bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B12: DNA methyltransferase 3A expression in cancer cells following treatment with DNMT inhibitors and in human solid tumors
Authors: Yang Sherry X. , Nguyen Dat , Rubinstein Larry , Chen Alice P. , Doroshow James H. 
Published: May 2016

Abstract
Background. The DNA methyltransferases (DNMTs) catalyze the addition of a methyl group to the 5-cytosine residue of CpG dinucleotides. This family of enzymes includes DNMT1 that functions as a DNA maintenance methyltransferase, and DNMT3A and DNMT3B that methylate previously unmethylated regions of DNA and are required for genome-wide de novo DNA methylation. However, there have been challenges to characterize DNMT3A protein expression in human tissue samples and it remains unclear its potential inhibition by classic and novel DNMT inhibitors. Materials and Methods. MCF-7 breast cancer and NCI-H23 non-small cell lung cancer cells were treated with DNMT inhibitors of 4'-thio-2'-deoxycytidine (T-dCyd), 4'-thio-5-aza-2'-deoxycytidine (aza-T-dCyd) and decitabine at 1 μM T-dCyd for 96h, and changes in DNMT3A expression were assessed by western blot and immunocytochemistry (ICC). DNMT3A expression was examined by immunohistochemistry in formalin-fixed and paraffin-embedded human breast, colorectal and lung cancers as well as lymphomas. Results. Expression of DNMT3A was decreased by all three DNMT inhibitors in MCF-7 and NCI-H23 cells detected by western blot and ICC. The mean staining index in NCI-H23 cells after T-dCyd treatment was 18.4, compared to 48.8 of vehicle control, by quantitative imaging and analysis (P &lt;0.0001 by 2-sided t test). DNMT3A was primarily localized to the nucleus, and constitutively expressed in tumor cells at intermediate to high levels in 3.3% (2/60) of breast cancer, 0% (0/47) of colorectal cancer, 12% (9/75) of lung cancers, and 23% (34/148) of lymphomas across histology types including T-cell and diffuse B small cleaved/non-cleaved lymphomas as well as Hodgkin's disease. Additionally, DNMT3A expression was low in benign breast diseases (n = 16), normal colon tissues (n = 7) and normal lymph nodes (n = 11). Conclusions. The data demonstrate that DNMT3A is targeted for decrease by DNMT inhibitors and may serve as a pharmacodynamic and perhaps efficacy biomarker in early clinical trials. The intermediate to high levels of DNMT3A expression are rare in colorectal and breast cancers, and in 23% or fewer patients with either lymphomas or lung cancers.
Citation Format: Sherry X. Yang, Dat Nguyen, Larry Rubinstein, Alice P. Chen, James H. Doroshow. DNA methyltransferase 3A expression in cancer cells following treatment with DNMT inhibitors and in human solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B12.
Abstract B120: Maternal embryonic leucine zipper kinase(MELK) induces invasion and migration of glioblastoma
Authors: Choi Sang-Un , Kim KwangRok , Cheon Hyo Zin , Shon Yoo Hwa 
Published: May 2016

