bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B74: Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors
Authors: Labidi-Galy Intidhar , Clauss Adam , Ng Vivian , Duraisamy Sekhar , Elias Kevin M. , Bilal Erhan , Davidowitz Rachel A. , Lu Yiling , Badalian-Very Gayane , Piao Hui-Ying , Kang Un-Beom , Ficarro Scott , Ganesan Shridar , Mills Gordon B. , Marto Jarrod , Drapkin Ronny 
Published: August 2014

Abstract
High grade serous ovarian carcinoma (HGSOC) and basal-like breast cancer (BLBC) share many features including TP53 mutations, genomic instability and poor prognosis. We recently reported that Elafin is overexpressed by HGSOC and is associated with poor overall survival. Here, we confirmed that Elafin overexpression is associated with shorter survival in 1000 HGSOC patients. Elafin confers a proliferative advantage to tumor cells through activation of the MAP kinase pathway. This mitogenic effect can be neutralized by RNA interference, specific antibodies, and a MEK inhibitor. Elafin expression in patient-derived samples was also associated with chemoresistance and strongly correlates with bcl-xL expression. We translated these findings into examination of 1100 primary breast tumors and 6 breast cancer cell lines. We observed that Elafin is overexpressed and secreted specifically by BLBC tumors and cell lines, leading to a similar mitogenic effect through activation of the MAP kinase pathway. Here too, Elafin overexpression is associated with shorter overall survival, suggesting that it may serve as a biomarker or therapeutic target in this setting.
Citation Format: Intidhar Labidi-Galy, Adam Clauss, Vivian Ng, Sekhar Duraisamy, Kevin M. Elias, Erhan Bilal, Rachel A. Davidowitz, Yiling Lu, Gayane Badalian-Very, Hui-Ying Piao, Un-Beom Kang, Scott Ficarro, Shridar Ganesan, Gordon B. Mills, Jarrod Marto, Ronny Drapkin. Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors. [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 B74.
Abstract IA11: Using publicly available databases for the functional characterization of cancer genes
Authors: Cheon Dong-Joo , Beach Jessica , Tong Yunguang , Cui Xiaojiang , Tighiouart Mourad , Liu Zhenqiu , Walts Ann E. , Karlan Beth Y. , Orsulic Sandra 
Published: August 2014

Abstract
It is now known that tumors are complex ‘organs’ consisting of multiple malignant and nonmalignant cells, blood vessels, and many other cell types, which are frequently lumped together as tumor stroma because their individual characteristics and roles in tumor progression and metastasis are not well defined. Despite the universal presence of cancer-associated stroma in solid tumors and wide clinical use as a prognostic marker, the origin of stromal cells in tumors is still the subject of extensive debate. The dynamic bi-directional interaction between the cancer cells and stroma is also not well understood although it is becoming increasingly apparent that the stroma can modify the aggressiveness of tumor cells and that tumor cells re-program the stroma to generate a nurturing microenvironment that is crucial for tumor survival, progression, and metastasis. Because of the prominent role of stroma in most aspects of tumor progression, it is believed that rational anticancer therapy design should not only target the cancer cells but also the stroma. Therefore, a better understanding of the cancer-stroma interaction and the identification of molecular events whose disruption may undermine tumor progression are required steps toward successful anticancer therapy.
Most public expression profile databases contain information from tumors with variable amounts of stroma. Thus, a snapshot of cross-signaling between cancer and stroma is captured in such transcription profiles although it is difficult to deconvolve the source and direction of the signals. The intensities of the signals are also difficult to determine because analysis of total mRNA from tissues dampens signals from rare cell types, such as cancer stem cells and activated fibroblasts. Expression profile databases that contain laser capture-microdissected samples or single-cell samples provide more information about specific cell types but typically suffer from a small number of patient samples. Through integration of multiple expression profile databases, we identified a set of highly co-regulated genes that are associated with poor patient survival. These genes are induced as a result of the epithelial-stromal interaction and define a microenvironment that serves as a favorable niche for ovarian cancer stem cells, thereby leading to chemotherapy resistance and metastasis and, ultimately, poor overall survival.
Citation Format: Dong-Joo Cheon, Jessica Beach, Yunguang Tong, Xiaojiang Cui, Mourad Tighiouart, Zhenqiu Liu, Ann E. Walts, Beth Y. Karlan, Sandra Orsulic. Using publicly available databases for the functional characterization of cancer genes. [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 IA11.
Abstract IA25: Immunotherapy opportunities and challenges in ovarian cancer
Authors: Coukos George 
Published: August 2014

