bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B61: Effects of anti-obesity dietary supplement DHEA on serum DHEA, DHEA-S, IGF-1 and IGFBP-3 in DMBA-induced breast cancer model.
Authors: Hakkak Reza , Korourian Soheila
Published: August 2014

Obesity has been epidemic in the US for over two decades. Obesity has been linked to the risk of development of various cancers, including breast cancer. Dehydroepiandrosterone (DHEA) is an over-the-counter dietary supplement used as an anti-cancer agent and anti-obesity supplement. The objectives of this study were to investigate the long-term effects of obesity and DHEA treatment on body weight gain and serum DHEA, DHEA-S, IGF-1and IGFBP-3 using 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor model. Forty-three six-week-old obese female Zucker rats were used. Rats were randomly assigned and had ad libitum access to water and a diet of either chow (2016) as a control diet or chow with the addition of DHEA at a concentration of 6 g/kg of chow as a DHEA diet. All rats were orally gavaged at age 50 days with 65 mg DMBA/kg body weight and were sacrificed 155 days post-DMBA treatment. Fifty-five percent (55%) of the control diet group developed mammary tumors, while no tumors were detected in the DHEA diet group (P<0.001). Obese rats fed the DHEA diet gained significantly less weight (P<0.001) and had an increased (P<0.001) serum DHEA and DHEA-S compared to control rats. Also, obese DHEA-Fed rats had significantly (P<0.001) lower serum IGF-1 and IGF-BP3. Our results suggest that DHEA treatment can reduce body weight gain by lowering serum IGF-1 and IGFBP-3 which might protects against breast cancer development caused by obesity. Also, this results suggests that breast cancer risk may be due to genetic predisposition to obesity might be related to body weight gain. It also suggests that these individuals could potentially reduce their risk by actively combating the weight gain. Supported by ABI to RH.

Citation Format: Reza Hakkak, Soheila Korourian. Effects of anti-obesity dietary supplement DHEA on serum DHEA, DHEA-S, IGF-1 and IGFBP-3 in DMBA-induced breast cancer model. [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 B61.
Abstract B74: Behavioral and social science: Recruitment/retention/adherence research.
Authors: Kanarek Norma F. , Kanarek Marty , Olatoye Dare , Carducci Michael
Published: August 2014

Background: Enrollment in interventional therapeutic clinical trials is a small fraction of all patients who might participate given reasonable access. A case series of new prostate cancer cases are evaluated for their participation in a clinical trial.

Methods: A hierarchical approach is utilized in measuring staged participation from trial availability to patient enrollment. Our framework suggests that concern for justice comes in the design and eligibility criteria for clinical trials; attention to beneficence is given in the eligibility and physician triage stages. The remaining four stages (doctor discussion with the patient, patient interest, patient consent, patient enrolled) rely on respect for persons.

Reasons for nonparticipation or barriers to participation in prostate cancer clinical trials are examined within the seven step framework. Ninety-seven medical oncology patients with an initial six month consultation are tracked from one stage to the next to assess comparability of participation by race.

Results: We illustrated seven transitions from being a patient to enrollment in a clinical trial in a case series of prostate cancer cases who consulted medical oncology in early 2010 (n=97). Pilot data suggest transition probabilities as follows for patients 65% had trial availability, of those 84% were eligible, of those 92% were triaged, of those 100% have trials discussion, of those 51% were interested, of those 71% consented, and of those 94% enrolled. The average transition probability was 77.7%. Trial availability, patient interest and patient consented were three transitions that were below average; none were statistically significant however. We combined steps to obtain the probability of a patient-trial-fit, 50%; the probability of opportunity, 51%; and the probability of acceptance, 66.7%. there were no differences in enrollments by race.

Conclusions: The framework may serve to streamline comprehensive and improved reporting of clinical trial participation to the benefit of patients and toward the ethical conduct of clinical trials. The seven step framework may aid trouble shooting of flagging trial enrollment.

Citation Format: Norma F. Kanarek, Marty Kanarek, Dare Olatoye, Michael Carducci. Behavioral and social science: Recruitment/retention/adherence research. [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 B74.
Abstract ED04-03: Health literacy and health information technology: Promises and pitfalls.
Authors: Sarkar Urmimala
Published: August 2014

