bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2372: Predictive markers in patients with non-small cell lung cancer with pemetrexed treatment.
Authors: Chae Hiun S. , Ko Yoon Ho , Jeon Eun Kyoung , Hong Sook Hee , Kim Jeong-Oh , Kim Seung Joon , Lee Kyo Young , Kim Young Kyoon , Kim HoonKyo , Park Seok young , Woo In Sook , Kang Jin Hyoung 
Published: August 2014

Abstract
Background: This study is desiged to evaluate biomarkers that are correlated with the efficacy of pemetrexed in patients with non-small-cell lung cancer (NSCLC).
Methods: Patients with stage III or IV NSCLC who received pemetrexed monotherapy after failure of one or more chemotherapy regimen between January 2003 and August 2011 were included. Polymorphism of reduced folate carrier gene (SLC19A, rs1051298), 5,10-methylenetetrahydroflate reductase (MTHFR, rs1801133) and thymidylate synthase (TS, rs45445694, rs16430) gene were analyzed by PCR and direct sequencing method using peripheral blood.
Results: Total 123 patients were included. The median age was 61 years (range 35-82). Fifty eight (47.2%) patients were female. Predominant histology was adenocarcinoma (92.7%). Metastatic diseases were 114 (80.5%) patients. Patients received one or more lines of systemic therapy before pemetrexed therapy, one line in 53 (43.1%) patients, two in 51(41.5%), three in 14 (11.02%), and four in 4 (3.3%). Median 4 cycles of chemotherapy were given (range 1-44). Response rate was 22.7% (CR, n=2, PR, n=26) and stable disease was detected in 54 patients (43.9%). Median follow up duration was 28.7months (range 4.07-84.33months). Median progression free survival (PFS) was 4.2 months (95% CI: 2.9-5.6) and median overall survival (OS) was 18.9 months (95% CI: 13.3-24.6). Clinical factors like, sex, histology of tumor (adenocarcinoma vs, nonadenocarcinoma), differentiation, smoking status and EGFR mutation status (active mutation vs. other mutation vs. wild type) did not have any significant difference on response and PFS. Only polymorphisms of TS promoter enhancer region (TSER) were related with PFS. 2R/2R repeat in the TSER (2R/2R vs 2R/3R, 3R/3R 1.0m vs 4.3m, p&lt;0.01) and CC homozygote variant in second repeat of the 3R allele (CC vs GC, GG 2.8m vs 5.0m, p=0.04) had poor PFS. All polymorphism did not have effect on response rate and overall survival.
Conclusions: This study suggests that polymorphisms of TSER associated PFS in pemetrexed treatment. Further prospective studies will be needed to validate these polymorphism as a useful biomarker of pemetrexed treatment in NSCLC patients.
Citation Format: Hiun S. Chae, Yoon Ho Ko, Eun Kyoung Jeon, Sook Hee Hong, Jeong-Oh Kim, Seung Joon Kim, Kyo Young Lee, Young Kyoon Kim, HoonKyo Kim, Seok young Park, In Sook Woo, Jin Hyoung Kang. Predictive markers in patients with non-small cell lung cancer with pemetrexed treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2372. doi:10.1158/1538-7445.AM2013-2372
Abstract 2373: The LCBRN: a biospecimen resource for lung cancer biomarker and discovery science.
Authors: Moskaluk Christopher A. 
Published: August 2014

Abstract
The Lung Cancer Biospecimen Resource Network (LCBRN) is an open access biorepository that obtains specimens from lung cancer patients (tissue, blood, urine, bronchial lavage fluid and saliva) and makes them available to biomedical researchers. Specimen collection is supported at 3 collection sites (Medical University of South Carolina, The University of Virginia, and Washington University at St. Louis) in compliance with uniform standard operating procedures. The specimens are annotated with clinical, radiologic and pathologic data. Histologic and molecular quality control procedures are in place for tissue samples. Lung cancer and non-neoplastic lung tissue aliquots are processed into DNA, RNA and protein fractions, which are also available. Fluid biosamples are available from subjects prior to, and after surgery to remove the cancer. A cohort of subjects are followed for recurrence with serial biofluid sampling. Specimens are currently available from over 300 research subjects. The application form for biospecimens and additional information is available at http://LCBRN.org.
