bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A18: Genome-wide methylation profiling to identify potential epigenetic biomarkers associated with response to sunitinib in metastatic renal cell cancer patients (pts)
Authors: Kim Jenny , Labots Mariette , Verheul Henk , Carducci Michael , Begum Shahnaz , Netto George , Hoque Mohammad 
Published: May 2015

Abstract
Background: Sunitiinib is a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) that is widely used in the front line setting for the treatment of advanced renal cell cancer. As with other targeted agents, there is a significant heterogeneity in the clinical response to sunintib and a biomarker which would predict patients' response up front would be an invaluable tool in the clinical management of patients (pts) afflicted with this disease. In this regard, whole genome methylation array was performed between sunitinib responders and nonresponders to identify differentially methylated genes between these two subsets of pts.
Methods: mRCC pts. who received sunitinib therapy with available frozen nephrectomy tissues and clinical data were identified. Responders (RES) were identified as patients with progression free survival (PFS)of &gt;11 months (mos) and nonresponders (NRES) as those with PFS &lt;3 mos. Whole genome methylation array was performed using Infinium Humanmethylation450 BeadChip Kit. The statistical analysis performed was based on one-way ANOVA and an empirical Bayes approach was used to moderate standard errors. The QC plots showed that all arrays were fine and successful.
Results: Thirteen pts treated with sunitinib for mRCC with available frozen nephrectomy tissues as well as clinical data were identified. Five were selected for each RES and NRES cohort as described above. Three pts had PFS that ranged between 3-11 mos (INT). All pts. In RES had clear cell subtype. Two of the NRES group were of non-clear cell type. For RES vs. NRES, one genomic location, DENND2D, was significantly hypermethylated in the RES group with a false discovery rate (FDR) of &lt;10%. For RES+INT vs NRES, DENND2D hypermethylation was also seen in the RES+INT group but 4 other genes (TTYH3, TRAPPC12, HLA-DRB6 and cg15042082) were shown to be hypermethylated in the NRES group, also with a FDR&lt;10%.
Conclusion: In this study, DENND2D was significantly hypermethylated in sunitinib RES vs. NRES in mRCC pts. Technical and clinical validation of DENND2D and the other 4 differentially methylated genes are planned as is immunohistochemistry study of DENND2D to evaluate downstream effects of methylation.
Citation Format: Jenny Kim, Mariette Labots, Henk Verheul, Michael Carducci, Shahnaz Begum, George Netto, Mohammad Hoque. Genome-wide methylation profiling to identify potential epigenetic biomarkers associated with response to sunitinib in metastatic renal cell cancer patients (pts). [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A18.
Abstract A22: Role of cap-dependent translation in response to upstream kinase-targeted therapy in colorectal cancer
Authors: Ye Qing , Cai Weijia , Evers B. Mark , Solit David , Rosen Neal , She Qing-Bai 
Published: May 2015

Abstract
Mutational activation of the PI3K/AKT and RAS/RAF/MEK/ERK pathways is associated with colorectal cancer (CRC) progression and metastasis. Several small-molecule inhibitors of PI3K, AKT, RAF and MEK have been tested in the clinic for the treatment of CRC but have shown only limited activity as a single agent. We find that a potential mechanism of AKT or ERK-independence is associated with redundant activation of eIF4E-initiated cap-dependent translation mediated by convergent regulation of the translation repressor 4E-BP1 by the AKT and ERK pathways. Combined inhibition of both pathways exhibits synergistic anti-CRC effects, both in vitro and in vivo, by effectively inhibiting cap-dependent translation via maximal activation of 4E-BP1 function. Specifically, we identify that survivin is a key translationally-regulated target of both pathways through convergence on the mTORC1/4E-BP1/eIF4E axis, and continuous translation of survivin by AKT and ERK signaling is crucial for CRC progression to metastasis. These findings reveal that the cap-dependent translation functions as a critical regulatory node that integrates oncogenic AKT and ERK signals for metastatic progression of CRC. Thus, targeting cap-dependent translation that could simultaneously block upstream oncogenic signals and their downstream targets may provide a promising therapeutic strategy for advanced CRC.
Citation Format: Qing Ye, Weijia Cai, B. Mark Evers, David Solit, Neal Rosen, Qing-Bai She. Role of cap-dependent translation in response to upstream kinase-targeted therapy in colorectal cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A22.
Abstract A33: Combined therapy of a novel anti-NOTCH2/3 antibody with paclitaxel inhibits tumor growth in a patient-derived breast tumor xenograft
Authors: Wei Jie , Cain Jennifer , Shah Jalpa , Wallace Breanna , Tang Tracy , Wang Min , Murriel Christopher , Belinda Cancilla , Gurney Austin , Sato Aaron , Lewicki John , Kapoun Ann , Hoey Tim 
Published: May 2015

