bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A10: Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer.
Authors: Fawdar Shameem , Trotter Eleanor W. , Li Yaoyong , Miller Crispin , Brognard John 
Published: August 2014

Abstract
Approximately 70% of patients with non-small-cell lung cancer present with late-stage disease and have limited treatment options, so there is a pressing need to develop efficacious targeted therapies for these patients. This remains a major challenge as the underlying genetic causes of ~50% of non-small-cell lung cancers remain unknown. We have recently demonstrated that a targeted genetic dependency screen is an efficient approach to identify somatic cancer alterations that are functionally important. By using this approach, we have identified three kinases with gain-of-function mutations in lung cancer, namely FGFR4, MAP3K9, and PAK5 (1). Mutations in these kinases are activating toward the ERK pathway, and targeted depletion of the mutated kinases inhibits proliferation, suppresses constitutive activation of downstream signaling pathways, and results in specific killing of the lung cancer cells. Genomic profiling of patients with lung cancer is ushering in an era of personalized medicine; however, lack of actionable mutations presents a significant hurdle. Our study indicates that targeted genetic dependency screens will be an effective strategy to elucidate somatic variants that are essential for lung cancer cell viability.
Citation Format: Shameem Fawdar, Eleanor W. Trotter, Yaoyong Li, Crispin Miller, John Brognard. Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A10.
Abstract A21: microRNA-200 regulates tumor cell PD-L1 expression to control lung cancer metastasis.
Authors: Gibbons Don L. , Chen Limo , Goswami Sangeeta , Ahn Young-Ho , Byers Lauren A. , Diao Lixia , Wang Jing , Cortez Angelica , Roybal Jonathon , Welsh James , Zhang Xuejun , Dwyer David , Yi Xiaohui , Lieping Chen , Wistuba Ignacio , Heymach John V. , Kurie Jonathan M. , Qin F. Xiao-Feng 
Published: August 2014

Abstract
Background: Tumor cell regulation of the recruitment and activity of diverse inflammatory cells creates an immunosuppressive microenvironment that favors both tumor growth and metastasis. However, the mechanistic basis of how tumor cells trigger intra-tumoral immunosuppression have not been fully defined. Here we show that metastasis-prone lung adenocarcinoma cells suppress the proliferation and activity of intra-tumoral CD8+ T cells through a PD-L1 dependent mechanism and that PD-L1 expression is regulated by microRNA-200 (miR-200), a known mediator of tumor cell EMT.
Results: Analysis of patient tumors from The Cancer Genome Atlas (TCGA) (230 adenocarcinomas) and a large MDACC cohort of resected tumors (N&gt;150) demonstrated that tumors with a mesenchymal gene expression signature had repression of miR-200 family expression and higher levels of PD-L1 expression. These findings were confirmed experimentally in human and murine NSCLC cell lines. In vivo experiments with a Kras/p53 mutant mouse model of lung adenocarcinoma showed that decreased miR-200 led to increased expression of PD-L1 levels on tumor cells, causing profound CD8+ T cell suppression. Upon suppression of CD8+ T cell activity tumors acquired a growth advantage and metastatic capability. Confirmation of these results with the LLC model in PD-L1 knockout mice also demonstrated that PD-L1 expression on the tumor cells, rather than other cells in the tumor microenvironment, was critical to defining tumor immunity and metastastic ability. The metastases could be suppressed by genetic and pharmacologic blockade of PD-L1.
Conclusion: Our findings demonstrate a novel biological role for miR-200 in cancer cells by simultaneous control of the cell-intrinsic EMT program and the cell-non-autonomous PD-L1-mediated immune evasion. These findings support further investigation into the mechanistic effects of miR-200 on metastasis and the use of specific EMT-related biomarkers to select immunomodulatory therapies.
Citation Format: Don L. Gibbons, Limo Chen, Sangeeta Goswami, Young-Ho Ahn, Lauren A. Byers, Lixia Diao, Jing Wang, Angelica Cortez, Jonathon Roybal, James Welsh, Xuejun Zhang, David Dwyer, Xiaohui Yi, Chen Lieping, Ignacio Wistuba, John V. Heymach, Jonathan M. Kurie, F. Xiao-Feng Qin. microRNA-200 regulates tumor cell PD-L1 expression to control lung cancer metastasis. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A21.
Abstract A23: Noxa determines localization and stability of MCL-1 and consequently ABT-737 sensitivity in small cell lung cancer.
Authors: Nakajima Wataru , Hicks Mark A. , Tanaka Nobuyuki , Krystal Geoffrey W. , Harada Hisashi 
Published: August 2014

