bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 699: PIK3CA/BRAF mutations negatively affect outcome of patients with KRAS wild-type metastatic colorectal cancer treated with front line anti-EGFR monoclonal antibodies: Meta-analysis results
Authors: Mohamed Amr , Schrapp Kelly , Attumi Taraq , Saba Nabil F. , El-Rayes Bassel F. 
Published: August 2015

Abstract
BACKGROUND:The aim of this meta-analysis is to evaluate the effect of PIK3CA and BRAF mutations in patients with KRAS wild-type metastatic colorectal cancer receiving an EGFR monoclonal antibody (anti-EGFR) inhibitor in the first line therapy.
METHODS:literature search was performed to identify studies exploring the association between PIK3CA/BRAF mutations and clinical outcomes of KRAS wild mCRC patients treated with anti-EGFR as a first line therapy. The primary clinical outcome is response rate (RR). The secondary outcomes include progression-free survival (PFS), and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed effect model or random effect model according to heterogeneity between studies.
RESULTS:Ten studies with 1,470 mCRC patients (357 for PI3K studies and 1,113 from BRAF studies) met selection criteria. We observed a trend towards lower RR in patients with PIK3CA mutations (2 studies, 137 patients; RR = 14.3% versus 52.4%; 95% confidence interval (CI) -0.12-0.02; P = 0.13). Patients with mutant-type PI3K have significant shorter PFS (3.8 vs 4.15 mos, HR = 1.36; 95% CI 1.04-1.77; P = 0.02), and OS (14.17 Vs 16.3 mos., HR = 1.50; 95% CI 1.14-1.97; P = 0.004) compared to those with wild PI3K. For BRAF, patients with mutant type have significant lower RR [4 studies, 416 patients; RR = 33% versus 39%; 95% confidence interval (CI) -0.16- 0.01; P = 0.03], shorter PFS (6 studies, 893 pts., 3.9 Vs 5.7 mos., HR = 1.72; 95% CI 1.47- 2.01; P = 0.00001), and shorter OS (6 studies, 1065 pts., 9.1 Vs 18.9 mos., HR = 1.22; 95% CI 1.04-1.44; P = 0.01) compared to those with wild type.
CONCLUSION:These analyses suggest that patients with colorectal cancer and either PIK3CA or BRAF mutation have worse outcome when treated with anti-EGFR in the first line. Given their worse outcome, trials evaluating novel agents are needed in this group of patients.
Meta-analyses on BRAFF and PIK3CA mutations in KRAS wild mCRCBRAF WildBRAF MutantHR (95% CI)p-valuePI3K WildPI3K MutantHR (95% CI)p-valueRR (%)39%33%-0.16 - 0.010.0352.4%14.3%-0.12 - 0.020.13PFS (mos)5.73.91.47 - 2.010.000014.153.81.04 - 1.770.02OS (mos)18.99.11.04 - 1.440.0116.314.71.14 - 1.970.004
Citation Format: Amr Mohamed, Kelly Schrapp, Taraq Attumi, Nabil F. Saba, Bassel F. El-Rayes. PIK3CA/BRAF mutations negatively affect outcome of patients with KRAS wild-type metastatic colorectal cancer treated with front line anti-EGFR monoclonal antibodies: Meta-analysis results. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 699. doi:10.1158/1538-7445.AM2015-699
Abstract 70: Targeted sequencing analyses of uterine and ovarian carcinosarcoma
Authors: Mori Seiichi , Gotoh Osamu , Amino Sayuri , Nakai Megumi , Takazawa Yutaka , Sugiyama Yuko , Noda Tetsuo 
Published: August 2015

Abstract
Carcinosarcoma (CS) of the uterus or the ovary, known as malignant mixed Muellerian tumor, is a biphasic neoplasm composed of malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements. CS is a rare disease (two per 100,000 women) and exhibits unfavorable outcomes (5-year survival rates: uterus and ovary; 31 and 7.5%, respectively). CS has been considered as an aggressive form of high-grade endometrioid adenocarcinoma (EC), therefore, the treatment regimen for CS follows to that for EC. Nevertheless, the fact that CS shows substantially poorer prognosis than EC implies a need to identify therapeutic targets for CS. Toward this aim, we have been performing targeted resequencing with a panel of 521 genes (including 30 introns), which were previously implicated as critical not only for uterine, ovarian or sarcomatus oncogenesis but also for molecular targets in therapeutics and the panel covers 2.161 Mbp with 38,105 probes on Agilent's SureSelect. Genomic DNA was extracted from matched tumor and normal pairs derived from more than 70 cases of uterine and ovarian CS patients and then used to construct pooled libraries, which were subsequently subjected to sequencing analysis with an Illumina HiSeq sequencer. Consensus clustering with genomic changes such as mutational spectrum and number of somatic SNVs revealed several subtypes that correlate with histopathology and patient outcomes. Moreover, potentially actionable mutations or copy number aberrations were identified in a number of genes including PIK3CA, MTOR, KRAS and CCNE1. This study would provide deep insights into the development of novel diagnostic and personalized treatment for CS patients.