Studies of cancer disparities would benefit from attention to health literacy limitations. Both inadequate (i.e., very low) and marginal health literacy (HL) appear to be important factors in the causal pathway to health disparities, especially in low income patients with chronic diseases. Patients with poorer health literacy skills are at greater risk for increased HgA1c & retinopathy, late stage presentation of cancer, depression/anxiety, poor self-rated health status, hospitalization, and mortality. Given the high prevalence (46% of the US population) of inadequate (i.e., very low) plus marginal HL, often described as limited HL and limited literacy's association with poor health outcomes, there has been great interest in including HL assessments in epidemiologic and clinical research. There are several standard health literacy measures including REALM TOFHLA, Newest Vital Sign, and sTOFHLA. Chew and colleagues developed three self-reported HL screening questions and found that a single item (“How confident are you filling out medical forms by yourself?”) may be sufficient to detect patients. As health information technology is burgeoning it is important to consider health literacy implications. A study by Sarkar et al. found that across each function of a patient portal, those reporting limited health literacy were consistently less likely to complete each function. Ensuring universal internet and computer access will become more important than ever. As services migrate to the internet, those most at risk for poor health outcomes are at risk of falling further behind as health systems increasingly rely on patient portal health service functions and limit the alternative modes of access and communication. Additionally, improving the usability of internet-based patient portals, such that those with limited health literacy can navigate them effectively, is critical to realizing health benefits. The internet has potential, via use of audio, graphic, video, and multiple languages, to greatly expand the capacity and reach of health care systems (Institute of Medicine, 2009). However, in the real world, that potential has yet to be realized. Barriers to internet-based health care services require improved technology access as well as tailoring of design and services to reach those with limited health literacy. In summary, interventions to address disparities in cancer screening and treatment should attend to the health literacy limitations of populations in order to improve their reach and effectiveness.

Citation Format: Urmimala Sarkar. Health literacy and health information technology: Promises and pitfalls. [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 ED04-03.
Abstract PL04-02: Genetics and health care disparities caused by smoking.
Authors: Benowitz Neal L.
Published: August 2014

In the U.S., racial/ethnic differences are seen in smoking behavior and related disease risk. Compared to smokers of European ancestry, African Americans smoke fewer cigarettes per day, but take in more nicotine and smoke per cigarette and appear to be more highly dependent. Asians also smoke fewer cigarettes per day put appear to be less dependent than smokers of European ancestry. Lung cancer incidence normalized by cigarettes smoked per day is higher for African Americans and lower in Asians compared to smokers of European Ancestry. Genetic variations in two genes are most strongly associated with smoking behavior and lung cancer risks, and these are found in different frequencies across races. CYP2A6 is the enzyme that is primarily responsible for nicotine metabolism, and is also involved in the bioactivation of the tobacco-specific nitrosamine and lung carcinogen NNK. There are many reduced function variants of the CYP2A6 gene, and these are more frequent in Asians and African Americans compared to those of European ancestry. The presence of reduced function CYP2A6 variants is associated with smoking fewer cigarettes per day and with lower dependence, the latter evidenced by more successful quitting. Among smokers of European ancestry and Asians, reduced function CYP2A6 variants are associated with lower lung cancer risk. However, for unknown reasons, despite having a higher prevalence of reduced function CYP2A6 alleles, African Americans have higher risks for lung cancer. Genes in the nicotine receptor subunit gene cluster CHRNA5-A3-B4 have been associated with lung cancer risk in a number of studies, and have also been associated with nicotine intake and with risk of chronic obstructive lung disease and peripheral arterial disease. It is that believed that the α5 nicotinic receptor subunit influences sensitivity to nicotine; and reduced function of the subunit results in a greater level of nicotine and smoke intake, and therefore a higher level of dependence. Relatively little is known about the effects of this gene cluster on smoking behavior or cancer risk in African Americans or Asians. Among European Ancestry smokers, the CYP2A6 gene and CHRNA5-A3-B4 gene cluster are additively associated with cigarette consumption, nicotine dependence and lung cancer risk. Genetic risk factors are important determinants of racial differences in smoking behavior and lung cancer risk, but explain only a relatively small amount of variation in risk among smokers.

Citation Format: Neal L. Benowitz. Genetics and health care disparities caused by smoking. [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 PL04-02.
Abstract PL04-04: Global tobacco control and disparities in smoking.
Authors: Cohen Joanna
Published: August 2014

Tobacco products are a major cause of death and disease across the globe. These products killed 100 million people in the 20th century, and they are currently responsible for almost 6 million deaths annually. In 2008, more people died from tobacco products than from AIDS, TB, and malaria combined.

If current trends persist, it is estimated that tobacco products will kill more than 8 million people worldwide each year by the year 2030. By the end of this century, tobacco products may kill a billion people or more unless urgent action is taken.

Not only are tobacco products are a major cause of preventable death and disease, but they are also responsible for increasing health disparities. In high income countries, the prevalence of tobacco use is highest among the most disadvantaged segments of society, including those with mental health illnesses, those of low socioeconomic status, and those with comorbidities. But there are also major disparities in the burden of illness from tobacco products across nations, with low and middle income countries (LMIC) bearing the lion's share of the devastating impacts of tobacco products. This presentation will focus on global health disparities caused by tobacco.

Because low and middle income countries are still in the early stages of the tobacco epidemic, they have yet to experience the full impact of tobacco-caused disease and death already evident in wealthier countries where tobacco use has been common for much of the past century. Many of these countries have fewer resources to respond to the health, social and economic problems caused by tobacco use, which will exacerbate the tobacco epidemic's impacts. Tobacco-caused disease and death will hit these countries very hard in the coming decades, absent a strong international effort to combat tobacco use. The good news is that many countries have made great strides in implementing evidence-based tobacco control policies to address this preventable epidemic.