Citation Format: Christopher A. Moskaluk. The LCBRN: a biospecimen resource for lung cancer biomarker and discovery science. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2373. doi:10.1158/1538-7445.AM2013-2373
Abstract 2387: Activation of Inhibin A signaling is associated with a basal-like HER2 subtype and resistance to lapatinib in breast cancer cell lines.
Authors: Korkola James E. , Rantala Juha , Bayani Nora , Heiser Laura , Wang Nicholas , Griffith Obi , Gray Joe 
Published: August 2014

Abstract
HER2 amplification occurs in ∼20% of all breast cancers, and is associated with poor prognosis. Targeted therapeutics such as trastuzumab and lapatinib have been developed and have improved outcomes for patients with HER2+ disease. However, a significant proportion of patients have tumors that either develop resistance or simply fail to respond to these therapies at all. To better understand the mechanism of resistance, we screened a panel of 22 HER2+ breast cancer cell lines with lapatinib. Of these, 6 showed significant resistance, failing to reach 50% growth inhibition (GI50) even at 5uM, the highest dose tested. The resistant lines were all more basal-like in expression patterns, and were more responsive to MEK inhibitors than their luminal-like counterparts. These two patterns of expression are similar to the different HER2 subtypes recently identified by the TCGA project. Differential expression analysis utilizing t-tests with Benjamini-Hochberg correction for multiple comparisons identified approximately 150 transcripts that were more highly expressed in resistant cell lines. We performed high-throughput screening using siRNA knockdown of the target genes in combination with lapatinib treatment. Staining for markers of proliferation (Ki67), apoptosis (cleaved PARP), and activity of the PI3K-AKT pathway showed that silencing of inhibin A resulted in a decrease in the ratio of proliferative to apoptotic cells in the resistant cell lines 21-NT and 21-PT. Concurrent with this decrease was a down-regulation of both p-MAPK and p-AKT. GO analysis revealed a strong enrichment for Inhibin A signaling amongst the 150 resistance associated transcripts. Mining of tumor databases revealed that there was a trend between high levels of Inhibin A expression and poor outcome in HER2 positive tumors (p=0.08). These data suggest that activation of Inhibin A signaling is associated with a more basal like subclass of HER2+ tumors, resistance to HER2 targeted therapeutics such as lapatinib, and that corresponding over-expression of Inhibin A is associated with poor outcome in HER2+ patients.
Citation Format: James E. Korkola, Juha Rantala, Nora Bayani, Laura Heiser, Nicholas Wang, Obi Griffith, Joe Gray. Activation of Inhibin A signaling is associated with a basal-like HER2 subtype and resistance to lapatinib in breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2387. doi:10.1158/1538-7445.AM2013-2387
Abstract 244: Cancer stem cells predict engraftment and poor prognosis of primary breast tumor.
Authors: Charafe-Jauffret Emmanuelle , Ginestier Christophe , Bertucci Francois , Cabaud Olivier , Adelaide Jose , Chaffanet Max , Xerri Luc , Viens Patrice , Birnbaum Daniel 
Published: August 2014

Abstract
Despite the promise of the cancer stem cell (CSC) model, its clinical relevance remains to be proven in breast cancer (BC) and requires a sensitive xenograft assay to define CSC on key functional properties i.e tumorigenicity, self-renewal and differentiation potential.
We report the establishment of primary breast tumor-derived xenografts (PDXs) that retain main primary tumors features (histo-phenotypic, molecular and genomic features, hierarchical organization of the tumoral cell population). We demonstrate that success in engraftment is correlated with the presence of CSC in primary tumor and predicts prognosis in patients (HR= 3.61; 95%CI [1.12-11.65], p=3.20E-02).
The xenograft assay demonstrated the hierarchical organization of BC. Analysis of gene expression from functionally validated CSC yield to a breast CSC signature (BCSC-GES) is an independent predictor of patient survival. We then identified a core of genes commonly expressed by BCSC and embryonic, hematopoietic, neural stem cells, the CE-4SC. This shared transcriptional program comprised 19 genes encoding mismatch and nucleotide excision repair proteins, proteins implicated in transport through the endoplasmic reticulum, RNA processing, translation and transcriptional regulators, enzymes of detoxification and mitochondrial/oxidative stress, or enzymes of lipid metabolism. This “universal” stem cell program is also an independent predictor of patient survival.
Using a screening of an RNA-interference library specially designed to block the expression of these 19 target genes, we validated the effect of single gene knock-down (KD) on the breast CSC population for 14 genes (KD of 5 genes decreased the CSC population and were called “self-renewers”genes, KD of 9 genes increased the CSC, and were designated as“differentiators”).