Abstract
Maternal Embryonic Leucine Zipper Kinase(MELK) induces invasion and migration of glioblastoma
Glioblastoma multiforme (GBM) is the most common cancer of the primary malignant brain tumors and one of the most difficult tumors to treat effectively. This tumor arises from star-shaped glial cells called “astrocytes.”
Maternal embryonic leucine zipper kinase (MELK) is a member of the snf1/AMPK family of serin-threonine kinase which is cell cycle-dependent protein kinase. Although several members of the family are known to play roles in cell survival under metabolically challenging condition, the exact function of MELK has not previously been identified. MELK has recently emerged as an important gene in the field of cancer research. Several studies have reported that MELK level is dramatically increased in cancer tissues and it possibly contributes to cancer development. The several proteins such as ZPR9, NIPP1, and Cdc25B are reported the substrates of MELK, so far, but the significance of their phosphorylation is not clear.
To identify the role of MELK in malignancy of GBM, we introduced the drug-induced transgene expression system to U87MG cell line by using the tetracycline(Tet)-inducible gene expression systems. To elucidate the MELK signaling pathway in brain cancer cells, we conducted human phospho-kinase array, 2D-PAGE and mass spectrometric analysis. We identified the vimentin as a downstream factor of MELK, and confirmed the expression of this target by artificial increased MELK.
Vimentin, the intermediate filament protein, is reported as an important marker of Epithelial-to-mesenchymal transition (EMT) and a requisite regulator of mesenchymal cell migration. EMT is a critical event in the induction of cell motility and increased survival both under physiological situations like wound healing and during development as well as in malignant cells undergoing invasion and metastasis. Vimentin is characteristically upregulated in tumor cells undergoing EMT.
Here, we show that MELK is necessary for the vimentin function in vitro, influencing their ability to cell migration. The data strongly support the hypothesis that MELK, unlike other family members, functions by regulating migration and invasion for tumor cell EMT induction rather than the cell cycle through regulation of vimentin.
Citation Format: Sang-Un Choi, KwangRok Kim, Hyo Zin Cheon, Yoo Hwa Shon. Maternal embryonic leucine zipper kinase(MELK) induces invasion and migration of glioblastoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B120.
Abstract B127: An innovative, ultra-accurate method for cancer mutation detection in cell-free DNA from plasma
Authors: Zhao Grace , Tang Paul , Sun Johnny , Lin Shengrong 
Published: May 2016

Abstract
The application of cell-free DNA (cfDNA) as a biomarker holds great potential in advancing personalized cancer treatments. However, two major limitations need to be addressed for the development of a practical cfDNA-based cancer diagnostic assay: 1) the low concentration of cfDNA in blood, which presents challenges for detecting mutations at low allele frequency, and 2) the relatively high background noise caused by next generation sequencing (NGS) error, which can mask bona fide cancer mutation signals. Here we introduce an innovative, ultra-accurate, and scalable NGS-based cancer mutation detection system that overcomes these limitations. Our system amplifies nanogram quantities of highly fragmented cfDNA from the whole genome to &gt;1000-fold, and no significant biases were observed. By combining molecular biology techniques with bioinformatics, we reduced the random background error from sequencing to achieve high accuracy (calculated error rate of 10-6), with a detection of 1:10,000 in a cell line gDNA model system, and 1:1000 in cfDNA. We implemented a 127-gene panel with 1 Mb target region, and 2000x-3000x deep sequencing to detect mutations from stage II hepatocellular carcinoma (HCC) cfDNA samples, and 75% of the HCC signature mutations (including those mutations with &lt;1% allele frequencies) were confirmed by tumor gDNA exome sequencing. Furthermore, we developed an algorithm for basic cancer type classification, which in a preliminary study, this algorithm classified our breast and pancreatic cancer cfDNA samples with a sensitivity of 85%, and a specificity of 100%. In summary, this unbiased cfDNA amplification and highly accurate mutation detection system serves as a first step toward developing a reliable, non-invasive cancer genome analysis, which will dramatically enhance options for personalizing cancer treatments and ultimately screening high risk populations.
Citation Format: Grace Zhao, Paul Tang, Johnny Sun, Shengrong Lin. An innovative, ultra-accurate method for cancer mutation detection in cell-free DNA from plasma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B127.
Abstract B15: Androgen receptor recruitment to c-Jun promoter region regulates chemosensitivity of prostate cancer cells to taxane therapy
Authors: Dizeyi Nishtman , Tinzl Martina V. , van der Molen Marieke , Semenas Julius , Abrahamsson Per-Anders 
Published: May 2016

