bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B65: Profiling and characterization of ethnicity-associated metabolic pathways in breast cancer.
Authors: Terunuma Atsushi , Putluri Nagireddy , Samanta Susmita , Mishra Prachi , Mathe Ewy , Dorsey Tiffany H. , Kittles Rick , Ambs Stefan
Published: August 2014

Large variations in breast cancer incidence and survival among the various population groups in the United States continue to exist and differences in the clinical presentation of the disease between African American (AA) and European-American women have been recognized. Specifically, AA develop breast cancer at a relatively younger age, have a two-fold increased risk of developing triple-negative (TN) tumors and present more commonly with the stage IV disease, when compared with EA women. While the precise reasons for this disparity are still debated, genetic, environmental, and health care access/utilization factors may all contribute to the excessive burden of breast cancer among the AA patients. We therefore asked the question whether metabolomic differences in either breast tissue or body fluids may exist between AA and EA women that could help explain the substantial inequality in TN breast cancer-related outcomes.

Metabolomics describes the science of quantifying the levels of metabolites (e.g., small molecules <1kDa) that are the byproducts of cellular metabolism. Metabolomic analysis is less complex than genomic, transcriptomic and proteomic studies (i.e., ~3,000 metabolites vs. 40,000 genes, 150,000 transcripts and 1x106 proteins) and may accentuate subtle upstream gene/protein level alterations. To date, a systematic breast cancer metabolomic analysis focusing on the distinction between AA and EA women has not been reported. Furthermore, a metabolomically derived prognostic model for TN in each of these ethnic groups has not yet been defined. The presentation will discuss our results on profiling and validating the levels of 120 metabolites in both TN breast tumors from AA and EA women and in cell lines representing the two patient groups. A subset of the functional pathways has been characterized for their activity using BIOLOG-based flux assays to identify their role in TN breast cancer. The information gleaned from this study could reveal the biochemical underpinnings of TN breast cancer health disparity

Citation Format: Atsushi Terunuma, Nagireddy Putluri, Susmita Samanta, Prachi Mishra, Ewy Mathe, Tiffany H. Dorsey, Rick Kittles, Stefan Ambs. Profiling and characterization of ethnicity-associated metabolic pathways in breast cancer. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B65.
Abstract B79: Assessing colorectal cancer screening behaviors and knowledge among at-risk Hispanics in southern New Mexico.
Authors: Sanchez Janet , Martinez Vanessa , Thompson Beti , O'Connell Mary
Published: August 2014

Introduction: Colorectal cancer (CRC) mortality rates in New Mexico have not decreased as much as the US national rates, and mortality rates among Hispanics in the state are higher than among this ethnic group in the US.

Methods: A Colorectal Cancer Knowledge Assessment Survey (KAS) was administered in either English or Spanish to 247 individuals attending community events and health fairs throughout southern New Mexico. A subset of these individuals completed an electronic CRC risk assessment managed by National Institutes of Health (NIH) National Cancer Institute (NCI). Data analysis was performed using SPSS (Statistical Package for the Social Sciences) to test for significant differences in knowledge, and/or screening rates based on ethnicity.

Results: There were significant differences among participants > 50 years old based on ethnicity for knowledge about CRC, physician discussions and recommendations, and screening rates. In all cases, with the exception of knowledge of CRC risk, Hispanics of CRC screening age, were less likely to be recommended for screening by their physician, less likely to discuss CRC screening, knew less about CRC and about the different types of screening modalities, and reported CRC screening in the past at about half the rate of their non-Hispanic white counterparts.

Conclusions: The increased mortality rates for New Mexican Hispanics with colorectal cancer are likely due to the very low screening rates, which in turn are related to the lack of knowledge about this condition. Expanded education and outreach efforts for minority populations to increase knowledge and awareness of prevention and screening behaviors is critical.

This work was supported in part by the NM AES and by grants NIH NCI 5 U54CA132383 (O'Connell) and NIH NCI 5 U54CA132381 (Thompson).