Citation Format: Joanna Cohen. Global tobacco control and disparities in smoking. [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 PL04-04.
Abstract PR04: Prostate cancer risk and dietary folate in a multiethnic population: Higher intake increases risk in the California Collaborative Prostate Cancer Study.
Authors: Rowland Glovioell W. , John Esther M. , Ingles Sue A.
Published: August 2014

Background: High intake of dietary folate has been associated with both increased and decreased risk of prostate cancer in some previous epidemiologic studies which included mostly non-Hispanic white men. Timing of high folate intake may determine its impact on lesion development. In studies of colon cancer, for instance, high dietary folate appears protective in prelesion men, whereas high folate consumption in postlesion men accelerates cancer cell proliferation. We investigated the association between dietary folate intake and risk of advanced and localized prostate cancer among African American and White men from the California Collaborative Prostate Cancer Study.

Methods: We examined 737 African American cases (233 advanced stage at diagnosis; 264 localized) and controls (N=240); and 1357 White cases (905 advanced stage; 452 localized) and controls (N=855). Folate intake during the reference year (1 year prior to diagnosis for cases or study selection for controls) was assessed by modified Block Food Frequency Questionnaire and categorized by quartiles. Risk was estimated by fitting conditional logistic regression models adjusted for race/ethnicity, age, and family history of prostate cancer.

Results: Dietary folate intake was linearly related to risk of prostate cancer (p<0.001). Risk increased by 16% for each increase of one quartile. Men in the upper quartile of intake (>632 mg/day) were at 45% increased risk compared to men in the lowest quartile (OR=1.45, 95% CI 1.16-1.81). The associations for advanced (OR=1.41, 95% CI 1.11, 1.81) and localized (OR=1.57, 95% CI 1.17, 2.11) disease were similar. The results were similar for African Americans and Whites.

Conclusions: Recent high folate intake appears to be a risk factor. Men who consume high levels of dietary folate in the postlesion period may be at substantially greater risk for both advanced stage and localized prostate cancer in this multi-ethnic study.

This abstract is also presented as Poster B43.

Citation Format: Glovioell W. Rowland, Esther M. John, Sue A. Ingles. Prostate cancer risk and dietary folate in a multiethnic population: Higher intake increases risk in the California Collaborative Prostate Cancer Study. [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 PR04.
Abstract A01: KRAS molecular profiling in non-squamous non-small cell lung cancer (NSCLC).
Authors: Karim Nagla Abdel , Starnes Sandra , Morris John , Pathrose Peter , Perry Ashley , Fathallah Hassana
Published: August 2014

Recent studies suggest that patients with KRAS-mutant NSCLC fail to benefit from standard systemic therapies and do not respond to EGFR inhibitors. Therefore, there is a clear need for therapies specifically developed for these patients. Molecular profiling has the potential to identify potential targets that might provide a better treatment and novel targeted therapy for KRAS-mutated NSCLC. In this study, we purified RNA from archived tumor and normal lung tissue obtained from 20 patients with wild type (wt) and 17 patients with mutant (mt) KRAS tumors undergoing resection for stage I and stage II NSCLC, and assessed by reverse transcriptase-real time polymerase chain reaction (RT-PCR) the expression of four genes involved in DNA synthesis and repair including thymidylate synthase (TS), BRCA1, ECCR1 and RAP80, and the proto-oncogene SRC. Our results show that in mt KRAS tumors, the levels of expression of ERCC1, TS and SRC were significantly increased in comparison to paired-normal lung tissue (p ≤ 0.04). Expression of BRCA1 and RAP80 were similar in both mt KRAS tumors and paired-normal tissue. Furthermore, the expression of BRCA1, TS and SRC were significantly increased in wt KRAS tumors relative to their expression in normal lung (p ≤ 0.044). Expression of ERCC1 and RAP80 was similar in wt KRAS tumors and paired normal tissue. Interestingly, SRC expression in mt KRAS tumors was decreased in comparison to wt KRAS tumors. Our results suggest that greater ERCC1 expression in mt KRAS tumors might increase platinum resistance in this group of patients, whereas the greater expression of BRCA1 in wt KRAS tumors might be suggestive for the sensitivity to taxanes. Our data also suggests that the combination of a SRC inhibitor with a TS inhibitor such as pemetrexed might improve the outcome of patients with wt KRAS tumors. In conclusion, these results suggest that the most effective treatment strategy for KRAS-mutant NSCLC is combined targeting of oncogenic KRAS in addition to other therapeutic agents specific to the molecular profile of the tumor.