Abstract
Introduction & Objectives. We have previously reported that response of prostate cancer (PC) to taxane therapy is based on the interplay between androgen receptor (AR) and c-jun However, the cellular mechanisms of taxane treatment in prostate cancer cells are not fully elucidated. The aim of this study was to investigate the effect of sustained down-regulation of c-jun on the outcome of taxane therapy using LNCaP cells transfected with c-jun shRNA, and to characterize the nature of the c-jun and AR interaction in regard to their corresponding promoter regions.
Material & Methods. Chromatin immunoprecipitation (CHIP) assay was performed to examine gene recruitment. LNCaP cells were treated with Docetaxel (Doc) or Paclitaxel (Pac) and resulting chromatin preparations were analyzed by PCR. To analyse the impact of c-jun downregulation on AR and prostate cancer response to therapy we used LNCaP cells harboring stable knocked down c-jun (LNsiJun). Cells were exposed to Doc, Pac DHT for different time-points and the medium were subjected for PSA analysis using DELFIA 1234 fluorometer and cell response to drugs assessed by MTT assay.
Results. Taxane treatment of LNsiJun cells led to a statistically significant decrease of cell viability compared to parental LNCaP cells (p&lt;0,05) independent on the substance used. Interestingly, exposure of LNsiJun cells to DHT resulted in increased cell death. LNsiJun cells treated with docetaxel (Doc) showed an up-regulation of AR and PSA protein levels after 24 hours, whereas Paclitaxel (Pac) treatment resulted in a down-regulation of both proteins which matched our observations in parental LNCaP cells. To further investigate this taxane specific effect on AR, ChIP assay revealed that AR binds to the c-jun promoter region upon Doc exposure. However, Pac treatment failed to do so. Both taxanes resulted in an enhanced binding of c-jun to the corresponding promoter region.
Conclusions. In conclusion, down-regulation of endogenous c-jun enhances sensitivity of LNCaP cells to taxane treatment. Binding of AR to the c-jun promoter is taxane specific and results in different expression levels of AR and PSA.
Citation Format: Nishtman Dizeyi, Martina V. Tinzl, Marieke van der Molen, Julius Semenas, Per-Anders Abrahamsson. Androgen receptor recruitment to c-Jun promoter region regulates chemosensitivity of prostate cancer cells to taxane therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B15.
Abstract B164: Identification and validation of PRMT1 as a therapeutic target in breast cancer
Authors: Silvestre David C. , Brisson Amelie , Marty-Prouvost Bérengère , Gentien David , Loew Damarys , Dingli Florent , Maire Virginie , Némati Fariba , Ye Mengliang , Meseure Didier , Nicolas André , Roman-Roman Sergio , Dubois Thierry 
Published: May 2016

Abstract
Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers (BC) associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In the present study, we found that Protein Arginine Methyltransferase 1 (PRMT1) is overexpressed in TNBC at the mRNA level. At the protein level, PRMT1 was overexpressed in all breast cancer subtypes compared to normal breast tissue. The depletion of PRMT1 using siRNA in BC cell lines triggered apoptosis, reduced cell viability and the ability to form colonies in an anchorage-independent manner. Treatment with Furamidine, a new PRMT1-specific inhibitor, blocked proliferation specifically in BC cells, with no measurable effect in normal breast cells. Furamidine treatment of a TNBC patient-derived xenograft (PDX) model significantly slowed tumor growth. To address the cellular pathways regulated by PRMT1, we identified its protein partners by mass spectrometry and the transcriptomic changes following its depletion in TNBC cell lines. Interestingly, we found that PRMT1 directly activates key oncogenic pathways. Furthermore, we found a synergistic interaction between PRMT1 inhibitors and inhibitors for some of those pathways. Our results show that PRMT1 activity is necessary for breast cancer cell survival and oncogenic pathway activation. Our results point out PRMT1 as an emerging target for the treatment of BC.
Citation Format: David C. Silvestre, Amelie Brisson, Bérengère Marty-Prouvost, David Gentien, Damarys Loew, Florent Dingli, Virginie Maire, Fariba Némati, Mengliang Ye, Didier Meseure, André Nicolas, Sergio Roman-Roman, Thierry Dubois. Identification and validation of PRMT1 as a therapeutic target in breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B164.
Abstract B198: Pharmacological profile of the PGE2 EP4 receptor antagonist E7046
Authors: Albu Diana I. , Wu Jiayi , Huang Kuan-chung , Wright-Michaud Renee , Xu Shanqin , Kuznetsov Galina , Bao Xingfeng , Woodall-Jappe Mary 
Published: May 2016