Citation Format: Seiichi Mori, Osamu Gotoh, Sayuri Amino, Megumi Nakai, Yutaka Takazawa, Yuko Sugiyama, Tetsuo Noda. Targeted sequencing analyses of uterine and ovarian carcinosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 70. doi:10.1158/1538-7445.AM2015-70
Abstract 702: BRAF V600E mutation in benign and malignant epithelial odontogenic tumors
Authors: Diniz Marina Goncalves , Gomes Carolina Cavalieri , Guimaraes Bruna Viana Antonini , Duarte Alessandra Pires , Gomez Ricardo Santiago 
Published: August 2015

Abstract
The classification of ameloblastoma in multicystic or unicystic variants is associated with its clinical behaviour. Recently, BRAF and SMO mutations have been reported in ameloblastomas. However, it is not clear if such mutations are shared by the multi- and unicystic variants of ameloblastoma or by odontogenic carcinomas. We assessed BRAFV600E and SMOF412E in multicystic, unicystic and desmoplastic ameloblastomas. In addition, we investigated whether the BRAFV600E mutation occurs in odontogenic carcinomas. A total of 28 formalin-fixed paraffin-embedded samples, comprising 17 ameloblastomas and 11 odontogenic carcinomas, were included. The BRAFV600E mutation was assessed by real-time PCR with a specific TaqMan probe and confirmed by Sanger sequencing. The SMOF412E mutation was assessed by Sanger sequencing. Fourteen out of 17 (82%) ameloblastomas showed the BRAFV600E mutation, specifically, 5/6 (83%) unicystic, 7/9 (78%) multicystic and 2/2 desmoplastic ameloblastomas. BRAFV600E mutation was detected in 4/11 (36%) malignant tumours, specifically, 3/8 (38%) ameloblastic carcinomas and 1/1 clear cell odontogenic carcinoma, while the two ghost cell odontogenic carcinomas did not harbour this mutation. The SMOF412E mutation was not detected in ameloblastoma. The BRAFV600E mutation was less frequent in odontogenic carcinomas than in ameloblastomas. In ameloblastomas, this mutation occurred at similar proportions in cases from the mandible and maxilla, as well as among unicystic, multicystic and desmoplastic variants, suggesting that there is no difference in their molecular pathogenesis. Our findings support the possibility for personalised, molecular targeted therapy for ameloblastomas and ameloblastic carcinomas harbouring the BRAFV600E mutation. Supported by: FAPEMIG (Fundação de Amparo à Pesquisa de Minas Gerais), CNPq (National Council for Scientific and Technological Development) and CAPES (Coordination for Improvement of Higher Education Personnel), Brazil
Citation Format: Marina Goncalves Diniz, Carolina Cavalieri Gomes, Bruna Viana Antonini Guimaraes, Alessandra Pires Duarte, Ricardo Santiago Gomez. BRAF V600E mutation in benign and malignant epithelial odontogenic tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 702. doi:10.1158/1538-7445.AM2015-702
Abstract 704: Scaffold protein KSR1 is negatively regulated by merlin and promotes tumor development in merlin deficient tumors
Authors: Hanemann Clemens O. , Zhou Lu , Ammoun Sylwia , Lasonder Edwin , Sharma Vikram , Muller Juergen , Ercolano Emanuela 
Published: August 2015

Abstract