Citation Format: Nagla Abdel Karim, Sandra Starnes, John Morris, Peter Pathrose, Ashley Perry, Hassana Fathallah. KRAS molecular profiling in non-squamous non-small cell lung cancer (NSCLC). [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 A01.
Abstract A04: Recurrent oncogenic mutations in the small GTPase RIT1 activate PI3K and MEK.
Authors: Berger Alice H. , Duke Fujiko , Imielinski Marcin , Kaplan Nathan , Wala Jeremiah , Shi Geng-Xian , Andres Douglas A. , Meyerson Matthew
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 (PR02) of the Conference Proceedings.

Citation Format: Alice H. Berger, Fujiko Duke, Marcin Imielinski, Nathan Kaplan, Jeremiah Wala, Geng-Xian Shi, Douglas A. Andres, Matthew Meyerson. Recurrent oncogenic mutations in the small GTPase RIT1 activate PI3K and MEK. [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 A04.
Abstract A09: Selector (HaloPlex) targeted resequencing of formalin-fixed paraffin-embedded (FFPE) specimens for mutation diagnostics in NSCLC.
Authors: Botling Johan , Moens Lotte N.J. , Falk-Sorqvist Elin , LaFleur Linnea , Sundstrom Magnus , Micke Patrick , Nilsson Mats
Published: August 2014

In recent years, the advent of massively parallel “next-generation” sequencing technologies (NGS) has enabled substantial advances in the study of cancer. In combination with targeted DNA enrichment methods, high sequence coverage can be obtained for many different genes simultaneously, creating unique opportunities for clinical cancer diagnostics. However, the process of formalin fixation and paraffin embedding (FFPE) of tissue samples results in DNA-fragmentation by cross-linking to other biomolecules, posing a number of technical challenges for downstream mutation analyses.

In this study, we have evaluated the HaloPlex target enrichment system for somatic mutation detection in DNA-extracts prepared from surgical non-small cell lung cancer (NSCLC) specimens with available paired tumor and normal tissue in FFPE blocks and matched fresh-frozen tumor and normal samples. In the design of the 56 gene panel, covering the most common mutations in lung colon cancer, several modifications to the standard method were introduced, including a reduced target fragment length, molecular barcoding, and “two strand capturing.

We show that FFPE material can be used for HaloPlex based target enrichment and NGS using as little as 50 ng of DNA, i.e. compatible with yields readily available from small biopsies. By specifically capturing both strands for each target fragment, we were able to reduce the number of false positive errors due to FFPE induced artifacts by a factor of 4. Furthermore, the combined approach of molecular barcoding and two strand capturing allowed us to identify two low frequency variants, demonstrating a sensitive and accurate detection of somatic mutations.

We believe that the HaloPlex method, provided some modifications are made, will be broadly applicable as a tool for somatic mutation detection. Genetic profiling of NSCLC FFPE tissues will add a new dimension to thoracic tumor pathology and will open vast opportunities for research as large, population-based cohorts of advanced stage NSCLC will be available for comprehensive molecular characterization.

Citation Format: Johan Botling, Lotte N.J. Moens, Elin Falk-Sorqvist, Linnea LaFleur, Magnus Sundstrom, Patrick Micke, Mats Nilsson. Selector (HaloPlex) targeted resequencing of formalin-fixed paraffin-embedded (FFPE) specimens for mutation diagnostics in NSCLC. [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 A09.
Abstract A16: Induction of activating transcription factor 3 is associated with cisplatin responsiveness in NSCLC: A potential predictive biomarker of response.
Authors: Bar Jair , Stewart David , Glenwood Goss D. , Villeneuve Patrick J. , Dimitroulakos Jim
Published: August 2014

The goal of this study was to identify treatment induced biomarkers of platin activity that may predict response to this important class of chemotherapeutic agents. We employed RNAseq transcriptome analysis comparing two parental NSCLC cell lines Calu6 and H23 to their resistant sub-lines, Calu6cisR1 and H23cisR1, derived following exposure to high dose cisplatin. To this end, we identified a stress pathway consisting of GADD45α, ATF3 and DDIT3/CHOP that was induced specifically in cisplatin treated parental but not their resistant sub-lines. Furthermore, ATF3 in particular was not expressed in untreated parental or resistant clones but was robustly induced only in the parental sensitive cell lines following cisplatin treatment. Cisplatin-induced MAPKinase activation, particularly the JNK pathway was abrogated in Calu6cisR1 cells that regulates ATF3 induction in Calu6 cells. In ex-vivo NSCLC tumors, ATF3 was induced in 2/4 tumors evaluated but not in their corresponding normal adjacent lung tissue (0/4) following cisplatin treatment. Thus, the lack of significant expression in untreated NSCLC cells and normal lung tissue but a robust induction following cisplatin treatment in sensitive parental NSCLC cell lines and a cohort of ex-vivo tumor samples suggest potential utility as a predictive biomarker of platin response that requires further study.