Abstract
E7046 is a potent and selective small molecule antagonist of the type 4 prostaglandin E2 (PGE2) receptor EP4. The discovery and evaluation of this novel EP4 antagonist for cancer treatment was recently presented at the AACR 2015 annual conference (abstract # 275). Here we show new evidence of E7046 in vivo activity against a series of syngeneic tumor models as well as its pharmacological effect on APCMin/+ mice, which possess a mutation in the adenomatous polyposis coli (APC) tumor suppressor gene. We found that daily oral administration of E7046 was able to both slow down the growth of established subcutaneous tumors and significantly delay the recurrence of tumors after surgical resection. These activities of E7046 correlated with differences in the immune cell composition of the microenvironments of each type of tumor. In this context, cyclooxygenase 2 - positive (COX-2+) tumors that were rich in myeloid cells showed an enhanced response to E7046 regardless of their T lymphocyte infiltration status. In addition, E7046 was superior to the COX-2 inhibitor celecoxib against mutant APC-driven neoplastic polyp formation in the intestines of APCMin/+ mice exposed to dextran sodium sulfate. Using the APCMin/+ mouse model, we found that E7046 significantly reduced the combined colon polyp area and the size of individual polyps without influencing the total polyp number. For each of these parameters, E7046 activity against colon and small intestine tumors was greater than that of a comparable dose of celecoxib. Quantification of cyclin D1 staining in colon and small intestine polyps further indicated that both compounds led to a significant reduction in the proliferation of tumor cells, with a greater effect for E7046 compared to celecoxib. Overall, these preclinical results suggest that this agent should be further investigated in patients with COX-2+ tumors infiltrated with myeloid cells, including patients with APC-mutated colon cancer. First-In-Human study of E7046 is currently enrolling patients (IND 125272).
Citation Format: Diana I. Albu, Jiayi Wu, Kuan-chung Huang, Renee Wright-Michaud, Shanqin Xu, Galina Kuznetsov, Xingfeng Bao, Mary Woodall-Jappe. Pharmacological profile of the PGE2 EP4 receptor antagonist E7046. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B198.
Abstract B202: Combined therapy of temozolomide and PF-562271, a PYK2 inhibitor, reduces glioma tumor growth and dispersal compare to temozolomide monotherapy
Authors: Rolon-Reyes Kimberleve , Cubano Luis A. , Quiñones-Hinojosa Alfredo , Kucheryavykh Lilia 
Published: May 2016

Abstract
Microglia infiltrate majority of gliomas and release factors, which favor tumor growth and dispersal. Previously we demonstrated that microglia residing within the tumor stimulate glioma cell dispersal through the proline rich tyrosine kinase 2 (Pyk2) signaling cascade (Rolon-Reyes et al. 2015). We hypothesize that the use of pharmacological inhibitors of Pyk2 in applied therapy can significantly reduce the dispersal of tumor cells and improve the outcome of treatment.
In the present study, we investigated both in vitro and in vivo, the effect of the combined treatment of glioblastoma with temozolomide (TMZ) together with PF-562271 (a Pyk2 and FAK inhibitor), vs. TMZ monotherapy. Proliferation and migration assays were performed for a number of primary human glioma cell lines, as well as U87 and HS683cell lines in the presence and absence of microglia. Tumor size and invasion area were evaluated in brains of GL261 tumor bearing C57BL/6 mice for the assessment of the effectiveness of treatment.
Our data demonstrate that PF-562271 (16nM) and TMZ (100μM) given alone reduced in vitro migration and proliferation of glioma cells in the presence of microglia. PF-562271 (16nM) given in combination with TMZ at a concentration of just 10μM provided the same effect as TMZ 100 μM along, without reduction of efficacy. In vivo experiments demonstrated that oral administration of PF-562271 (twice/daily, 25 mg/kg, orally) reduced invasion of glioma cells at the tumor edge, while TMZ (50 mg/kg, once/day, orally) reduced the tumor growth. Combined treatment revealed significantly more prominent effect on both tumor growth and invasion compare to monotherapy.
These data indicate that the combination of TMZ and PF-562271 reduces both tumor growth and dispersal of tumor cells to surrounding areas. Moreover, in vitro experiments revealed a complex effect of these drugs on glioma cell proliferation and migration, allowing the reduction of the applied concentration of TMZ without the loss of its therapeutic effect.
This research was made possible by NIH grant numbers: 1SC2GM102040-01A1, 8G12MD007583-27, Title V PPOHA grant number P031M105050, NIH NIMH R25 MH055929 and RO1-CA18382701A1.
Citation Format: Kimberleve Rolon-Reyes, Luis A. Cubano, Alfredo Quiñones-Hinojosa, Lilia Kucheryavykh. Combined therapy of temozolomide and PF-562271, a PYK2 inhibitor, reduces glioma tumor growth and dispersal compare to temozolomide monotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B202.
Abstract B45: Molecular modeling approach for exploring the MDM2 active site for the discovery of new P53-MDM2 inhibitors
Authors: Atatreh Noor , Mansour Ramez A. , Ghattas Mohammad A. 
Published: May 2016

