015

Abstract
BACKGROUND: BRAF V600E is the most common genetic alteration in thyroid cancer. However, there is still controversy regarding its clinicopathological significance and clonal mutation frequency. To clarify these inconsistent results, we investigated the association between the allelic frequency of BRAF V600E and the clinicopathological features in classic papillary thyroid carcinoma (PTC).
DESIGN: Tumor tissues from 321 patients with classic PTC were microdissected under a dissecting microscope and analyzed for the presence or absence of the BRAF mutation and mutant allelic percentage using quantitative pyrosequencing.
RESULTS: BRAF V600E was found in 264 (82.2%) of 321 classic PTC. In the BRAF V600E-positive tumors, the mutant allelic frequency varied from 8% to 41% of total BRAF alleles (median, 20%). The frequency of BRAF V600E alleles directly correlated with tumor size (R-squared = 0.162, P&lt;0.001) and number of metastatic lymph nodes (R-squared = 0.063, P&lt;0.001). Out of 264 BRAF-positive PTCs, 136 (51%) had ≥20% of BRAF mutant alleles. Extrathyroidal extension and lymph node metastasis were more frequent in PTCs with high (≥20%) abundance of mutant alleles than in those with low abundance of mutant alleles (55% vs 37%, P=0.003 and 62% vs 46%, P=0.012, respectively). However, if the mutant allelic percentage was not considered, the presence of BRAF V600E was only associated with extrathyroidal extension, but not with tumor size and lymph node metastasis.
CONCLUSION: High abundance of BRAF V600E alleles predicts tumor progression in classic PTC. We suggest that the clonal, subclonal, or oligoclonal occurrence of BRAF V600E mutation may have different biological and clinicopathological significance in the PTC.
Citation Format: Chan Kwon Jung, Min Hee Kim, Ja Seong Bae, Dong Jun Lim, Hyoungnam Lee, So Ra Jeon, Gyeong Sin Park. Quantitation of BRAF V600E alleles predicts papillary thyroid cancer progression. [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 4697. doi:10.1158/1538-7445.AM2014-4697
Abstract 4703: Genome & exome analysis of early colon cancers reveals new targets
Authors: Majumdar Avijit , Chen Jian , Lin Sue Hwa , Katz Lior , Raju Gottumukkala Subba , Shetty Kirti , White Jon , Wu Xifeng , Rashid Asif , McMurray John S. , Shaw Kenna R. , Su Xiaoping , Weston Brian , Thirumurthi Selvi , He Aiwu Ruth , Mishra Lopa 
Published: May 2015