Abstract
Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancers diagnosed in the US and causes a fatality rate of more than 90%. Over the past 25 years, progress has been made in limited stage SCLC, where the combination of concurrent radiation and chemotherapy has resulted in a long term survival rate of 20-25%. However, progress has been slow in extensive SCLC (70% of all cases), with long term survival rates of approximately 3% when treated with a variety of multi-agent chemotherapy regimens.
Tumor cell death induced by chemotherapy or lack of appropriate cellular survival signals is mediated by the intrinsic apoptotic pathway. We and others have demonstrated that the anti-apoptotic member BCL-2, as well as BCL-XL and MCL-1, is overexpressed in SCLC. However, until recently, the precise role of these proteins in SCLC biology and therapeutic resistance was poorly understood. The breakthrough came with the development of BH3 mimetic antagonists that block the function of pro-survival BCL-2 family members. ABT-737, the prototype of this new drug class, binds to and blocks BCL-2 and BCL-XL, but not MCL-1 function. Surprisingly, the sensitivity to ABT-737 varies in a broad range in SCLC cells. We have previously shown that the expression of Noxa, a BH3-only pro-apoptotic BCL-2 family protein, is the critical determinant of ABT-737 sensitivity. We show here that Noxa regulates the localization and stability of MCL-1, an anti-apoptotic member, which results in modulating ABT-737 sensitivity. Mutations in Noxa within either the BH3 domain, the carboxyl terminus mitochondrial targeting domain, or of ubiquitinated lysines not only change the localization and stability of Noxa itself, but also affect the mitochondrial localization and phosphorylation/ubiquitination status of MCL-1 and consequently modulate sensitivity to ABT-737. Results of studies utilizing these mutant proteins indicate that Noxa recruits MCL-1 from the cytosol to the mitochondria. Translocation of MCL-1 initiates its phosphorylation and subsequent ubiquitination, which triggers proteasome-mediated degradation. The precise regulatory mechanisms of Noxa/MCL-1 expression and stability could provide alternative targets to modulate apoptosis induced by BH3 mimetic drugs or other chemotherapeutic reagents.
Citation Format: Wataru Nakajima, Mark A. Hicks, Nobuyuki Tanaka, Geoffrey W. Krystal, Hisashi Harada. Noxa determines localization and stability of MCL-1 and consequently ABT-737 sensitivity in small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A23.
Abstract A31: Comparison of direct sequencing and peptide nucleic acid clamping of EGFR gene in patients with non-small cell lung cancer.
Authors: Kim Young-Chul , Yoon Seong-Hoon , Choi Yoo-Duk , Oh In-Jae , Kim Kyu-Sik , Lee Bo-Ram , Yu Jin-Yeong , Lee Min-Ki 
Published: August 2014