Accumulated evidence suggests that the Ras/Raf/MEK/ERK pathway plays a crucial role in the development of Merlin-deficient tumours. However, the mechanism in which Merlin precisely suppresses this mitogenic signalling pathway has remained poorly understood. In addition, drug specificity, side effects and drug resistance are serious problems when treating patients with MEK inhibitors and therefore a more specific therapeutic target needs to be identified. Using our primary human in vitro model and three complementary approaches including lentiviral shRNA, active mutants and use of a clinically approved inhibitor, we report that Ras/Raf/MEK/ERK scaffold protein Kinase Suppressor of Ras 1 (KSR1) plays a vital role in promoting schwannoma proliferation, multipolar morphology and other pathological phenotypes. Proteomic analysis suggests that merlin shares multiple binding partners with KSR1 incl DCAF1 from the E3 Ubiquitin Ligase CRL4DCAF1, which is directly associated with and functionally inhibited by the tumour suppressor Merlin in the nucleus. Functional study suggests that KSR1 and DCAF1 might co-operate and/or complement to regulate schwannoma's proliferation. These findings demonstrate that Merlin disrupts Ras/Raf/MEK/ERK activity at the scaffold protein level and also suggest that KSR1 is a specific therapeutic target for Merlin-deficient tumours.
Citation Format: Clemens O. Hanemann, Lu Zhou, Sylwia Ammoun, Edwin Lasonder, Vikram Sharma, Juergen Muller, Emanuela Ercolano. Scaffold protein KSR1 is negatively regulated by merlin and promotes tumor development in merlin deficient tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 704. doi:10.1158/1538-7445.AM2015-704
Abstract 705: Combinatorial therapeutic targeting of BMP2 and MEK in NF1-null malignant peripheral nerve sheath tumors
Authors: Ahsan Sidra , Sun Daochun , Tainsky Michael A. 
Published: August 2015

Abstract
Our lab has identified and validated bone morphogenetic protein 2 (BMP2) signaling pathways as a therapeutic target in malignant peripheral nerve sheath tumors (MPNSTs), independent of the NRAS and MEK1/2 regulation. BMP2/SMAD signaling is associated with enhanced motility and invasion, a hallmark feature of the biological aggressiveness of MPNSTs. We have shown that inhibition of BMP2 leads to decreased motility and invasiveness in MPNST cell lines. Consistent with our data, gene expression studies from NF1 patient tissue samples demonstrated that increased expression of BMP2 is associated with malignancy in NF1 patients. Ras-GAP related domain (GRD) is the most widely studied functional target of Nf1 implicated in tumorigenesis, however, therapeutic interventions targeting Ras activity have met with limited success. Our objective is to target the BMP2/SMAD pathway, involved in migration and invasion, in combination with MEK inhibitors to develop a novel therapeutic approach for treatment of MPNSTs.
The mechanism by which NF1-deficiency leads to activation of BMP2 signaling pathways, and consequently increased cellular motility and invasion is unknown. Using NF1(+/-) and NF1 knockdown MPNST cell lines, we are investigating the transcriptional regulation of BMP2 by NF1 to identify signaling mechanisms downstream of NF1 mediating increase in BMP2 levels. We will present data showing that BMP2 is regulated at the level of transcript stability upon NF1 deficiency. We will identify and design a rational approach of targeting of the molecular components involved in stability of the BMP2 3′ UTR in MPNSTs. Furthermore, we will present a combinatorial approach that targets the growth and proliferative potential of MPNSTs by RAS-MEK inhibitors, along with motility and invasive capability by inhibition of the BMP2-Smad axis for better targeting of these tumors. The overall goal of our research is to use the regulation of BMP2 transcriptional control to define mechanism-based novel druggable targets that can be exploited in combinatorial therapies with RAS-MEK inhibitors to treat NF1-related tumors.