Abstract
Introduction: Advanced colorectal cancer (CRC) remains lethal and difficult to treat with over 140,000 new cases a year in the United States. One contributing factor that has emerged is the rapid development of cancers in small, sessile adenomas(polyps) (less than 1cm), which might be overlooked.
Results: Using whole genome and whole exome sequence (WGS) analyses of four pairs of colorectal adenoma (early CRC) tissue samples along with their normal counterparts, we observe dramatic genomic instability in two of the samples, suggesting that these two adenomas could be on the brink of overt CRC. We proceeded to analyze a further 20 samples through RNA sequence and/or immunohistochemical analysis. The two polyps are associated with hyper mutated profile of multiple genes including Carcinoembryonic antigen (CEA) and CEACAM6 in one of the samples. Analyses of the expression levels of CEA and TGF-β signaling pathway members in 20 early adenomas and normal colon tissues demonstrate a marked increase in CEA expression in 25% of adenoma samples linked to a concomitant loss of TGF-β signaling. We proceeded to mechanistic studies examining CEA and it role in inactivating the tumor suppressive arm of transforming growth factor-β (TGF-β) signaling, providing crucial new information for CEA in promoting aggressive CRC. We found that CEA interacts directly with the transforming growth factor-β (TGF-β) receptor 1 (TBR1) with inhibition of downstream TGF-β tumor suppressor signaling through its B3 domain. Moreover, we previously found that deletion of Smad3/4 adaptor β2SP results in loss of TGF-β signaling, with dramatic and spontaneous formation of adenomas as well as CRC. Ectopic expression of CEA also induces CRC metastases, potentially indirectly through activation of STAT3 and stimulating production of IL-6, IL-10 and others, in addition to inactivating TGF-β tumor suppressor signaling. Conclusions: Our data suggest that enhanced CEA levels and oncogenic mutations in the colon adenomas can be used as prognostic markers for early detection of aggressive CRC and the B3 domain of CEA can be targeted by monoclonal antibody/peptide inhibitors/small molecule inhibitors targeting CEA and CRC cell proliferation.
Citation Format: Avijit Majumdar, Jian Chen, Sue Hwa Lin, Lior Katz, Gottumukkala Subba Raju, Kirti Shetty, Jon White, Xifeng Wu, Asif Rashid, John S. McMurray, Kenna R. Shaw, Xiaoping Su, Brian Weston, Selvi Thirumurthi, Aiwu Ruth He, Lopa Mishra. Genome & exome analysis of early colon cancers reveals new targets. [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 4703. doi:10.1158/1538-7445.AM2014-4703
Abstract 4704: Prognostic significance of T gene SNP s2305089 in individuals with spinal column chordoma
Authors: Varga Peter , Fisher Charles , Rhines Lawrence , Gokaslan Ziya , Boriani Stefano , Lazary Áron , Wang Wei-Lien ‎ , Germscheid Niccole , Yip Stephen , Bettegowda Chetan 
Published: May 2015

Abstract
Chordoma is the most common primary spinal column tumor with a median survival of only 6-7 years, with extremely high recurrence rates. Radical surgical resection remains the mainstay of treatment for these tumors, with radiation often utilized to enhance local disease control. There are no approved chemotherapeutic agents for chordomas. Recently, Pillay and colleagues found that the single nucleotide polymorphism (SNP) rs2305089 in the T gene was strongly associated with chordoma development1. The variant A allele at rs2305089 results in a p.GLy177Asp alteration in brachyury, the protein encoded by the T gene. Brachyury has been implicated in the pathogenesis of chordomas and is highly expressed in most of these tumors. Given the rarity of this disease, with an incidence of 0.08 per 100,000 individuals, determining the clinical significance of this SNP has been challenging. In order to address whether the rs2305089 SNP was associated with altered prognosis in individuals with spinal column chordomas, we performed a retrospective analysis on 82 chordomas from 5 different high volume centers in Europe and North America. Each sample was linked to well curated clinical outcomes data that were collected after receiving institutional review board approval. The A variant at rs2305089 was present in 74 of 82 cases analyzed. In our cohort, there were no differences in gender, age, location, ethnicity, histologic subtype or time to local recurrence based on the presence of the A variant. However, overall survival was significantly worse (log-rank = 0.003) in individuals who lacked the A variant. To our knowledge, this is the first time the rs2305089 SNP has been implicated in the prognosis and survival of individuals with chordoma. This finding warrants further investigation and may have important implications on clinical decision-making.
1Nature Genetics. 2012 Nov;44(11):1185-7
Note: This abstract was not presented at the meeting.
Citation Format: Peter Varga, Charles Fisher, Lawrence Rhines, Ziya Gokaslan, Stefano Boriani, Áron Lazary, Wei-Lien ‎ Wang, Niccole Germscheid, Stephen Yip, Chetan Bettegowda. Prognostic significance of T gene SNP s2305089 in individuals with spinal column chordoma. [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 4704. doi:10.1158/1538-7445.AM2014-4704
Abstract 4705: Integrating germline cancer predisposition gene testing into routine clinical practice - The Mainstreaming Cancer Genetics programme
Authors: Rahman Nazneen ,   The Mainstreaming Cancer Genetics Consortium
Published: May 2015