Abstract
Epithelial ovarian cancer (EOC) cells are antigenic and express a multitude of proteins that have been validated as known tumor-associated antigens (TAAs) including Her-2/neu, p53, NY-ESO-1, cdr2, hTERT, mesothelin, survivin, SP-17, WT1 and others. Clinical data indicate that the immune system affects the outcome of patients with EOC; the presence of intraepithelial tumor-infiltrating lymphocytes correlates with improved progression-free and overall survival, as shown by numerous correlative studies conducted on hundreds of ovarian cancer samples. Tumor infiltrating lymphocytes (TILs) isolated from ovarian cancers are oligoclonal, recognize autologous tumor, are specific to known TAAs ex vivo, and exhibit tumor-specific cytolytic activity. Tumor-specific T-cell precursors can also be detected in the blood of patients with advanced ovarian carcinoma. These observations suggest that activation of antitumor immunity could be feasible and could produce clinical results in patients with EOC. To date, immunotherapy investigations with intraperitoneal IL-2 infusion, CTLA-4 antibody, vaccines using NY-ESO-1 peptide, virus-modified autologous tumor cells, or dendritic cells (DCs) pulsed with whole autologous tumor lysate have yielded limited but encouraging results in EOC. We will review lessons from previous studies and will discuss various opportunities and challenges in the development of effective immunotherapy for EOC.
Citation Format: George Coukos. Immunotherapy opportunities and challenges in 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 IA25.
Abstract IA5: Discovering the distal fallopian tube as the origin for high-grade serous ovarian cancer
Authors: Drapkin Ronny 
Published: August 2014

Abstract
Recent developments in the study of epithelial ovarian cancer have called into question the traditional views regarding the site of tumor initiation. Histopathologic studies and genomic analyses suggest that extra-ovarian sites, like the fallopian tube (FT) epithelium, may harbor the coveted cell of origin and could therefore contribute significantly to the development of high-grade serous ovarian carcinoma (HGSOC). Our ability to validate these emerging genomic and pathologic observations and characterize the early transformation events of HGSOC hinges on the development of novel model systems.
The tubal hypothesis of serous tumorigenesis has led us to develop a number of experimental platforms. These platforms provide us with a unique view into the susceptibilities of the FT epithelium to neoplastic transformation and provide a vehicle to query the contribution of any given genetic alteration to tumor development in vitro and in vivo. These models include the ex-vivo bioanalytical platform of benign FT epithelium, the in vitro FT secretory cell transformation model, a series of patient-derived primary tumor xenograft (PDX) models that retain the phenotypic and genotypic properties of the original patient tumors, and a genetically-engineered mouse model (GEMM) that specifically targets the FT epithelium in vivo.
Our GEM model specifically targets the Müllerian secretory cell. It uses the Pax8 promoter to drive expression of the Cre recombinase in the fallopian tube (FT) secretory cells. Pax8 is a lineage marker for the Müllerian system. It is necessary for the development of the female reproductive tract and its expression is retained in the adult FT secretory cell and in nearly all HGSOCs. By crossing our Pax8-Cre deletor mouse with mice carrying floxed alleles of BRCA genes, TP53 (or mutant) and/or PTEN, we could specifically manipulate the expression of these genes in the FT secretory cell. Using this approach, in collaboration with the laboratory of Daniela Dinulescu, we showed that HGSOC can originate in secretory cell of the FT and also established that serous tubal intraepithelial carcinoma (STIC) is the precursor lesion to high-grade serous ovarian and peritoneal carcinomas. Importantly, the tumors that arise in this model not only look like high-grade serous carcinomas but they also retain the genomic complexity that is a hallmark of human HGSOC. In addition to providing mechanistic insight into the origin and pathogenesis of HGSC, this model provides a platform to explore HGSOC sensitivity to novel therapeutic strategies and to develop better detection strategies for early tumor diagnosis in high-risk women.
Citation Format: Ronny Drapkin. Discovering the distal fallopian tube as the origin for high-grade serous 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 IA5.
Prostate Cancer Cell Response to Paclitaxel Is Affected by Abnormally Expressed Securin PTTG1
Authors: Castilla Carolina , Flores M. Luz , Medina Rafael , Pérez-Valderrama Begoña , Romero Francisco , Tortolero María , Japón Miguel A. , Sáez Carmen 
Published: August 2014