Abstract
Background: Direct sequencing is considered as a gold standard for the detection of epidermal growth factor receptor (EGFR) gene mutation in non-small cell lung cancer (NSCLC), but low sensitivity is a problem. The aim of this study is to prove higher detection rate of EGFR mutation with peptide nucleic acid (PNA) clamping compared to direct sequencing.
Methods: This is a single arm, open label, prospective, observational study for patients with stage IIIB, IV or relapsed NSCLC. A sample size of 140 pairs will have 90% power to detect a difference in proportions of 0.1 when the proportion of discordant pairs is expected to be 0.16 and the method of analysis is a McNemar's test of equality of paired proportions with a 0.05 one-sided significance level and 20% drop out rate. Tumor DNA samples were obtained from paraffin block or cytology specimen. Both direct sequencing and PNA clamping for EGFR gene in exon 18, 19, 20 and 21 were performed.
Results: Of 138 paired test sets, 24 mutations of EGFR gene were detected by direct sequencing (17.4%) and 45 mutations were detected by PNA clamping (32.6%). The difference of detection rate between two methods was 15.2% (95% Confidence Interval: 8.7-17.8%, p&lt;0.001). After treatment with EGFR-tyrosine kinase inhibitors, 20 of 26 response evaluable patients with EGFR mutation by PNA clamping showed partial responses (PR, 76.9%). And 8 among 13 patients with EGFR mutation by direct sequencing showed PR (61.5%).
Conclusion: This study proved that PNA clamping has significantly higher detection rate of EGFR mutation compared with direct sequencing. (ClinicalTrials.gov number, NCT01767974)
Citation Format: Young-Chul Kim, Seong-Hoon Yoon, Yoo-Duk Choi, In-Jae Oh, Kyu-Sik Kim, Bo-Ram Lee, Jin-Yeong Yu, Min-Ki Lee. Comparison of direct sequencing and peptide nucleic acid clamping of EGFR gene in patients with non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A31.
Abstract B04: Targeting CREB-CBP transcription factor complex using small molecule inhibitors with multifunctional anticancer mechanisms.
Authors: Lee Jong Woo , Park Hee Sun , Park Sin-aye , Herbst Roy S. , Koo Jaseok Peter 
Published: August 2014

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR03) of the Conference Proceedings.
Citation Format: Jong Woo Lee, Hee Sun Park, Sin-aye Park, Roy S. Herbst, Jaseok Peter Koo. Targeting CREB-CBP transcription factor complex using small molecule inhibitors with multifunctional anticancer mechanisms. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B04.
Abstract IA02: A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer.
Authors: Jahchan Nadine , Joel Dudley , Mazur Pawel , Neal Joel , Khatri Purvesh , Butte Atul , Sage Julien 
Published: August 2014

Abstract
Small cell lung carcinoma (SCLC) is highly aggressive and metastatic neuroendocrine lung cancer with a dismal 5-year survival. While a majority of patients is initially responsive to chemotherapy, chemoresistant tumors rapidly recur. There are no approved targeted therapies for SCLC. We used a systematic drug-repurposing computational approach querying a large number of gene expression datasets to identify new candidate FDA-approved drugs that may be used to treat SCLC. This analysis identified tricyclic antidepressants (TCAs) and related molecules as possible inhibitors of SCLC. Indeed, these compounds potently induce apoptotic cell death in chemonaïve and chemoresistant tumor cells in culture, in a genetically engineered mouse model, and in human SCLC tumor cells transplanted into immunocompromised mice. Imipramine and Promethazine, the two top candidate drugs, activate stress pathways and induce apoptosis and necrosis in SCLC cells, in part by blocking autocrine survival signals involving neurotransmitters and their receptors (GPCRs). The candidate drugs inhibit the expansion of other neuroendocrine tumors, including pancreatic neuroendocrine tumors. These experiments underscore the power of bioinformatics-based drug-repositioning approaches to rapidly repurpose FDA-approved drugs and identify a novel class of candidate molecules to treat patients with SCLC. In addition, our experiments highlight the importance of autocrine mechanisms promoting the growth of neuroendocrine tumor cells.
Citation Format: Nadine Jahchan, Dudley Joel, Pawel Mazur, Joel Neal, Purvesh Khatri, Atul Butte, Julien Sage. A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA02.
Abstract A24: A possible role for GSK3β in epithelial ovarian cancer chemoresistance by epigenetic regulation
Authors: Cutter Noelle L. , Yacoub Mena , Lucito Robert D. , Dimitrova Nevenka , Lum Elena , Vigliotti Michael , Wrzeszczynski Kazimierz , Levine Douglas A. 
Published: August 2014