Citation Format: Jair Bar, David Stewart, Goss D. Glenwood, Patrick J. Villeneuve, Jim Dimitroulakos. Induction of activating transcription factor 3 is associated with cisplatin responsiveness in NSCLC: A potential predictive biomarker of response. [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 A16.
Abstract A17: A blood test for early detection of lung cancer using a mixed panel of tumor proteins and autoantibodies.
Authors: Doseeva Victoria , Woodcock Juliana , Freedy James , James William , Knezevic Vladimir
Published: August 2014

Lung cancer is the second most common non-cutaneous cancer and a leading cause of cancer-related mortalities worldwide, resulting in over 156,000 deaths per year in the United States alone (1). Tobacco use has been identified as the primary causal factor for lung cancer and is thought to account for some 90% of cases. Thus, individuals over 50 years of age with a smoking history of greater than 20 pack-years have a 1 in 7 lifetime risk of developing the disease.

20/20 GeneSystem's PAULA test (Protein Assays Utilizing Lung Cancer Analytes), a multiplex immunoassay clinical blood test that detects four tumor proteins and autoantibodies, determines the risk that lung cancer is present in asymptomatic individuals from the high risk population described above. The test has been developed and tested using over 1,500 patient samples, including patients from 6 different regional cancer centers as well as age- and smoking history-matched controls. Here we report a new retrospective study of PAULA test using a total of 380 patients from 3 different cohorts, consisting of 190 confirmed diagnoses of lung cancer and 190 age- and smoking history matched controls. The PAULA test demonstrated 74% clinical sensitivity and 80% specificity, with an AUC value of 0.85 using Receiver Operating Characteristic (ROC) analysis.

This study confirms the value of using both tumor proteins and autoantibodies in the early detection of lung cancer, and is the first demonstration of a diagnostic multiplex immunoassay using this kind of mixed panel. We believe that the clinical performance of the PAULA test makes it suitable for use as an aid to determine which high-risk patients need to be directed to appropriate non-invasive diagnostic follow-up, especially chest CT scan for patients at high-risk for lung cancer.

Citation Format: Victoria Doseeva, Juliana Woodcock, James Freedy, William James, Vladimir Knezevic. A blood test for early detection of lung cancer using a mixed panel of tumor proteins and autoantibodies. [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 A17.
Abstract A30: Melatonin suppresses invasion and epithelial to mesenchymal transition in non-small cell lung cancer cells via inhibition of ZNF746 signaling.
Authors: Kim Bonglee , Lee Duckgue , Kim Sunghoon
Published: August 2014

Though ZNF 746 known as Parkin-interacting substrate (PARIS) was reported to repress PGC-1α and its target gene NRF-1 leading to the neurodegeneration in Parkinson's disease, its function in tumorigenesis has not been investigated until now. Thus, in the present study, the role of ZNF746 was investigated in the invasion and epithelial to mesenchymal transition (EMT) in ZNF746 overexpressed H460 non-small cell lung cancer (NSCLC) cells. Invasion assay showed that inhibition of ZNF 746 using siRNA transfection method inhibited the invasion of H460 cells using Boyden chamber. Real-time quantitative RT-PCR (RT-qPCR) revealed that the silencing of ZNF 746 attenuated the expression of matrix metalloproteinase (MMP) 1, MMP2 and MMP 9, but not MMP7 in H460 cells. Immunoblotting assay revealed that the expressions of E-cadherin of epithelial phenotype were up-regulated, while Slug was down-regulated in ZNF746 siRNA transfected H460 cells. Consistently, mRNA expression of E-cadherin was up-regulated while Vimentin or Slug, Twist, ZEB as EMT key transcriptional factors were suppressed in ZNF746 siRNA transfected H460 cells. Also, mRNA expression of transcriptional marker Nanog and Octamer-binding transcriptional factor 4 (OCT4) known to enhance malignancy and metastasis in lung adenocarcinoma was suppressed in ZNF746 siRNA transfected H460 cells. Interestingly, the endogenous expression of ZNF746 was induced in parallel with Twist at protein level during hypoxia. Moreover, we found that ZNF746 overexpressed cell lines, A549 and H460 were inhibited invasion and migration along with ZNF746 by melatonin.

Overall, our findings suggest that ZNF746 can be an important target molecule in metastasis of lung cancer and melatonin may have the potential as an inhibitor of ZNF746 in NSCLC cells

Citation Format: Bonglee Kim, Duckgue Lee, Sunghoon Kim. Melatonin suppresses invasion and epithelial to mesenchymal transition in non-small cell lung cancer cells via inhibition of ZNF746 signaling. [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 A30.
Abstract B03: Identification of R-spondin fusions in NSCLC.
Authors: Karkera Jayaprakash , Martinez Gabriela , Bell Katherine , Portale Joseph , Gaffney Dana , Lorenzi Matthew V. , Platero Suso
Published: August 2014