Abstract
Cancer stem cells (CSCs) have been identified as the small subpopulation of cells in many cancers and are thought to be responsible for cancer initiation, progression, metastasis, recurrence and drug resistance. The NOTCH pathway, comprised of ligands JAG1, JAG2, DLL1, DLL3 and DLL4 and receptors NOTCH1, NOTCH2, NOTCH3 and NOTCH4, plays a critical role in stem cell signaling, cell proliferation, survival, apoptosis, and differentiation. Because of the existing body of data that implicates aberrant NOTCH pathway activation in resistance to chemotherapeutic agents in epithelial and hematologic tumors, we hypothesized that NOTCH inhibition would enhance the anti-tumor activity of chemotherapeutic agents.
We have identified a NOTCH3 activating mutation in a patient breast cancer and developed a xenograft tumor model from the primary patient sample, OMP-B37. The combination of paclitaxel and OncoMed's anti-Notch2/3 antibody, OMP-59R5, inhibited the tumor growth of OMP-B37 xenograft tumors. In addition, we found that treatment with OMP-59R5 drove changes in tumor heterogeneity as indicated by the increased expression of markers associated with a mature cellular fate. The down-regulation of tumor growth promoting genes and NOTCH pathway markers was observed with OMP-59R5 treatment. The enhanced activity of combined OMP-59R5 and paclitaxel therapy in patient-derived tumor xenografts suggests that there is therapeutic potential in combining targeted NOTCH pathway inhibition with chemotherapeutic agents.
Citation Format: Jie Wei, Jennifer Cain, Jalpa Shah, Breanna Wallace, Tracy Tang, Min Wang, Christopher Murriel, Cancilla Belinda, Austin Gurney, Aaron Sato, John Lewicki, Ann Kapoun, Tim Hoey. Combined therapy of a novel anti-NOTCH2/3 antibody with paclitaxel inhibits tumor growth in a patient-derived breast tumor xenograft. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A33.
Abstract A50: Crotamine derived fusion short-peptides and their effect on melanoma and breast cancer cells cultured in vitro
Authors: Mambelli Nicole Caroline , De-Sá-Júnior Paulo Luis , Ferreira Adilson Kleber , Azevedo Ricardo Alexandre , Câmara Diana Aparecida , Kerkis Irina 
Published: May 2015