Citation Format: Janet Sanchez, Vanessa Martinez, Beti Thompson, Mary O'Connell. Assessing colorectal cancer screening behaviors and knowledge among at-risk Hispanics in southern New Mexico. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B79.
Abstract ED01-04: Advancing the science of recruitment and retention of ethnically diverse populations.
Authors: Nápoles Anna M.
Published: August 2014

We highlight two critical challenges that must be addressed to accelerate the advancement of the science of recruitment and retention of ethnically diverse populations into clinical research. First, we present evidence of the relative lack of attention by researchers to recruitment and retention of ethnically diverse populations. Then, we present data on the inadequacy of dedicated funding to advance systematically this field. To begin to address these challenges, we describe strategies used by the National Institute on Aging (NIA)-funded Resource Centers on Minority Aging Research and other NIA-funded programs to advance the science of recruitment and retention. Finally, we propose broad recommendations for generating a body of evidence on successful methods of recruitment and retention of ethnically diverse populations in clinical research. To eliminate cancer health disparities in ethnically diverse populations, much more research is needed on effective strategies for increasing minority enrollment in cancer research. Experimental studies in the recruitment literature that rigorously test recruitment or retention methods are an exception despite the valuable evidence they contribute. Comparative effectiveness research on recruitment and retention methods designed to address mechanisms of underrepresentation in clinical research will require dedicated funding and concerted efforts by investigators.

Citation Format: Anna M. Nápoles. Advancing the science of recruitment and retention of ethnically diverse populations. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr ED01-04.
Abstract ED02-03: Gaining epidemiologic insights from ancestry associations with cancer risk factors.
Authors: Signorello Lisa B.
Published: August 2014

The ability to estimate ancestry using genetic markers brings the potential for deeper understandings of the biological basis for cancer health disparities but also presents challenges regarding how best to incorporate this information into epidemiologic studies. New insights can be gained by evaluating the association between ancestry and established cancer risk factors. Using an example of African ancestry, strong associations between the level of African ancestry and various cancer-related biomarkers may provide compelling new information that leads to a better understanding of genetic underpinnings of excess cancer burden in the African American population. African ancestry also has the potential, however, to be correlated with sociodemographic, geographic, and/or behavioral factors. Investigators should be cognizant of these potential correlations to avoid misinterpretation of ancestry-related findings.

Citation Format: Lisa B. Signorello. Gaining epidemiologic insights from ancestry associations with cancer risk factors. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr ED02-03.
Abstract PL05-02: Global perspective on the prevention of HPV-related cancers in men: From epidemiology to intervention.
Authors: Giuliano Anna R.
Published: August 2014

HPV causes multiple cancers in both men and women; HPV 16 is a cause of vulvar, vaginal and anal cancers in women, as well as anal, penile, and oropharyngeal cancers in men. While cervical cancer incidence is declining, the incidence of anal cancers and HPV related oropharyngeal cancers is rising. In some regions of the world penile cancer incidence is also increasing. This increase in cancer incidence is occurring for cancers for which there is no routine method for screening and early detection, as there is for cervical cancer. In this presentation the epidemiology of HPV infection in men, and HPV vaccine efficacy in men by race/ethnicity and world region will be presented.

Citation Format: Anna R. Giuliano. Global perspective on the prevention of HPV-related cancers in men: From epidemiology to intervention. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr PL05-02.
Abstract PL05-05: Molecular profiling of stage II and III breast cancer in Latin American women receiving standard-of-care treatment.
Authors: Gomez Jorge
Published: August 2014