Autocrine Wnt signaling has been reported in a significant fraction of NSCLC. The R-spondin (RSPO) protein family is a small family of four secreted growth factors. The four paralogs share 40–60% pairwise amino acid sequence identity and are predicted to share substantial structural homologies. RSPO proteins are involved in vertebrate development and their ligand-type activities overlap substantially with those of canonical Wnt ligands. A characteristic feature of all four RSPO members is their ability to activate β-catenin signaling and enhance WNT-mediated β-catenin activation. It has recently been described that recurrent gene fusions involving RSPO family members of RSPO2 and RSPO3 that occur in ~10% of colon tumors and are mutually exclusive with other WNT pathway genetic alterations. In this study we developed a TaqMan qRT-PCR-based approach to evaluate systematically the expression of these three (3) RSPO fusion transcripts in formalin-fixed paraffin embedded tissue (FFPET) samples. We examined 324 NSCLC samples that included 197 squamous and 127 adenocarcinoma subtypes for the presence of EIF3E(e1)-RSPO2(e1), PTPRK(e1)-RSPO3(e2), PTPRK(e7)-RSPO3(e2). EIF3E(e1)-RSPO2(e1) was identified in 1% and this fusion transcript is expected to produce a functional RSPO2 protein driven by the EIF3E promoter. The PTPRK(e1)–RSPO3(e2) transcript found in 2% and is an in-frame fusion that preserves the entire coding sequence of RSPO3 and replaces its secretion signal sequence with that of PTPRK. Interestingly, all the fusions were detected only in the squamous subtype of NSCLC. These findings suggest an important role for dysregulated Wnt-β-catenin signaling in lung cancer and identify a new driver segment in NSCLC for therapeutic intervention.

Citation Format: Jayaprakash Karkera, Gabriela Martinez, Katherine Bell, Joseph Portale, Dana Gaffney, Matthew V. Lorenzi, Suso Platero. Identification of R-spondin fusions in NSCLC. [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 B03.
Abstract B06: Development of novel thiobarbituric acid derivative compounds for treatment of lung cancers.
Authors: Lee Sang Y. , Ramisetti Srinivasa , Slagle-Webb Becky , Sharma Arun K. , Connor James R.
Published: August 2014

Previously, we reported the identification of a cytotoxic chemotype compound CC-I (a derivative of thiobarbituric acid) that is effective against chemotherapy resistant glioblastomas (GBMs) and neuroblastoma in an in vitro cell culture and in vivo mouse tumor models. In this study, we determined the cytotoxicity of CC-I and structurally similar compounds along in lung cancers to determine whether CC-I is toxic to lung cancers and to identify additional analog compounds that could be more toxic than CC-I. We designed several CC-I analog compounds by manipulating functional substitutions at N1-, N3- and C5-positions (either furan ring or benzene ring) of CC-I. For example, the novel compounds were synthesized starting from substituted thioureas, key precursors for the synthesis of substituted thiobarbituric acids, and finally by condensing cinnamaldehyde (CMC-2 series: benzene ring compound) or trans-3-(2-furyl)-acrolein (CC-I series: furan ring compound) with appropriately substituted thiobarbituric acids in the presence of catalytic amounts of pyridine. We used MTS cell proliferation or SRB cytotoxicity assay to determine the toxic level of compounds on the human lung cancer cell lines (e.g., A549, H520, H460, H69). The data suggest that the functional group at N1-, N3- and C5 sites is important for toxicity. Among the compounds with similar structures, CC-I-v3 and CC-I-v4 are the two most cytotoxic compounds to lung cancer cells and also the cisplatin resistant lung cancer cell lines such as H1993 and H520. In some of the cell lines we investigated, CC-I-v1 and CMC-2 compounds showed greater toxicity than CC-I compound. Currently, we are studying the anti-tumor effect of these compounds in an in vivo nude mouse tumor model. In summary, this structure-activity study clearly indicates that we can develop more efficacious compounds compared to our original compounds by rational modifications of the chemotype compounds.

[This project is supported by the Elsa U. Pardee Foundation]

Citation Format: Sang Y. Lee, Srinivasa Ramisetti, Becky Slagle-Webb, Arun K. Sharma, James R. Connor. Development of novel thiobarbituric acid derivative compounds for treatment of lung cancers. [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 B06.
Abstract B26: Design and synthesis of furoquinoline derivatives as potential drug candidates for the treatment of lung cancers.
Authors: Tzeng Cherng-Chyi , Tseng Chih-Hua , Chen Yeh-Long
Published: August 2014

Quinoline moiety is present in many classes of biologically active compounds. Recently, we have synthesized certain quinolone, 2-phenylquinoline, 2-furanylquinoline, and 4-anilinofuro[2,3-b]quinoline derivatives for biological evaluations. Among them, 1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone (CIL-102) was the most potent with a mean GI50 value of 0.025 μM against the growth of nine types of cancer cells and therefore, was further evaluated on its effects of cell cycle distribution. Results indicated CIL-102 induces cell cycle arrest in G2/M followed by apoptosis. CIL-102 bounds to tubulin at a single site with a dissociation constant of 0.4 μM. An analysis of the modified Dixon plot suggested that CIL-102 competitively inhibited the binding of podophyllotoxin, a colchicine-binding site agent, to tubulin. However, some drawbacks such as lack of selective cytotoxicity, poor oral bioavailability, and poor water solubility exhibited by CIL-102 prompted us to search for newer derivatives. Through extensive structural optimization, the new lead compound named as CYW-1865 which possesses aminoalkoxyimino side chain, exhibited selective anticancer activity, higher oral bioavailability, and higher water solubility than that of CIL-102. Xenographic studies indicated the tumor size with CYW-1865 treated nude mice was significantly lower than control. Further evaluation in an orthotopic lung cancer model indicated that CYW-1865 can be absorbed readily through oral administration, distributed to lung tissue, and exhibited significant efficacy in inhibiting the growth of lung cancers. Strategies for design and synthesis of CYW-1865 and its further structural optimization will be presented.