Abstract
MDM2 is a protein that regulates the action of tumor suppressor protein P53. Inhibiting the interaction between the two proteins is widely considered in anti-cancer drug discovery approach. Targeting p53-bindig site on the MDM2 protein can be useful for the development of new anticancer agents. Several drugs with selective activity have been introduced to the market and are used for treatment of several types of cancers.
In this study we explored the inhibition of MDM2 activity through studying 32 crystal structures of MDM2-ligand complexes downloaded from protein data bank (PDB). MDM2 protein structures were analyzed using protein-ligand interaction fingerprint to determine key residues for ligand binding. A 3D pharmacophore set was created and validated with a set of features that include aromatic and hydrophobic properties. Furthermore libraries of potential small lead-like ligands were screened on the pharmacophore. Ligands which pose three pharmacophoric features were carried to the next step where receptor-based virtual screening was performed using GLIDE docking software.
The top 10% obtained from this screening were then redocked into the MDM2 binding site using more extensive search and scoring technique (GLIDE_XP) in order to enhance screening accuracy. The resultant top list was visually examined and compounds with best binding mode were selected for experimental testing. This virtual technique for discovering new lead-like MDM2 inhibitors will take into consideration several features that current inhibitors may lack such as solubility and bioavailability.
Citation Format: Noor Atatreh, Ramez A. Mansour, Mohammad A. Ghattas. Molecular modeling approach for exploring the MDM2 active site for the discovery of new P53-MDM2 inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B45.
Abstract B51: Tumor genetic shift post standard of care therapy
Authors: Jonathan Dry R. , Greenawalt Danielle , Lai Zhongwu , Barrett Carl 
Published: May 2016

Abstract
Our current understanding of the mutation spectrum of relapse/refractory patients is limited. Public sequencing efforts have focused, by design, on diagnostic (pre-treatment) biopsies, while re-biopsy of patients who are refractory to first line therapy or who relapse on treatment is not standard protocol. Many gold standard algorithms used to call mutations perform poorly in ultra-deep sequencing data necessary for sensitive detection of resistance mutations emerging in circulating tumor DNA. They can also miss a wide range of complex genetic aberrations prevalent in cancer genomes. We have performed whole exome sequencing on post treatment core needle biopsies from 47 DLBCL patients post-relapse following anthracycline-based therapy such as R-CHOP, 8 with matched diagnostic biopsies. Similarly we have profiled 88 post-treatment solid tumor biopsies from triple negative breast and lung adenocarcinoma patients recurrent following platinum or multi-agent chemotherapy, 12 with matched diagnostic biopsies. We compared the somatic variant frequencies and copy number variation between matched pre- and post-treatment samples, and with published data for cohorts of primary (diagnostic) samples matched by patient and tumor characteristics. NGS data from all samples were processed using the same mutation caller, VarDict http://github.com/AstraZeneca-NGS/VarDict, optimized to call large InDels and complex variants in ultra-deep sequencing. For DLBCL, the average mutation rate and founding driver mutation profile were similar, however a number of oncogenic driver mutations were found to have emerged in the post-treatment biopsies. Collectively these data further highlight the value of re-assessing the tumor genetic landscape at the time therapeutic choices are made.
Citation Format: Dry R. Jonathan, Danielle Greenawalt, Zhongwu Lai, Carl Barrett. Tumor genetic shift post standard of care therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B51.