Abstract
Ovarian cancers are highly heterogeneous and while chemotherapy is the preferred treatment many patients are intrinsically resistant or quickly develop resistance. Furthermore, all tumors that recur ultimately become resistant. Recent evidence suggests that epigenetic deregulation may be a key factor in the onset and maintenance of chemoresistance. We set out to identify epigenetically silenced genes that affect chemoresistance. The epigenomes of a total of 45 ovarian samples were analyzed to identify epigenetically altered genes that segregate with platinum response, and further filtered with expression data to identify genes that were suppressed. A tissue culture carboplatin resistance screen was utilized to functionally validate this set of candidate platinum resistance genes. Our screen correctly identified 19 genes that when suppressed altered the chemoresistance of the cells in culture. Of the genes identified in the screen we further characterized one gene, Glycogen Synthase Kinase 3 Beta (GSK3β), a proline-directed serine-threonine kinase, to determine if we could determine the mechanism by which it increased resistance. Preliminary results have indicated that the loss of GSK3b decreased the level of apoptosis in response to carboplatin. Furthermore, ovarian cell lines transcriptionally silenced for GSK3β are more invasive, have migratory ability, and display a transformed epithelial to mesenchymal (EMT) phenotype. Taken together, we provide the evidence of a role for GSK3β as an important epigenetic regulator of chemoresistance in ovarian cancer and hypothesize EMT as one of the underlying mechanisms.
Citation Format: Noelle L. Cutter, Mena Yacoub, Robert D. Lucito, Nevenka Dimitrova, Elena Lum, Michael Vigliotti, Kazimierz Wrzeszczynski, Douglas A. Levine. A possible role for GSK3β in epithelial ovarian cancer chemoresistance by epigenetic regulation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A24.
Abstract A42: An albumin leader sequence coupled with a cleavage site modification enhances the yield of recombinant c-terminal Mullerian inhibiting substance
Authors: Pepin David , Hoeng Mien , Nicolaou Fotini , Hendren Katherine , Benedict Leo , Sosulski Amanda , Al-Moujahed Ahmad , Vavvas Demetrious , Donahoe Patricia K. 
Published: August 2014

Abstract
Mullerian Inhibiting Substance (MIS) has been shown to inhibit ovarian cancer cells both in-vitro and in-vivo. MIS inhibits a putative ovarian cancer progenitor cell population enriched by a panel of CD44+, CD24+, Ep-CAM+, and E-cadherin- cell surface markers. In order to accommodate clinical testing of MIS in ovarian cancer patients, the production of recombinant human MIS must be optimized to increase yield and purity. Here, we show that the substitution of the MIS leader sequence to that of human serum albumin (HSAL), combined with a modification of the endogenous cleavage site from RAQR/S to a furin/kex2 RARR/S consensus site results in high expression, increased c-terminus cleavage and a reduction in unwanted cryptic internal cleavage products when produced in CHO cells. Purified MIS containing the HSAL modification displays increased potency to induce regression of the Mullerian duct in fetal rat embryonic urogenital ridge assays, reflecting the increased cleavage. The modifications herein described, which may be applicable to other TGF-beta family members, will facilitate production of active recombinant c-terminal MIS for clinical trials in ovarian cancer.
Citation Format: David Pepin, Mien Hoeng, Fotini Nicolaou, Katherine Hendren, Leo Benedict, Amanda Sosulski, Ahmad Al-Moujahed, Demetrious Vavvas, Patricia K. Donahoe. An albumin leader sequence coupled with a cleavage site modification enhances the yield of recombinant c-terminal Mullerian inhibiting substance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A42.
Abstract A73: A bioengineered ovarian cancer microenvironment to assess protease-associated functions
Authors: Loessner Daniela , Rizzi Simone C. , Stok Kathryn S. , Magdolen Viktor , Hutmacher Dietmar W. , Clements Judith A. 
Published: August 2014