Citation Format: Sidra Ahsan, Daochun Sun, Michael A. Tainsky. Combinatorial therapeutic targeting of BMP2 and MEK in NF1-null malignant peripheral nerve sheath tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 705. doi:10.1158/1538-7445.AM2015-705
Abstract 708: Androgen receptor activation inhibits papillary thyroid carcinoma cell cycle progression
Authors: Jones Melanie Elizabeth , O'Connell Timmy , Gupta Anvita , Zhao Hong , Iacob Codrin , Moscatello Augustine , Shin Edward , Darzynkiewicz Zbigniew , Tiwari Raj K. , Geliebter Jan 
Published: August 2015

Abstract
The American Cancer Society predicts 62,980 new cases of thyroid cancer and 1,890 deaths due to the disease in 2014, making thyroid cancer the most prevalent endocrine malignancy. This is particularly concerning for women who have an approximately three-fold higher incidence of thyroid cancer than men. Significant research has been done to elucidate the role of estrogen as a driver of thyroid cancer. Taking the reverse approach, that men have a much lower incidence of thyroid cancer, led us to hypothesize that androgens and/or androgen receptors play a protective role and that PTC represents the escape from androgen-mediated cell regulation. Analysis of AR expression in 24 PTC patient tissue samples indicated a 2.7 fold reduction in AR expression compared to matched normal tissue (P&lt;0.005). This suggests that the reduction of AR levels in the neoplastic process of thyroid tissue may be one mechanism of escape from androgen regulation. To more fully understand the function of androgen/AR in thyroid cells, the AR was stably transfected into 8505C anaplastic/PTC cells. Addition of DHT to the 8505C-transfected clone, 84E7, resulted in AR translocation into the nucleus and a 70% reduction in proliferation, as well as a shift in the cell cycle toward G1 arrest. Transcription profiling using RNA-Seq and gene ontology analysis revealed significant changes in genes associated with proliferation, cell cycle, and cell cycle regulation confirming the proliferation assay and cell cycle analysis above. Further, when we examined G1 associated cell cycle proteins, we found significant decreases in cell cycle progression proteins cdc25a, CDK6, CDK4, and CDK2 as well as significant increases in the inhibitors p27 and p21. Thus, protein, RNA and cell cycle analysis data are concordant and demonstrate an accumulation of cells in G1 when treated with DHT. Together these data demonstrate that expression of androgen/AR in normal thyroid cells may play a protective, anti-proliferative role that is lost in PTC resulting in dysregulation of genes normally under AR control. The differential expression of androgen/AR in males verses females may provide new insight into the different clinical presentations and outcomes between women and men.
Citation Format: Melanie Elizabeth Jones, Timmy O'Connell, Anvita Gupta, Hong Zhao, Codrin Iacob, Augustine Moscatello, Edward Shin, Zbigniew Darzynkiewicz, Raj K. Tiwari, Jan Geliebter. Androgen receptor activation inhibits papillary thyroid carcinoma cell cycle progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 708. doi:10.1158/1538-7445.AM2015-708
Abstract 71: Epigenetic control of signature gene expression in the inducible differentiation of acute promyelocytic leukemia cells
Authors: Song Chunhua , Pan Xiaokang , Li Zhanjun , Ding Yali , Mudhusami Sunil , Gowda Chandrika , Ge Zheng , Steffens Sadie , Tan Bi-hua , Dovat Sinisa 
Published: August 2015

Abstract
[Background] Epigenetic changes in DNA and chromatin are regarded as emerging major players for hematopoietic stem cells development and lineage differentiation. Epigenetic deregulation of gene expression leads to leukemia and reversibility of epigenetic modifications makes DNA and chromatin changes attractive targets for therapeutic intervention. The promyelocytic leukemia HL-60 cell can differentiate into microphage, granulocyte and monocyte with stimulation of phorbol myristic acid (PMA), all-trans retinoic acid (ATRA) or dimethylsulfoxide (DMSO), and Vitamin D3, respectively, by affecting the gene expression on cell cycle and cell differentiation. However, how epigenetic regulation on gene expression in the inducible differentiation is still not well determined. [Methods and Results] We did the microarray analysis to identify the genome-wide gene expression profile of HL-60 cells in various time points(0h, 6h, 1d,2d,4d and 6d) under the treatment of PMA, ATRA/DMSO and D3 and found that around 3000 genes are significantly altered commonly under those treatments in the process. The percentage of down-regulated genes in the all commonly altered genes is significantly higher than that of up-regulated genes, and the significantly altered genes showed significantly physical clustering on chromosome loci, indicating the epigenetic regulation involved in the regulation of the gene expression. We did observed the expression changes of epigenetic enzymes in the process and further did the ChIP-on-ChIP analysis by using the customer array tiling the selected changed genes and 5 genomic loci hybridizing with ChIP’d DNA of histone markers (H3K4me3, H3K9me3 and H3K27me3). We found that the obvious decrease of H3K4me3 binding and increase of H3K9me3 and H3K27me3 are observed in the promoter of common down-regulated genes. These data indicated histone H3K4, H3K9 and H3K27 marker play important roles in shaping the chromatin state and regulating gene expression. [Conclusion] We identified the signature genes controlling the inducible differentiation of promyelocytic leukemia cells and found the epigenetic mechanism regulating the gene expression in the process.