Abstract
PTTG1 protein, the human securin, has a central role in sister chromatid separation during mitosis, and its altered expression has been reported in many tumor types. Paclitaxel is a widely used chemotherapeutic drug, whose mechanism of action is related to its ability to arrest cells in mitosis and the subsequent induction of the intrinsic apoptotic pathway. By using two prostate cancer cell lines with different responses to paclitaxel treatment, we have identified two situations in which PTTG1 influences cell fate differentially. In slippage-prone PC3 cells, both PTTG1 downregulation and overexpression induce an increase in mitotic cells that is associated with diminished apoptosis after paclitaxel treatment. In LNCaP cells, however, PTTG1 downregulation prevents mitotic entry and, subsequently, inhibits mitosis-associated, paclitaxel-induced apoptosis. In contrast, PTTG1 overexpression induces an increase in mitotic cells and apoptosis after paclitaxel treatment. We have also identified a role for Mcl-1 protein in preventing apoptosis during mitosis in PC3 cells, as simultaneous PTTG1 and Mcl-1 silencing enhances mitosis-associated apoptosis after paclitaxel treatment. The finding that a more efficient mitotic arrest alone in PC3 cells is not enough to increase apoptosis was also confirmed with the observation that a selected paclitaxel-resistant PC3 cell line showed an apoptosis-resistant phenotype associated with increased mitosis upon paclitaxel treatment. These findings could contribute to identify putative responsive and nonresponsive cells and help us to approach incomplete responses to paclitaxel in the clinical setting. Mol Cancer Ther; 13(10); 2372–83. ©2014 AACR.
Lipid Catabolism via CPT1 as a Therapeutic Target for Prostate Cancer
Authors: Schlaepfer Isabel R. , Rider Leah , Rodrigues Lindsey Ulkus , Gijón Miguel A. , Pac Colton T. , Romero Lina , Cimic Adela , Sirintrapun S. Joseph , Glodé L. Michael , Eckel Robert H. , Cramer Scott D. 
Published: August 2014