The United States-Latin America Cancer Research Network (US-LA CRN) launched its first breast cancer pilot study in 2010 in 29 hospitals and research facilities in Argentina, Brazil, Chile, Mexico, and Uruguay. The primary goal is to characterize molecular profile distribution (luminal A, luminal B, HER2-like, and basal) in Latin American women with non-metastatic stage II or III breast cancer. Molecular profiles are correlated with epidemiological, histological, and clinical data, including pathologic response to standard neoadjuvant chemotherapy. This prospective cohort study (1) will not dispense investigational drugs, (2) will characterize molecular profiles of breast cancer in Latin America and (3) will examine associations between response to neoadjuvant therapy and molecular profiles. Tissue samples for gene expression profiling will be collected during routine core biopsies or surgery. Core biopsies and surgical resection specimens will undergo histopathologic evaluation and tumor ER, PgR, HER2, and Ki67 status assessment. Next, patients will be sorted by hormone receptor and HER2 status and receive standard neoadjuvant chemotherapy. Tissue samples will be re-assessed for residual cancer burden for pathologic response to neoadjuvant treatment and gene expression. Five-year patient follow-up will determine associations between molecular profiles and disease evolution after standard treatment. Besides providing data on the effectiveness of standard chemotherapy in Latin American women, the study will establish biobanks in participating countries to conduct new clinical trials on complex genomic and pathologic biomarkers and investigational therapies. Studying the molecular profile of breast cancer in Latin America will improve diagnosis and treatment, correlate molecular subtypes with long-term survival and response to therapy, and identify indolent-disease subpopulations of cancer patients, perhaps enabling future personalized cancer management. Dr. Gomez will provide outcomes of the study to date and reflect on the implications of creating international biobanking repositories and gene studies in Latin America.

Citation Format: Jorge Gomez. Molecular profiling of stage II and III breast cancer in Latin American women receiving standard-of-care treatment. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr PL05-05.
Abstract PL06-03: Inflammation and cancer: Interweaving microRNA, free radical, innate immune, and p53 networks.
Authors: Harris Curtis C.
Published: August 2014

Infection and chronic inflammation contribute to the etiology and pathogenesis of about 1 in 4 of all cancer cases. Mediators of the inflammatory response, e.g., cytokines, free radicals, prostaglandins, non-coding RNAs, and growth factors, can induce genetic and epigenetic changes including point mutations in tumor suppressor genes, DNA methylation and post-translation modifications, causing alterations in critical pathways responsible for maintaining the normal cellular homeostasis and leading to the development and progression of cancer IL-6 and IL-8 cooperate with microRNA in the induction of cellular senescence in benign tumors and as autocrine growth factors in carcinoma.

Cellular senescence is also a tumor suppressor mechanism of p53. We are studying the molecular mechanisms of cellular senescence in normal and malignant human cells and the role of the telomeric multiprotein complex, shelterin, that includes TRF2 and POT1. Our ongoing studies have revealed that p53 and its endogenous isoforms regulate both specific microRNAs and TRF2 expression as mechanisms of replicative senescence. In addition, POT1 isoforms are functionally diverse in both maintaining telomeric integrity and preventing p53-dependent senescence induced by telomeric shortening. A switch in the expression patterns of p53 isoforms Δ133Np53 and p53beta can cause cellular senescence in vitro and is also associated with the transition of benign to malignant human colon tumors in vivo. A positive feedback between p53 and TRF2 during telomere-damage signaling and cellular senescence has been discovered.

Expression of microRNAs and inflammatory genes are biomarkers of cancer risk, diagnosis, prognosis, and therapeutic outcome. We are especially interested in the interaction of the innate immune pathway with environmental tobacco smoking in lung cancer risk and the interaction of inflammatory cytokines, p53 isoforms, and microRNAs as prognostic classifiers of early stage lung, esophageal, and colon cancer and their functional role in the development of micrometastases.