Abstract
Cancer-associated proteases promote peritoneal dissemination and chemoresistance in malignant progression. In this study, kallikrein-related peptidases 4, 5, 6, and 7 (KLK4-7)-cotransfected ovarian cancer cells were embedded in a bioengineered three-dimensional (3D) microenvironment that contains RGD motifs for integrin engagement to analyse their spheroid growth and survival after chemotreatment. KLK4-7-cotransfected cells formed larger spheroids and proliferated more than controls in 3D, particularly within RGD-functionalized matrices, which was reduced upon integrin inhibition. In contrast, KLK4-7-expressing cell monolayers proliferated less than controls, emphasising the relevance of the 3D microenvironment and integrin engagement. In a spheroid-based animal model, KLK4-7-overexpression induced tumor growth after 4 weeks and intraperitoneal spread after 8 weeks. Upon paclitaxel administration, KLK4-7-expressing tumors declined in size and showed less metastatic outgrowth. KLK4-7-expressing spheroids showed 53% survival upon paclitaxel treatment, accompanied by enhanced chemoresistance-related factors; their survival was further reduced by combination treatment of paclitaxel with KLK (22%) or MAPK (6%) inhibition. The concomitant presence of KLK4-7 in ovarian cancer cells together with integrin activation drives spheroid formation and proliferation. Combinatorial approaches of paclitaxel and KLK/MAPK inhibition may be more efficient for late-stage disease than chemotherapeutics alone as these inhibitory regimens reduced cancer spheroid growth to a greater extent than paclitaxel alone.
Citation Format: Daniela Loessner, Simone C. Rizzi, Kathryn S. Stok, Viktor Magdolen, Dietmar W. Hutmacher, Judith A. Clements. A bioengineered ovarian cancer microenvironment to assess protease-associated functions. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A73.
Abstract A75: miR-200 family in endometriosis-associated ovarian cancer
Authors: Suryawanshi Swati , Vlad Anda , Edwards Robert , Budiu Raluca , Huang Xin 
Published: August 2014

Abstract
Introduction: Epithelial ovarian cancer (EOC) is detected in late stages, when mortality is high due to the lack of an effective screening modality. One of the possible accepted precursors for endometrioid, clear cell and low grade serous ovarian tumors is endometriosis, a chronic inflammatory disease that can affect up to 10-15% of women in the reproductive age group. MicroRNAs (miRNAs) are important regulators of numerous biological pathways. In the current study, we investigated role of miRNAs in the transition from benign endometriosis to cellular atypia and to malignancies.
Experimental procedure: We extracted RNA from 150 paraffin tissue blocks comprising of normal endometrium (n=31), benign endometriosis consisting of ovarian and extra ovarian endometriosis cases (n=32,) atypical endometriosis (n=15) and endometriosis associated ovarian cancer, consisting of clear cell and endometrioid ovarian cancer cases (n=41). Serous tumors (n=15) were included as non-endometriosis associated controls. Using NanoString miRNA Expression Assay, we globally profiled the expression of 800 miRNAs in these samples. Cluster analyses and differential expressions (DE) were calculated using EdgeR. We also validated our NanoString results across all disease categories by miRNA real-time PCR assays.
Results: Many miRNAs are dysregulated in atypical endometriosis and cancer samples. Interestingly, several novel miRNAs have been identified that are predicted to regulate genes that may promote carcinogenesis in endometriosis, such as genes involved in estrogen signaling pathways and immune response. Among these miRNAs, differential expression of the miR-200 family between healthy controls and patients with endometriosis and EAOC is particularly intriguing. The miR-200 family of microRNAs consisting of miR-200a, 200b, 200c, 141 and 205, functions in various biological and pathological processes, especially on cellular oxidative stress response and during epithelial to mesenchymal transition (EMT). Our analysis demonstrated that expression of miR-200 family members is downregulated in endometriosis and highly upregulated in EAOC tissue as compared to normal tissues.
Conclusion: Our global miRNA profiling results suggest that miR-200 family potentially plays an important role during the transition from benign endometriosis to endometriosis-associated ovarian cancer.
Citation Format: Swati Suryawanshi, Anda Vlad, Robert Edwards, Raluca Budiu, Xin Huang. miR-200 family in endometriosis-associated ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A75.