Abstract
The search for molecules with therapeutic potential against cancer is a crucial issue to reduce the amount of death in human population around the world. Previously, we showed that crotamine, a natural polypeptide from the venom of the rattlesnake Crotalus durissus terrificus, has ability to induce cancer cells apoptosis in vitro, as well as, delay and inhibit melanomas formation in vivo in mice. In order to reduce crotamine length and toxicity, while maintaining its anti-cancer properties, two short peptides were designed and synthetized. Such short peptides represent an intermediate potential step toward to the development of drugs targeted cancer death. The aim of present study was to analyze pro-apoptotic activity of both of these peptides (1 and 2), composed by crotamine (crot.) and BAX (pro-apoptotic protein from BCL2 family) both derived sequences in melanoma and breast cancer cells in vitro. Melanoma and breast cancer cells (MEL-85, A2058, B16-F10 and SKBR3) were used. The MTT assay was performed after addition of both of these peptides used in different concentrations into cancer cells. The expression of proteins (PARP, Cleaved - Caspase 3, Caspase 3, Phospho - BAD) was evaluated by western blotting. Flow cytometry was performed to evaluate the cell cycle. The mitochondria potential was also verified before and after peptides addition. Morphologic changes, such as, detachment from substrate, cell contraction, loss of inter-cell elongations and several others effects were observed in cancer cells after 24 hours of incubation with peptides. At that time, the peptides exhibit cytotoxic activity as verified by MTT assay. Cell cycle analyses demonstrated that they decrease the timing of G2/M phases, while increasing a sub-G0/G1 phase. Unexpectedly, both peptides increase mitochondria potential of cancer cells, when compared with control cultures (without addition of peptides). Increase of expression pro-apoptotic proteins, such as, cleaved Caspase 3 and PARP was evidenced in cancer cells after addition of peptide -1, while Phospho-BAD was increased after addition of peptide - 2. Our data suggest that both peptides are efficient to trigger cell death in melanoma and breast cancer cells in vitro. Crot alone was not able to induce such changes in cancer cells.
Citation Format: Nicole Caroline Mambelli, Paulo Luis De-Sá-Júnior, Jr., Adilson Kleber Ferreira, Ricardo Alexandre Azevedo, Diana Aparecida Câmara, Irina Kerkis, Sr.. Crotamine derived fusion short-peptides and their effect on melanoma and breast cancer cells cultured in vitro. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A50.
Abstract A53: Integrative data analysis of colorectal cancer reveals the frequently metastatic sample cluster
Authors: Tsuji Shingo , Midorikawa Yutaka , Seki Motoaki , Takayama Tadatoshi , Sugiyama Yasuyuki , Aburatani Hiroyuki 
Published: May 2015

Abstract
High-throughput biological technologies enabled to identify cancer related key molecules and subclasses. However, single experiment could only elucidate one feature of the tumor pathway. In order to identify the clusters and pathways significant for cancer progression, we performed integrated analysis using gene expression and DNA methylation profiles of colorectal cancer samples. Extracting core CpG sites from CpG island with our newly developed method, iClusterPlus, one of integrated analyses methodologies, was applied to expression array and methylation profiling data and 116 colorectal cancer samples were divided into various cluster size (2≤k≤11). We examined clusters (k=3 and k=6), and found that each cluster (k=3) clearly corresponds to three groups consisting of the combination of two clusters in cluster (k=6) with different prognosis. Expression profiles of two clusters in each group were significantly different, which suggests that aberrant DNA methylation is accumulated during the early stage of cancer, while alteration of gene expression profile is the late event of cancer progression. Furthermore, network-based analysis using expression profiles demonstrated that modules including hnRNP family was down-regulated in one of the cluster (k=6) which frequently harbored liver metastasis and poor prognosis. Integrated clustering analysis applied to multidimensional methods is available to identify disease characteristics such as survival rate and distant metastasis, which might be valuable for improving cancer therapy.
Citation Format: Shingo Tsuji, Yutaka Midorikawa, Motoaki Seki, Tadatoshi Takayama, Yasuyuki Sugiyama, Hiroyuki Aburatani. Integrative data analysis of colorectal cancer reveals the frequently metastatic sample cluster. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A53.
Abstract B03: Cisplatin-resistant cells possess collateral sensitivity to folate antimetabolites
Authors: Chang Shih-Shin , Yamaguchi Hirohito , Hung Mien-Chie 
Published: May 2015