Citation Format: Curtis C. Harris. Inflammation and cancer: Interweaving microRNA, free radical, innate immune, and p53 networks. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr PL06-03.
Abstract A05: Ubiquilin1 represses migration and epithelial to mesenchymal transition of human non-small cell lung cancer cells.
Authors: Shah Parag P. , Lockwood William W. , Saurabh Kumar , Kurlawala Zimple , Waigel Sabine , Zacharias Wolfgang , Beverly Levi J.
Published: August 2014

Ubiquilin1 (UBQLN1) is a ubiquitin-like domain and a ubiquitin-associated domain containing protein that has been reported to be involved in shuttling proteins to the proteasome, especially during endoplasmic reticulum-associated protein degradation (ERAD). Thus, UBQLN1 function has been shown to be critical for combating a number of neurological disorders caused by protein aggregation, such as Amyotrophic lateral sclerosis (ALS), Alzheimer's disease and Huntington's disease. A role for UBQLN1 in regulating processes involved in tumorigenesis has not been demonstrated. Herein, we show that loss of UBQLN1 causes increased cell migration and invasion, actin cytoskeleton reorganization and induction of epithelial mesenchymal transition (EMT). Loss of UBQLN1 results in a significant decrease in the expression of epithelial markers including E-cadherin and claudin1, whereas expression of mesenchymal markers including Vimentin, Snail and ZEB1 are significantly elevated. Interestingly, we found that ZEB1 is required for induction of mesenchymal-like properties following loss of UBQLN1 and ZEB1 is capable of repressing expression of UBQLN1, suggesting a physiological, reciprocal regulation of EMT by UBQLN1 and ZEB1. Furthermore, we observed that loss of UBQLN1 sensitizes lung cancer cells to treatment with cytotoxic drugs. These observations have potential clinical relevance because the UBQLN1 gene is lost and under-expressed in a large percentage of human cancer cell lines and primary human lung cancer samples. Taken together, our results suggest for the first time a role of UBQLN1 in the regulation of EMT and a potential role in cancer biology and in predictive cancer therapeutics.

Citation Format: Parag P. Shah, William W. Lockwood, Kumar Saurabh, Zimple Kurlawala, Sabine Waigel, Wolfgang Zacharias, Levi J. Beverly. Ubiquilin1 represses migration and epithelial to mesenchymal transition of human non-small cell lung cancer cells. [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 A05.
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

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

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>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

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

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<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

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

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

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

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

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

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.
Abstract A9: A whole-locus sequencing approach to identify polymorphisms associated with juvenile-onset granulosa cell tumor susceptibility in SWR mice
Authors: Dorward Ann M. , Smith Kerri N. , Rabie Zoha , Yaskowiak Edward S. , Reinholdt Laura G.
Published: August 2014

Genes that are fundamental for normal development and regulation of the mammalian ovary have been identified through genetic investigations of unusual cases of altered fecundity, infertility or ovarian pathology in model species. In the SWR/Bm (SWR) inbred mouse, we have mapped three distinct loci on Chromosome (Chr) 4 (Gct1) and Chr X (Gct4, Gct6) that have a deleterious effect on ovarian development leading to the formation of juvenile-onset granulosa cell (GC) tumors. GC tumors in SWR female mice have strong parallels with juvenile-type GC tumors that appear in infants and young girls based on endocrinological, histological and malignant criteria. As such, the genetic and epigenetic determinants for tumorigenic processes operative in SWR mice will provide novel information for translational investigations of human juvenile-type GC tumors.

The Gct1 allele derived from the SWR strain (Gct1SW) is unique in its support of androgen-sensitive GC tumor-susceptibility, with the expectation that a unique mutation underlies this trait. The X-linked Gct4 locus is a modifier locus for early-onset GC tumorigenesis, acting in conjunction with the Gct1 allele to enhance or diminish tumor susceptibility with a strong paternal, parent-of-origin effect. The X-linked Gct6 locus harbors a tumor suppressor for GC tumorigenesis, with a unique allele contributed by the Castaneus mouse strain. Forward genetic crosses and congenic strain mapping have resolved the candidate gene intervals for Gct1, Gct4 and Gct6 to 1.31, 1.34 and 1.02 Mb, respectively. It was our goal to evaluate all potential protein-coding or regulatory sequence polymorphisms between the GC tumor-sensitive SWR inbred strain and SWR-derived congenic strains that are resistant to androgen-inducible GC tumorigenesis. The individual locus regions were subsequently captured in a custom library approach prior to high-throughput, next generation sequencing. Informatics analyses of all polymorphisms are underway in the search for unique variants that will be investigated for their causal role in GC tumor susceptibility in this mouse model. For the Gct1SW locus, protein-coding variants have been excluded by our analysis, suggesting that regulatory variant(s) support the juvenile-onset GC tumor susceptible phenotype.