Abstract
Prostate cancer is the most commonly diagnosed malignancy among Western men and accounts for the second leading cause of cancer-related deaths. Prostate cancer tends to grow slowly and recent studies suggest that it relies on lipid fuel more than on aerobic glycolysis. However, the biochemical mechanisms governing the relationships between lipid synthesis, lipid utilization, and cancer growth remain unknown. To address the role of lipid metabolism in prostate cancer, we have used etomoxir and orlistat, clinically safe drugs that block lipid oxidation and lipid synthesis/lipolysis, respectively. Etomoxir is an irreversible inhibitor of the carnitine palmitoyltransferase (CPT1) enzyme that decreases β oxidation in the mitochondria. Combinatorial treatments using etomoxir and orlistat resulted in synergistic decreased viability in LNCaP, VCaP, and patient-derived benign and prostate cancer cells. These effects were associated with decreased androgen receptor expression, decreased mTOR signaling, and increased caspase-3 activation. Knockdown of CPT1A enzyme in LNCaP cells resulted in decreased palmitate oxidation but increased sensitivity to etomoxir, with inactivation of AKT kinase and activation of caspase-3. Systemic treatment with etomoxir in nude mice resulted in decreased xenograft growth over 21 days, underscoring the therapeutic potential of blocking lipid catabolism to decrease prostate cancer tumor growth. Mol Cancer Ther; 13(10); 2361–71. ©2014 AACR.
Abstract A25: Systematic analysis of gene-drug interactions in isogenic cells reveals novel unexpected dependencies in lung cancer cells
Authors: Smida Michal , Cruz Ferran Fece de la , Uras Iris , Nijman. Sebastian MB 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide, killing more people than colon, breast and prostate cancer together. Although the majority of genes that cause lung cancer have been identified, the translation of this knowledge into effective treatments has proven challenging. Thus, an interrogation of functional gene-drug interactions and identification of cancer vulnerabilities for approved or experimental drugs can help bridge the gap between cancer genomics and effective treatments. We constructed a genetically tractable and flexible lung cancer model consisting of a panel of isogenic cell lines that captures parts of the molecular heterogeneity and complexity of lung adenocarcinoma. This panel was screened against a collection of drugs, mainly kinase inhibitors and lung cancer chemotherapeutics. The screen revealed several known or expected gene-drug interactions, thus providing the proof of principle for our approach. For instance, RAS mutant cells were resistant to p38 inhibitors, presumably as RAS is able to activate p38 MAPK. Also the resistance of RAS mutant cells to VEGFR inhibitors can be assigned to the fact that RAS is a downstream effector of VEGFR. On the other hand, we observed that DNA-PK(cs)-deficient cells display hypersensitivity to the DNA-damaging agents etoposide and doxorubicin. Interestingly, we also found strong sensitivity of ATM loss-of-function cells to CHK1/2 inhibitor. As CHK activates DNA-PK(cs) and this substrate was shown to be synthetically lethal with ATM, this may provide plausible explanation for the mechanism. Importantly, we have identified several unexpected vulnerabilities to multiple protein kinase inhibitors that are currently in clinical trials. These sensitivities were consequently reproduced in a panel of patient derived lung cancer cell lines and the physiological relevance was demonstrated. Currently, we are investigating the mechanisms responsible for the exquisite dependency observed. Overall, these data may provide a direct and testable rational to apply these kinase inhibitors in stratified lung cancer patient cohorts with the relevant genetic makeup.
Citation Format: Michal Smida, Ferran Fece de la Cruz, Iris Uras, Sebastian MB Nijman. Systematic analysis of gene-drug interactions in isogenic cells reveals novel unexpected dependencies in lung cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr A25.
Abstract A28: Identification of HDAC inhibitor potentiating targets in acute myeloid leukemia cells by large-scale RNA-interference
Authors: Bogenberger James M. , Rudd James E. , Chow Donald , Kassner Michelle , Yin Holly , Greene Casey S. , Tibes Raoul 
Published: August 2014

Abstract
The lysine deacetylase inhibitor suberoylanilide acid (SAHA) has shown promising but limited activity in the treatment of acute myeloid leukemia (AML). To identify potential targets for rational combination therapies that increase the efficacy of SAHA in AML, we used a functional RNA-interference (RNAi) screening approach to identify genes, that when inhibited, potentiate the in vitro anti-leukemic activity of SAHA. A total of 901 kinase, phosphatase and associated signaling genes were silenced, with four different siRNA sequences per gene, in combination with SAHA treatment. Log2 values of the ratio [(siRNA + SAHA)/(siRNA alone)] were calculated, with median and standard deviation determined on a per-plate basis. Hits were defined as ≥ 2 standard deviations from the log2 ratio median. Hit lists for each cell line were over-laid on an integrated functional relationship network. We applied a community detection algorithm to this sub-network and identified siRNA sensitive modules. Each module represents a highly connected set of genes in the integrated network. To identify the pathways represented by each module, we evaluated enrichment using the National Cancer Institute (NCI) Protein Interaction Database (PID) pathways. Several novel sensitizing targets, grouped into a small number of pathways, emerged from these screens. Some hits exhibit little to no anti-leukemic activity when silenced alone, indicative of synthetic lethal interaction with SAHA treatment. Initial validation experiments with siRNA and novel small molecule inhibitors confirm RNAi screen results and pharmacological sensitization is observed. The first reported large-scale HDAC inhibitor RNAi screen in leukemias has identified a novel rational combination that can be translated into design of a clinical trial.
Citation Format: James M. Bogenberger, James E. Rudd, Donald Chow, Michelle Kassner, Holly Yin, Casey S. Greene, Raoul Tibes. Identification of HDAC inhibitor potentiating targets in acute myeloid leukemia cells by large-scale RNA-interference. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr A28.
Abstract B01: Nonsteroidal anti-inflammatory drugs selectively kill colon cancer cells through a synthetic lethal interaction
Authors: Leibowitz Brian , Moyer Mary P. , Yu Jian , Zhang Lin 
Published: August 2014