Hence, this study validated the clinical relevance of CSC model in breast cancer for the first time, and the ability of PDXs to accelerate transfer for personalized CSC therapy into clinics.
Citation Format: Emmanuelle Charafe-Jauffret, Christophe Ginestier, Francois Bertucci, Olivier Cabaud, Jose Adelaide, Max Chaffanet, Luc Xerri, Patrice Viens, Daniel Birnbaum. Cancer stem cells predict engraftment and poor prognosis of primary breast tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 244. doi:10.1158/1538-7445.AM2013-244
Abstract 2449: The bromodomain inhibitor JQ1 blocks growth of pancreatic cancer cells in 3D collagen.
Authors: Sahai Vaibhav , Kumar Krishan , Ebine Kazumi , Nimeiri Halla , Munshi Hidayatullah G. 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with a pronounced collagen-rich stromal reaction that has been shown to contribute to chemo-resistance. We have found that the collagen microenvironment promotes expression of histone acetyltransferases (HATs) and thereby promotes chemo-resistance; however, HATs have proven to be difficult ‘druggable’ targets. Bromodomain proteins are chromatin readers that can bind to acetylated histones and thereby regulate gene expression. JQ1, an inhibitor of BET class of human bromodomains, was shown to have efficacy against leukemia and lymphoma cell lines. Thus, we examined the effect of JQ1 on a panel of PDAC cells grown in 3D collagen. AsPC1, CD18 and Panc02.03 cells were particularly sensitive to the effects of JQ1, while Panc1 cells were relatively resistant to JQ1 treatment. JQ1 decreased myc mRNA and increased p21 mRNA in CD18 cells, but not in Panc1 cells. JQ1 also decreased growth of chemo-resistant CD18 cells grown in 3D collagen, and blocked EGF and TGF-β1-induced growth and scattering of Panc1 and CD18 cells in 3D collagen. The MEK1/2 inhibitor U0126 and JQ1 synergistically attenuated growth of CD18 and Panc1 cells in 3D collagen. In addition, EGFR inhibitors (AG1478 and PD153035) and JQ1 also synergistically attenuated the growth of CD18 and Panc1 cells in 3D collagen. In contrast, the p38 MAPK inhibitor SB202190 did not attenuate the effect of JQ1 on growth of CD18 and Panc1 cells in 3D collagen. Finally, JQ1 potentiated the effect of gemcitabine on the growth of CD18 and Panc1 cells in 3D collagen. Overall, these results suggest that JQ1 and other bromodomain inhibitors are potential therapeutic agents for the treatment of pancreatic cancer.
Citation Format: Vaibhav Sahai, Krishan Kumar, Kazumi Ebine, Halla Nimeiri, Hidayatullah G. Munshi. The bromodomain inhibitor JQ1 blocks growth of pancreatic cancer cells in 3D collagen. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2449. doi:10.1158/1538-7445.AM2013-2449
Abstract 2456: Discovery of orally active 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes with dual EGFR and HER2 inhibitory activity.
Authors: Connolly Peter J. , Adams Mary , Beck Amanda K. , Emanuel Stuart L. , Fuentes-Pesquera Angel R. , Greenberger Lee M. , Gruninger Robert H. , Hughes Terry V. , Middleton Stephen A. , Moreno-Mazza Sandra , Pandey Niranjan , Wetter Steven K. , Xu Guozhang 
Published: August 2014

Abstract
Growth factor receptors of the ErbB family, especially ErbB1 (EGFR) and ErbB2 (HER2), have attracted considerable attention in recent years as therapeutic targets for the treatment of numerous malignancies including cancers of the lung, colon, and breast, either through blockade of the extracellular ligand binding site by monoclonal antibodies (e.g. anti-EGFR antibodies cetuximab and panitumumab, and anti-HER2 antibody trastuzumab) or inhibition of the intracellular tyrosine kinase domain by small molecule inhibitors (e.g. EGFR kinase inhibitors gefitinib and erlotinib, and dual EGFR/HER2 inhibitor lapatinib). The abundance of small molecule kinase inhibitors in clinical development or on the market attests to the acceptance of ErbB inhibition as a clinically relevant paradigm. Nevertheless, the emergence of resistance mechanisms in ErbB driven or dependent tumors indicates that continued research is required to discover more effective drugs. We previously reported the discovery of JNJ-28871063, a potent inhibitor of EGFR and HER2 kinases in vitro that also showed excellent antitumor efficacy in EGFR (A431 epidermoid carcinoma) and HER2 (N87 gastric carcinoma) overexpressing xenograft models and significant extension of survival in a mouse intracranial tumor model. This compound is a 4-amino-6-arylaminopyrimidine-5-carbaldehyde oxime, a monocyclic chemotype that mimics the traditional bicyclic quinazoline scaffold via an intramolecular hydrogen-bonded pseudocycle involving the adjacent 4-amino and 5-oximino groups. In this study, we present results of a structure-guided analog program designed to optimize in vitro kinase potency and in vivo antitumor efficacy of the pyrimidine-oximes. While substituents on the 6-arylamino group are critical for ErbB inhibitory potency and kinase selectivity, substitution on the oxime oxygen may be changed to modify physico-chemical properties and bioavailability. We will discuss structure-activity relationships for the 5-oximino and 6-arylamino groups as well as the important role played by O-aminoalkyl oxime substituents in improving in vivo activity.