Citation Format: Chunhua Song, Xiaokang Pan, Zhanjun Li, Yali Ding, Sunil Mudhusami, Chandrika Gowda, Zheng Ge, Sadie Steffens, Bi-hua Tan, Sinisa Dovat. Epigenetic control of signature gene expression in the inducible differentiation of acute promyelocytic leukemia cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 71. doi:10.1158/1538-7445.AM2015-71
Abstract 715: Regulation of the ABCG2 drug efflux transporter in breast cancer cells
Authors: Chua Vivian YL , Harvey Jennet , Bentel Jacqueline 
Published: August 2015

Abstract
The ABC transporters, including ABCG2 or breast cancer resistance protein (BCRP) are drug efflux transporters. Their overexpression in cancers including breast cancer has been associated with the development of multidrug resistance (MDR) due to ABC transporter-mediated export from tumour cells of therapeutic drugs such as chemotherapeutic (eg. mitoxantrone, doxorubicin) and targeted agents (eg. tyrosine kinase inhibitors). PCR microarray analysis identified that ABCG2 expression was downregulated in the breast cancer cell lines, MCF-7 and T-47D following treatment of cells with the androgen, 5α-dihydrotestosterone (DHT), the Hedgehog pathway inhibitor, cyclopamine, or a combination of 10-8M DHT and 2μM cyclopamine. RT-qPCR analysis confirmed that DHT and cyclopamine treatments of MCF-7 cells rapidly downregulated ABCG2 mRNA levels by 24 hours. ABCG2 protein levels were also progressively decreased over 8 days of treatment, with earlier reductions in ABCG2 levels observed in cells co-treated with DHT and cyclopamine. As the ABC transporters are primarily active on membrane surfaces as drug exporters, the intracellular localisation of ABCG2 was investigated by immunofluorescence microscopy. In MCF-7 cells, DHT and/or cyclopamine decreased ABCG2 accumulation in cell-to-cell membrane junction complexes and interestingly, accumulation of ABCG2 into cytoplasmic vesicles which resembled aggresomes was observed in cells exposed to cyclopamine. Consistent with the reduced levels of membrane-bound ABCG2, export of the fluorescent ABCG2-specific substrate, mitoxantrone from MCF-7 cells was delayed following treatment of cultures with DHT and cyclopamine, thereby indicating diminished ABCG2 efflux activities. Moreover, these DHT- and cyclopamine-treated cells were also more responsive to the cytotoxic effects of mitoxantrone as the IC50 for mitoxantrone was decreased by ∼80% in treated cells compared to controls. Resistance to drug therapies, which is often facilitated by the ABC transporters, is a major cause of treatment failure and recurrence of breast cancer. As such, development and implementation of adjuvant compounds such as androgens and Hedgehog inhibitors, which inhibit expression and function of ABCG2 and other efflux transporters in breast cancer cells, may improve treatment outcomes and prolong recurrence-free survival of patients.
Citation Format: Vivian YL Chua, Jennet Harvey, Jacqueline Bentel. Regulation of the ABCG2 drug efflux transporter in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 715. doi:10.1158/1538-7445.AM2015-715