Citation Format: Cherng-Chyi Tzeng, Chih-Hua Tseng, Yeh-Long Chen. Design and synthesis of furoquinoline derivatives as potential drug candidates for the treatment of lung cancers. [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 B26.
CHK It Out! Blocking WEE Kinase Routs TP53 Mutant Cancer
Authors: Bauman Julie E. , Chung Christine H.
Published: August 2014

Mutations in TP53, encoding the master tumor suppressor p53, have posed a developmental therapeutic dilemma due to inability to target loss of function. Inhibition of WEE1 or CHK1 kinase, negative regulators of the G2–M checkpoint, selectively sensitizes p53-deficient cells to exogenous DNA damage, abrogating G2 arrest and precipitating mitotic catastrophe. Clin Cancer Res; 20(16); 4173–5. ©2014 AACR.
Abstract A15: Distinct gene expression profiles in Lynch syndrome-associated ovarian cancer
Authors: Jönsson Jenny-Maria , Bartuma Katarina , Valentin Mev Dominguez , Harbst Katja , Ketabi Zoreh , Malander Susanne , Jönsson Mats , Carneiro Ana , Måsbäck Anna , Jönsson Göran , Nilbert Mef
Published: August 2014

Background: Ovarian cancers linked to Lynch syndrome represent a rare subset that typically present at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We aimed to identify molecular profiles of Lynch syndrome-associated ovarian cancer for application in refined diagnostics and targeted therapeutics.

Methods: Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation (WG-DASL) was applied to 48 histopathologically matched ovarian cancers, which represented Lynch syndrome-associated tumors and sporadic tumors. The results were validated by application of an external ovarian cancer data set and by immunohistochemistry.

Results: Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, predominantly involved in the mTOR and MAPK/ERK signaling pathways.

Conclusion: The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to different tumorigenic routes and suggest that targets within the mTOR and MAPK/ERK signaling pathways may be relevant to consider for molecular diagnostics and targeted therapeutics.

Citation Format: Jenny-Maria Jönsson, Katarina Bartuma, Mev Dominguez Valentin, Katja Harbst, Zoreh Ketabi, Susanne Malander, Mats Jönsson, Ana Carneiro, Anna Måsbäck, Göran Jönsson, Mef Nilbert. Distinct gene expression profiles in Lynch syndrome-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 A15.
Abstract A27: The ovarian tumor tissue analysis (OTTA) consortium
Authors: Ramus Susan J. , Köbel Martin , Sieh Weiva , Anglesio Michael S. , Millstein Joshua , Bowtell David D. , Brenton James D. , Høgdall Estrid , Pharoah Paul DP , Goode Ellen L. , Huntsman David G.
Published: August 2014

Our understanding of ovarian cancer is complicated by disease heterogeneity. There are five major histological types, each with alterations in different pathways and distinct clinical outcomes. Even within these histological types there is clinical and molecular heterogeneity. The Ovarian Tumor Tissue Analysis (OTTA) consortium was established to validate prognostic markers for ovarian cancer in a large population of patients to allow stratification by histological type and molecular subtype. OTTA is currently a collaboration among 38 studies and has tissue microarrays (TMAs) from over 8,000 tumors available for immunohistochemical (IHC) analysis. In addition formalin fixed paraffin embedded (FFPE) tissue on slides or cores are available from the majority of OTTA studies for DNA and RNA analysis. Approximatley 60% of the cases are part of the Ovarian Cancer Association Consortium (OCAC) and have genotype data on over 200,000 single nucleotide polymorphisms and extensive epidemiological data. We recently performed IHC analysis of 12 markers using centralised staining and scoring to reduce heterogeneity and improve power to validate biomarkers. We showed that estrogen receptor and progesterone receptor were prognostic markers for endometrioid and high-grade serous carcinomas by performing the first robust subtype-specific analyses of these biomarkers in nearly 3000 patients. In contrast, FOLR1 expression was not associated with survival in 1507 high-grade serous carcinomas. We have shown that FFPE material from OTTA is suitable for RNA expression analysis on high through-put platforms such as the NanoString GX system. Expression analysis of 50 candidate genes in 244 high grade serous ovarian cancer cases has validated prognostic markers identified by The Cancer Genome Atlas (TCGA) project and investigated a series of novel candidate genes. IHC and RNA expression profiling from formalin fixed paraffin embedded (FFPE) tumor tissue is being used to better subclassify the ovarian tumors for further analysis. We would welcome groups with collections of ovarian tumor samples and corrsponding clinical data to join OTTA and participate in ongoing collaborative projects.