Citation Format: Peter J. Connolly, Mary Adams, Amanda K. Beck, Stuart L. Emanuel, Angel R. Fuentes-Pesquera, Lee M. Greenberger, Robert H. Gruninger, Terry V. Hughes, Stephen A. Middleton, Sandra Moreno-Mazza, Niranjan Pandey, Steven K. Wetter, Guozhang Xu. Discovery of orally active 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes with dual EGFR and HER2 inhibitory activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2456. doi:10.1158/1538-7445.AM2013-2456
Abstract 2457: Ex vivo analysis of novel isoflavanoids (ME-143 and ME-334) in patient derived triple negative breast cancer tumors.
Authors: Praveen Kesavan Nair , Broudy Thomas , Mirsaidi Cyrus , Moreno Ofir , Gold Daniel 
Published: August 2014

Abstract
There is an unmet need for novel effective therapeutics to treat triple negative (ER, PR and Her2 negative) breast cancer in clinics. Phase I clinical studies of 2 novel isoflavonoid investigational drugs, ME-143 and ME-344 have been shown them to be generally well tolerated in patients with solid tumors. ME-143, a next analogue of the investigational anti-cancer drug Phenoxodiol binds at low nanomolar concentrations to a tumor-specific variant of cell surface associated NADH oxidase (tNOX), resulting in caspase activation and apoptotic tumor cell death. ME-344, a second investigational anti-cancer isoflavonoid, is structurally related to ME-143 but functionally distinct. ME-344 is a mitochondrial targeting agent that interferes with tumor cell energy generation resulting in cell death via mitochondrial membrane destabilization and autophagy induction through the disruption of both mTOR1 and mTOR2 upstream and downstream signal transduction pathways. Pre-clinical studies using in vitro cell lines showed significantly high potency for both compounds either when used as single agents or when combined with cytotoxic and targeted anti-cancer agents. The present study investigated the ex vivo efficacy of ME-143 and ME-344 using patient-derived tumor cells from triple negative breast cancer. Tumor tissue was disintegrated into single cell suspension and expanded in mouse as subcutaneous patient-derived xenograft before harvesting for the studies. Mouse tumor cells were disintegrated into single cells and were grown as spheroids to mimic the tumor micro-environment and single agent as well as combination treatments were performed. Using a high content imaging platform, various endpoints were evaluated to compare the efficacies of the drugs. Both ME-143 and ME-344 as single agents showed efficacy in inhibiting cell proliferation as well as colony formation in patient-derived triple negative breast cancer cells while combination of these agents with Cisplatin and Gemcitabine demonstrated additive or synergistic effects. Use of high content imaging has enabled the identification of patient population that has tumor cells resistant to very high doses of drugs. Follow-up studies are planned to characterize the sub-population of cells that are resistant to high dose of these drugs.
Citation Format: Kesavan Nair Praveen, Thomas Broudy, Cyrus Mirsaidi, Ofir Moreno, Daniel Gold. Ex vivo analysis of novel isoflavanoids (ME-143 and ME-334) in patient derived triple negative breast cancer tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2457. doi:10.1158/1538-7445.AM2013-2457
Abstract 246: Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the dynamic equilibrium between cancer stem cells and non-stem cancer cells.
Authors: Kim Seog-Young , Kang Jin W. , Kim Bokyoung , Yoo Young D. , Kwon Yong T. , Lee Yong J. 