Abstract
Colorectal tumorigenesis is initiated by genetic alterations in the APC tumor suppressor pathway. Nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit tumorigenesis by eliminating APC-deficient early pre-malignant cells. However, how and why NSAIDs selectively kill APC-deficient cells while leaving normal cells unharmed has remained elusive. We demonstrate that the NSAID sulindac sulfide initiates death receptor signaling in both colon cancer cells and NCM356 normal colonic epithelial cells, but only induces apoptosis in colon cancer cells and APC-deficient NCM356 cells. Loss of APC leads to down-regulation of c-FLIP, largely due to increased expression of c-Myc. Sulindac sulfide treatment further enhanced down-regulation of c-FLIP. Loss of c-FLIP allows death receptor signaling to progress through caspase-8 and BID cleavage, leading to amplified apoptotic signaling via the mitochondria. Depleting APC in NCM356 cells recapitulates this pathway, and is sufficient to lead to sulindac sulfide-induced apoptosis. Based on these data, we conclude that NSAIDs selectively kill colon cancer cells through a synthetic lethal interaction between death receptor signaling and APC deficiency. These findings potentially open a door to development of more effective colon cancer prevention and treatment strategies.
Citation Format: Brian Leibowitz, Mary P. Moyer, Jian Yu, Lin Zhang. Nonsteroidal anti-inflammatory drugs selectively kill colon cancer cells through a synthetic lethal interaction. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B01.
Abstract B24: Using KRAS synthetic lethality to design novel therapeutic approaches to cancer
Authors: Costa-Cabral Sara , Marinari Eliana , Aarts Marieke , Riffell Jenna L. , Torrence Christopher , Lord Christopher L. , Ashworth Alan 
Published: August 2014

Abstract
Background: KRAS is among the most commonly mutated human cancer genes, and is mutated in approximately 20% of human tumors. In colorectal cancer KRAS mutation is a predictor of anti-EGFR treatment resistance and different KRAS mutations can lead to different anti-EGFR treatment responses. Despite this, KRAS has proven difficult to target with small molecule inhibitors. Identifying synthetic lethal interactions that occur only in the context of tumor specific KRAS mutations represents one approach that could be used to target tumor cells.
Material and methods: To identify KRAS synthetic lethal interactions we have generated functional profiles of constitutively activated KRAS mutant cancers, using an integrated approach that involves cell viability screening. We used a panel of isogenic tumor cell lines carrying different KRAS mutations (G12D, G12S, G12V and G13D) where we performed siRNA screens using a library targeting kinases and kinase-related and tumor suppressor genes. The validation of the siRNA hits was performed in a panel of non-isogenic colorectal and pancreatic cell lines to assess the generality of the effect. By determining the effect on cell viability of each siRNA in each cell model we were able to identify KRAS mutation specific effects.
Results: By using high throughput functional viability profiling in KRAS mutant models we have been able to identify a series of genetic dependencies specific for tumor cells with oncogenic KRAS mutations. We have also some exciting preliminary results with small molecule inhibitors, which target some of the genes that we identified as being critical for the survival of KRAS mutant cancers.
Conclusion: Using functional viability profiling of a series of KRAS isogenic cell lines we have now identified and confirmed several KRAS synthetically lethal candidate genes. Our subsequent work will focus on dissecting of the molecular mechanisms responsible for these KRAS mutant selective effects, and possible combinations with other drugs clinically available.
Citation Format: Sara Costa-Cabral, Eliana Marinari, Marieke Aarts, Jenna L. Riffell, Christopher Torrence, Christopher L. Lord, Alan Ashworth. Using KRAS synthetic lethality to design novel therapeutic approaches to cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B24.