Abstract
Cisplatin is widely used as a first-line chemotherapeutic agent for lung cancers. Although effective initially, lung cancer cells eventually acquire resistance to cisplatin, causing tumor recurrence. Understanding mechanisms that govern cisplatin resistance is expected to improve therapeutic efficacy in lung cancer patients. Although various studies using cisplatin-resistant cell lines have revealed possible mechanisms of resistance, the applicability of these mechanisms in a clinical setting are debatable. One possible reason for this discrepancy may be the use of cell line models which are exposed to unnaturally high doses of cisplatin to yield cells with a resistant phenotype. These cell lines may not be representative of naturally arising cisplatin-resistant cells in tumors that are treated according to a clinically established dose and schedule. Therefore, to improve the experimental model, we have established two new cisplatin-resistant lung cancer cell lines through intermittent low dose challenges that mimic a clinical treatment schedule (one pulse/month for up to six cycles). The resistant cell lines resulting from this procedure demonstrate improved clonogenic potential and sphere-forming properties, suggesting an increase in the population of tumor-initiating cells. Interestingly, via testing with several different anti-cancer drugs, we found that these resistant cells are more sensitive to the antifolate Pemetrexed, in comparison to their parental cells. To conclude, our study suggests that sequential administration of antifolates might be useful in the treatment of lung cancers that have acquired cisplatin resistance.
Citation Format: Shih-Shin Chang, Hirohito Yamaguchi, Mien-Chie Hung. Cisplatin-resistant cells possess collateral sensitivity to folate antimetabolites. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B03.
Abstract B08: New Abelson interactor-1(Abi-1)-driven mechanism of acquired drug resistance
Authors: Chorzalska Anna , Salloum Ibrahem , Marjon Philip , Treaba Diana , Schorl Christoph , John Morgan , Bryke Christine R. , Reagan John , Winer Eric , Olszewski Adam J. , Dubielecka Patrycja M. 
Published: May 2015

Abstract
In hematological malignancies, quiescent leukemic stem cells are responsible for persistence of minimal residual disease and relapse. We have recently identified a new signaling pathway that is significantly dysregulated in imatinib mesylate (IM) resistant leukemic cells (Chorzalska et all, Leukemia in press). A key player in this pathway is Abelson interactor-1 (Abi-1). Abi-1 was originally identified as Abl kinase associating protein that was later confirmed to be one of the Bcr-Abl interactors. Abi-1 was recently shown to interact directly with α4 integrin, which controls lodging of hematopoietic and leukemic stem cells (HSCs/LSCs) in the bone marrow microenvironment. We have recently obtained evidence that Abi-1 plays a role in signaling cross-talk between Bcr-Abl and α4 integrin. We have found that loss of Abi-1 leads to increased adhesion and quiescence, resulting in increased chemoresistance of leukemic CD34+ progenitor cells. Comparison of Abi-1 (ABI-1) and α4 integrin (ITGA4) gene expression in relapsing Bcr-Abl positive CD34+ progenitor cells demonstrated a reduction in Abi-1 and an increase in α4 integrin mRNA in the absence of Bcr-Abl mutations. This inverse correlation between Abi-1 and α4 integrin expression, as well as linkage to elevated phospho-Akt and phospho-Erk signaling, was confirmed in imatinib mesylate (IM) resistant leukemic cells. These results indicate that the α4-Abi-1 signaling pathway may mediate acquisition of the drug resistant phenotype of leukemic cells. Based on our findings, we hypothesize that chemoresistance arises as a consequence of dysregulation of a pathway involving α4 integrin and Abi-1, and is mediated through a previously unknown mechanism that is independent of oncogene activity.
Citation Format: Anna Chorzalska, Ibrahem Salloum, Philip Marjon, Diana Treaba, Christoph Schorl, Morgan John, Christine R. Bryke, John Reagan, Eric Winer, Adam J. Olszewski, Patrycja M. Dubielecka. New Abelson interactor-1(Abi-1)-driven mechanism of acquired drug resistance. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B08.
Abstract B16: Combination of docetaxel with histone deacetylase inhibitor inhibits AR signaling synergistically in hormone-independent 22Rv1 prostate cancer cells
Authors: Kim Ha-Gyeong , Hwang Jung Jin , Kim Choung-Soo 
Published: May 2015