Citation Format: Ann M. Dorward, Kerri N. Smith, Zoha Rabie, Edward S. Yaskowiak, Laura G. Reinholdt. A whole-locus sequencing approach to identify polymorphisms associated with juvenile-onset granulosa cell tumor susceptibility in SWR mice. [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 A9.
Abstract B29: The role of C-Terminal Binding Proteins in BRCA1 silencing and genetic instability of ovarian cancer cells
Authors: Liu Shubai , Yang Junzheng , May Taymaa , Hua Yuanyuan , Lu Shi , Elias Kevin , Drapkin Ronny , Welch William , Crum Christopher , Berkowitz Ross S. , Ng Shu-Wing
Published: August 2014

Objective: Ovarian cancer is the leading cause of mortality from gynecological malignancy in Western countries. High-grade serous ovarian carcinoma (HGSOC) is characterized by genetic instability and frequently harbors defects in genes such as BRCA1 for homologous recombination (HR) pathway. Our group recently demonstrated that the transcriptional co-repressors, C-Terminal Binding Proteins (CtBP1 and CtBP2), are overexpressed in epithelial ovarian carcinoma and CtBP2 overexpression is associated with poor patient survival. We sought to relate the expression of CtBP to genetic instability and chemoresponse in HGSOC cells.

Methods: Gene expression profiling was performed for the control and CtBP2-knockdown ovarian cancer cell lines. Chromatin Immunoprecipitation (ChIP)-qPCR assays and a BRCA1 promoter-luciferase reporter assay were performed to compare the binding of CtBP complex to BRCA1 promoter and the activity of BRCA1 promoter in the ovarian cancer cells. Cell cycle status of the cell lines was determined by flow cytometry. DNA double-strand breaks (DSB) were determined by comet assay.

esults: Analysis of gene expression profiles revealed potential functions of CtBP2 in silencing the expression of a panel of genes such as BRCA1 and Fanconi anemia complementation group gene FANCD2 that are involved in HR pathway, cell cycle checkpoints, and genetic instability. ChIP analyses and the luciferase assays strongly suggest that the CtBP2 complex binds to the BRCA1 promoter and represses BRCA1 transcription. Ovarian cancer cell lines with knockdown of either CtBP1 or CtBP2 showed increased expression of BRCA1 protein. CtBP2-knockdown ovarian cancer cells showed increased apoptosis and arrest in cell cycle. These cell lines also showed a significant increase in DSB after gamma irradiation than wild-type control cells in a comet assay.

Conclusions: CtBP1 and CtBP2 function in the suppression of a panel of target genes such as BRCA1 and FANCD2 that are involved in cell cycle checkpoints and HR pathway. CtBP-mediated BRCA1 silencing may be a significant contributing mechanism for genetic instability and clinicopathologic development of HGSOC. Targeting this epigenetic mechanism may enhance the sensitivity of HGSOC to DNA damaging agents and contribute to improved outcome of ovarian cancer patients.

Citation Format: Shubai Liu, Junzheng Yang, Taymaa May, Yuanyuan Hua, Shi Lu, Kevin Elias, Ronny Drapkin, William Welch, Christopher Crum, Ross S. Berkowitz, Shu-Wing Ng. The role of C-Terminal Binding Proteins in BRCA1 silencing and genetic instability of ovarian cancer cells. [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 B29.