Citation Format: Susan J. Ramus, Martin Köbel, Weiva Sieh, Michael S. Anglesio, Joshua Millstein, David D. Bowtell, James D. Brenton, Estrid Høgdall, Paul DP Pharoah, Ellen L. Goode, David G. Huntsman. The ovarian tumor tissue analysis (OTTA) consortium. [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 A27.
Abstract A28: Analyses of FOXM1 isoforms in ovarian cancer
Authors: Altadill Tatiana , Rigau Marina , Majem Blanca , Lanau Lucia , Castellví Josep , García Ángel , Pérez-Benavente Assumpció , Sánchez José Luis , Cabrera Silvia , Xercavins Jordi , Campo Josep Maria del , Gil-Moreno Antonio , Llauradó Marta , Reventós Jaume
Published: August 2014

Introduction & Objectives: Epithelial ovarian cancer (OC) is the most lethal gynaecological malignancy and the fifth leading cause of cancer death in women in the Western world. Forkhead box M1 (FOXM1) transcription factor was already been described to be overexpressed in various malignancies, playing a key role in cell-cycle progression, chromosomal segregation and genomic stability, and oxidative stress. Moreover, it can also promote drug resistance to herceptin, paclitaxel and cisplatin in breast cancer cells. A recent report from our group has shown, for the first time, that FOXM1 is also overexpressed in OC, being associated with tumor grade. This result seem to indicate an interesting role of this molecule in the progression and resistance to therapy in OC. Our aim is to characterize FOXM1 isoforms in OC through the use of human tissue samples.

Material & Methods: Fresh ovarian primary tumors, ascites and peritoneal metastases from patients suffering advanced serous OC were collected from surgery room and processed for microarray analysis to detect FOXM1 expression levels. FOXM1 isoforms were analysed at mRNA expression level by using RTqPCR in a set of new frozen tissue samples.

Results: We found that FOXM1 overexpression is increased in OC peritoneal metastases. Now, we are characterizing the isoforms of FOXM1 in primary, ascites and metastatic tumors. Nevertheless, more samples need to be analysed in order to have conclusive results.

Conclusions: The present study highlights the role of FOXM1 isoforms in OC dissemination and pursues the idea to elucidate the biologic role of FOXM1 in OC tumorigenesis.

Citation Format: Tatiana Altadill, Marina Rigau, Blanca Majem, Lucia Lanau, Josep Castellví, Ángel García, Assumpció Pérez-Benavente, José Luis Sánchez, Silvia Cabrera, Jordi Xercavins, Josep Maria del Campo, Antonio Gil-Moreno, Marta Llauradó, Jaume Reventós. Analyses of FOXM1 isoforms 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 A28.
Abstract A41: Harnessing neural stem cell tumor tropism for targeted nanoparticle delivery: Potential for ovarian cancer therapy
Authors: Mooney Rachael , Gilchrist Megan , Weng Yiming , Annala Alexander , Bhojane Sukhada , Garcia Elizabeth , Roma Luella , Schnarr Kenna , Dellinger Thanh , Han Ernest , Karen Aboody S. , Berlin Jacob M.
Published: August 2014

Intraperitoneal as compared to intravenous administration of chemotherapy has shown improved survival rates for stage III ovarian cancer. While this demonstrates that concentrating chemotherapy at the tumors has therapeutic benefit, intraperitoneal therapy was also accompanied by significantly increased toxic side effects. There is thus an urgent need for a targeted delivery system that could localize therapy at the tumors and decrease the side-effects. Here we show that stem cell/nanoparticle hybrids may be used for such targeted therapy. In pre-clinical brain and other invasive and metastatic tumor models, neural stem cells have been shown to overcome a variety of biological barriers and migrate selectively to invasive tumor foci, even penetrating hypoxic tumor regions. Here we present data confirming that neural stem cells also migrate selectively to ovarian cancer. Moreover, the neural stem cells can engineered to transport to the tumors nanoparticles that either contain chemotherapy drugs or can be induced to heat. The combination of neural stem cells and nanoparticles that can either be used for thermal ablation or slowly release chemotherapy drugs offers the potential to realize a modular and general drug targeting system for the treatment of stage III ovarian cancer.

Citation Format: Rachael Mooney, Megan Gilchrist, Yiming Weng, Alexander Annala, Sukhada Bhojane, Elizabeth Garcia, Luella Roma, Kenna Schnarr, Thanh Dellinger, Ernest Han, Aboody S. Karen, Jacob M. Berlin. Harnessing neural stem cell tumor tropism for targeted nanoparticle delivery: Potential for ovarian cancer therapy. [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 A41.