Abstract
Globally prostate cancer is the sixth leading cause of cancer-related death in men, and it is now the first in the United Kingdom and second in the United States. At the early stage, prostate cancer growth and progression depend on androgen receptor (AR) signaling. Therefore, androgen-deprivation therapy (ADT) is effective to patient with prostate cancer by inhibition of androgen synthesis. With time, however, most patients with prostate cancer eventually lose sensitivity to androgen withdrawal and progress to the development of castration-resistant prostate cancer (CRPC). Though docetaxel is a standard of care therapy in CRPC, most of patients develop resistance to this therapy. Therefore, the novel therapeutic strategies and combination therapy are needed to overcome this resistance. In this study, we examined whether histone deacetylase inhibitor (HDACI), suberoylanilide hydroxamic acid (SAHA) might enhance the effect of docetaxel in CRPC. Hormone-independent 22Rv1 cells harboring AR were treated with docetaxel and/or SAHA. Co-treatment of docetaxel and SAHA inhibited the growth of 22Rv1 cells synergistically. Combination treatment decreased the levels of AR, prostate specific antigen (PSA), and anti-apoptotic Bcl-2 proteins (Mcl-1, Bcl-xl) more efficiently compared with docetaxel or SAHA alone, when it analyzed by Western blot. And combination treatment increased activation of caspase-3 remarkably, while docetaxel or SAHA alone increased it slightly. Moreover, immunocytochemistry and analysis of nuclear fractionated proteins showed that combination treatment induced acetylation and bundling of tubulin, inhibiting nuclear accumulation of AR significantly. These results suggested that docetaxel in combination with SAHA inhibited cell growth efficiently and induced apoptosis by repressing expression and translocation to nucleus of AR in 22Rv1 cells, and this combination can be a useful therapeutics for the treatment of CRPC patients.
Citation Format: Ha-Gyeong Kim, Jung Jin Hwang, Choung-Soo Kim. Combination of docetaxel with histone deacetylase inhibitor inhibits AR signaling synergistically in hormone-independent 22Rv1 prostate cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B16.
Abstract B24: Attenuated expression of a novel mitochondrial and metabolic gene contributes to acquired gefitinib resistance in lung tumors
Authors: Okon Imoh S. , Coughlan Kathleen A. , Zou Ming-Hui 
Published: May 2015

Abstract
Therapeutic benefits provided by tyrosine kinase inhibitors (TKIs), such as Gefitinib (Iressa) and Erlotinib (Tarceva) have been limited by resistance which contributes to treatment failure and cancer-related mortality. Dysregulated metabolism (Warburg effect), a property of cancer cells has been linked to drug resistance, but the mechanisms remain unknown. In this study, MRC-9 (normal “non-cancer” cells), as well as A549, H1650, H1792 and H1975 lung adenocarcinoma cell lines (from ATCC; Manassas, VA) were used in order to examine those process(es) involved in the development of gefitinib resistance. Gefitinib is a specific, targeted agent against the epidermal growth factor receptor (EGFR) that competes for ATP-binding sites in the tyrosine activation domain of the receptor. Gefitinib-resistant H1650G cells were generated by subjecting parental H1650 cells to chronic gefitinib exposure for 12-16 weeks, and continuous culture under gefitinib selection. Consistent with existing literature, micro-array analysis of gefitinib-resistant H1650G cells confirmed differential expression of epithelial-mesenchymal transition (EMT) genes, such as vimentin, fascin1 and keratin19 compared to parental H1650 cells. Importantly, we uncovered the loss of a mitochondrial/metabolic gene intimately involved with glycolysis as a contributor to acquired gefitinib resistance in lung cancer cell lines and clinical specimens. Loss of expression of the novel target correlated with decreased ATP generation, and concomitant up-regulation of autophagy marker (LC3II), consistent with a compensatory mechanism of energy generation. Depletion (siRNA) of EGFR in parental H1650 cells was employed to mimic attenuated expression of the receptor due to sustained gefitinib treatment in H1650G cells, and correlated with decreased expression of the mitochondrial/metabolic target. This observation connects the EGFR signaling pathway with a novel mitochondrial/metabolic gene, and provides new insight into the development of acquired gefitinib resistance and adaptations by resistant cancer cells. The findings identify a novel potential target for therapeutic intervention, or biomarker functions that would enable informed patient selection with respect to gefitinib resistance.
Citation Format: Imoh S. Okon, Kathleen A. Coughlan, Ming-Hui Zou. Attenuated expression of a novel mitochondrial and metabolic gene contributes to acquired gefitinib resistance in lung tumors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B24.