Published: August 2014

Abstract
Previous studies have demonstrated that a small subset of cancer cells is capable of tumor initiation. The existence of tumor initiating cancer stem cells (CSCs) has several implications in terms of future cancer treatment and therapies. However, recently, several researchers proposed that differentiated cancer cells (non-CSCs) can convert to stem-like cells to maintain equilibrium. These results imply that removing CSCs may prompt non-CSCs in the tumor to convert into stem cells to maintain the equilibrium. Interleukin-6 (IL-6) has been found to play an important role in the inducible formation of CSCs and their dynamic equilibrium with non-stem cells. In this study, we used CSC-like MDA-MB231 human breast adenocarcinoma cells and their alternate subset non-CSCs to investigate how IL-6 regulates the conversion of non-CSCs to CSCs. CSC-like cells formed mammospheres well, whereas most of non-stem cells died by anoikis and only part of the remaining non-stem cells produced viable mammospheres. Similar results were observed in xenograft tumor formation. Data from cytokine array assay show that IL-6 was secreted from non-CSCs when cells were cultured in ultra-low attachment plates. IL-6 regulates CSC-associated OCT-4 gene expression through the IL-6-JAK1-STAT3 signal transduction pathway in non-CSCs. Inhibiting this pathway by treatment with anti-IL-6 antibody (1 μg/ml) or niclosamide (0.5-2 μM)/LLL12 (5-10 μM) effectively prevented OCT-4 gene expression and suppressed mammosphere formation of non-stem cells. These results suggest that the IL-6-JAK1-STAT3 signal transduction pathway plays an important role in the conversion of non-CSCs into CSCs through regulation of OCT-4 gene expression.
Citation Format: Seog-Young Kim, Jin W. Kang, Bokyoung Kim, Young D. Yoo, Yong T. Kwon, Yong J. Lee. Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the dynamic equilibrium between cancer stem cells and non-stem cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 246. doi:10.1158/1538-7445.AM2013-246
Abstract 2466: Characterization and development of on-target Mcl-1 inhibitors; BH3 profiling provides a valuable drug discovery tool.
Authors: Richard David J. , Carlson Nicole , Pierceall William , Lena Ryan , Bannister Thomas , Hodder Peter , Spicer Timothy , Andreeff Michael , Opferman Joseph , Koss Brian , Kung Andrew , Cardone Michael 
Published: August 2014

Abstract
Anti-apoptotic Bcl-2 family proteins are central to the regulation of the intrinsic apoptotic pathway, and as such constitute an important group of targets with great potential as oncology therapeutics. The Bcl-2 family protein Mcl-1 has been demonstrated to facilitate survival and chemoresistance in multiple myeloma, AML, and other cancers, and agents which affect this pathway have become highly sought after. Currently, however, no therapies exist which directly target Mcl-1. We have identified compounds that target Mcl-1 which may be characterized as both Mcl-1-selective and pan-Mcl-1/Bcl-2 inhibitors. This effort has been facilitated by utilization of the BH3 profiling technology to guide SAR. This assay allows for determination of the mitochondrial priming state of both cell culture samples and primary patient samples. We have demonstrated a correlation between myeloma and leukemia cell line response to treatment with our inhibitors and the mitochondrial priming state of such cell lines. Such correlations have also been shown with respect to the extent of cytochrome C release. In the case of the selective Mcl-1 inhibitor, we have shown that cytochrome C release occurs preferentially in leukemia cell lines which are highly primed for Mcl-1 rather than Bcl-2. In addition, our Mcl-1 selective inhibitor demonstrates enhanced cell killing ability in leukemia cells which have been engineered to selectively express Mcl-1, Bcl-2, and Bcl-xL. Our current lead candidate possesses excellent drug-like properties and displays impressive efficacy in a multiple myeloma disseminated xenograft model. This work demonstrates the utility of the BH3 profiling assay as providing a functional biomarker for drug discovery tool and its ability to validate the on-target activity of Mcl-1 and Bcl-2 inhibitors.
Citation Format: David J. Richard, Nicole Carlson, William Pierceall, Ryan Lena, Thomas Bannister, Peter Hodder, Timothy Spicer, Michael Andreeff, Joseph Opferman, Brian Koss, Andrew Kung, Michael Cardone. Characterization and development of on-target Mcl-1 inhibitors; BH3 profiling provides a valuable drug discovery tool. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2466. doi:10.1158/1538-7445.AM2013-2466