Abstract
Over 100 cancer predisposition genes with clinical utility are recognised. Testing of these genes is increasingly in demand and is one of the major activities of Clinical Genetics. However, in most countries, testing is very restricted with respect to the number of genes and the number of people tested. Furthermore, the value of genetic testing in individuals with cancer is underappreciated; it provides important information with respect to the cause and optimal treatment of the current cancer, and the risk and optimal management of future cancer. Moreover, testing cancer patients followed by cascade testing of mutation carriers is an effective and efficient way of identifying unaffected mutation carriers in whom screening and risk-reducing strategies can be deployed. The Mainstreaming Cancer Genetics (MCG) Programme is a UK national cross-disciplinary initiative to develop the NGS assays, analytical and interpretive pipelines, clinical infrastructure, training, ethical and evaluation processes required for routine genetic testing to be integrated into cancer patient care.
In collaboration with Illumina we have developed a NGS panel targeting 97 cancer predisposition genes with &gt;1500 probes (called the TruSight cancer panel) and have completed detailed evaluation of performance, sensitivity and specificity under different levels of multiplexing, coverage and throughput. We have developed bespoke analytical pipelines developed for high-throughput clinical diagnostic data analysis (called GAMA) and clinical interpretation (called CIGMA). We are implementing a new mixed-model of cancer gene testing whereby consent for medical testing (i.e. in cancer patients) is undertaken by trained oncologists, with only the mutation carriers seen by geneticists. Predictive testing (i.e. in unaffected individuals) continues to be undertaken in genetics. We have developed protocols and e-learning modules to deliver the required training for oncologists to consent for testing. The system is faster and cheaper, whilst retaining flexibility and robustness to provide increased input where required. We are completing a 6 month pilot that has included &gt;100 patients and we are acquiring patient and clinician feedback, the results of which will be presented. www.mcgprogramme.com
Citation Format: Nazneen Rahman, The Mainstreaming Cancer Genetics Consortium. Integrating germline cancer predisposition gene testing into routine clinical practice - The Mainstreaming Cancer Genetics programme. [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 4705. doi:10.1158/1538-7445.AM2014-4705
Abstract 471: Transcriptional coactivator CBP regulates hTERT expression through the cooperation with Sp1/AP-2β and predicts poor prognosis in human lung cancers
Authors: Guo Wei 
Published: May 2015

Abstract
Human telomerase reverse transcriptase (hTERT) is linked to tumorigenesis and development. However, how hTERT is upregulated in tumor cells remains poorly understood. In this study, we identified CBP as a transcriptional coactivator that specifically binds to hTERT promoter through co-anchoring with transcriptional factors Sp1 and AP-2β and promotes hTERT expression in human lung cancer cells. Streptavidin-agarose pulldown and chromatin immunoprecipitation assays revealed the tumor-specific binding of CBP, Sp1 and AP-2β on the hTERT promoter. The colocalization and interaction between CBP and Sp1 or AP-2β in lung cancer cells were detected. High expression levels of CBP and hTERT in lung cancer cells and tissues were also detected compared to normal lung cells and adjacent normal lung tissues. Tissue array immunohistochemistry of lung adenocarcinomas showed a strong postive correlation between CBP and hTERT expression, and demonstrated the patients with high CBP and hTERT expression had a significantly shorter overall survival than those with low CBP and hTERT expression. Ectopic expression of CBP activated hTERT promoter-driven luciferase gene and endogenous hTERT gene expression in lung cancer cells. Inhibition of CBP expression by CBP-specific siRNA or chemical inhibitor attenuated hTERT promoter-driven luciferase expression and the endogenous hTERT activity, and abrogated the binding of Sp1 and AP-2β on hTERT promoter region. Moreover, CBP knockdown by siRNA significantly inhibited lung cancer cell proliferation, whereas CBP overexpression promoted cell proliferation. These results therefore indicate overexpression of CBP contributes to hTERT upregulation through its cooperation with transactivators Sp1 and AP-2β and predicts poor prognosis in human lung cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Wei Guo. Transcriptional coactivator CBP regulates hTERT expression through the cooperation with Sp1/AP-2β and predicts poor prognosis in human lung 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 471. doi:10.1158/1538-7445.AM2014-471