bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-196: Anti-DLL4 reduces tumor growth and tumorigenicity in B-RAF V600E melanomas including those with acquired resistance to B-RAF inhibitors
Authors: Beviglia Lucia , Yeung Pete , Fischer Marcus , Yen Wang-Ching , Gurney Austin , Lewicki John , Kapoun Ann , Hoey Timothy
Published: August 2012

Melanoma is frequently driven by oncogenic mutation in the B-RAF gene (V600E) and this mutation is found in approximately 60% of patients. These patients are highly sensitive to kinase inhibitors targeting B-RAF. However, recent clinical experience has shown that after an initial response, a high percentage of patients develop resistance to B-RAF inhibitors through various mechanisms. In our studies, we evaluated whether inhibition of DLL4-Notch signaling might be effective in B-RAF mutant melanoma. We utilized two patient-derived melanoma xenografts containing the B-RAFV600E mutation, OMP-M2 and OMP-M8. The OMP-M8 xenograft was derived from a patient who was treated with the B-RAF inhibitor Vemurafenib (PLX-4032) and showed an early response to treatment, but later became resistant. We performed combination efficacy experiments with the B-RAF inhibitor PLX-4720 (doses 20-80 mg/kg, oral gavage, qdx5) and anti-DLL4 antibodies (30 mg/kg, IP once a week), and found that PLX-4720 combined with anti-DLL4 treatment caused a significant inhibition of tumor growth in OMP-M2 tumors. In serial transplant limiting dilution assay (LDA) studies with the OMP-M2 model, PLX-4720 treatment induced a significant enrichment of tumor initiating cells. In contrast, anti-DLL4 reduced the frequency of tumor initiating cells compared to controls, as a single agent and in combination with PLX-4720. We also found that the OMP-M8 tumor xenografted in mice retained the lack of response to the B-RAF kinase inhibitor, showing that the xenografts responded to treatment similarly as the patient in the clinic. Interestingly, the B-RAF inhibitor resistant tumor OMP-M8 was sensitive to anti-DLL4, which inhibited the growth of the primary tumor and significantly reduced the frequency of tumor initiating cells as a single agent and in combination with a chemotherapeutic agent. These findings suggest that DLL4-Notch inhibition can be effective in B-RAF V600E mutant melanoma including patients with acquired resistance to B-RAF kinase inhibitors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-196. doi:1538-7445.AM2012-LB-196
Abstract LB-306: Multiplex RT-qPCR study on the expression of stem cell markers CD24, CD44, and ALDH1 in circulating tumor cells of breast cancer patients
Authors: Strati Areti D. , Georgoulias Vassilis , Lianidou Evi S.
Published: August 2012

Background: Molecular characterization of Circulating Tumor Cells (CTC) can give important information on their suspected connection to cancer stem cells. In breast cancer, putative cancer stem cells have been identified to have a CD44+CD24-/low and ALDH1+ cell phenotype. Patients and methods: We developed a tetraplex quantitative RT-qPCR assay for CD24, CD44, ALDH1 and HPRT based on the in-silico design of primers and probes with different fluorescence emission spectra. Specificity and sensitivity experiments were performed using the SKBR-3 cancer cell line. We isolated CTC from peripheral blood according to our previously described methodology (Strati et al, BMC cancer 2011) from 40 patients with early breast cancer before the administration of adjuvant chemotherapy, 23 patients with verified metastasis and 18 female healthy volunteers. We evaluated all our data with respect to CD24, CD44, ALDH1 expression of healthy volunteers using the 2βΔΔCt method. Results: In 23 patients with verified metastasis 9.0% were found to have CD44+CD24-/low phenotype and 13% ALDH1high/CD24-/low phenotype. In 40 operable breast cancer patients 8 patients (20.0%) were found to have CD44+CD24-/low phenotype and 12 patients (30.0%) were found to have ALDH1high/CD24-/low phenotype. CK-19, MAGE-A3, HER-2, TWIST1, hTERT α+β+, and mammaglobin gene transcripts were also quantified in the same samples. Discussion: Molecular characterization of CTC has shown that in breast cancer patients CTCs are partly characterized by a putative stem cell phenotype. The clinical significance of these findings in early breast cancer remains to be elucidated when the clinical outcome of these patients is known.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-306. doi:1538-7445.AM2012-LB-306
Abstract LB-312: Egfl7 is expressed in a broad range of human tumors with apparent restriction to the endothelium
Authors: Peale Franklin , Sanders Laura , Yu Ron , Chan Sara , Chen daniel , Raja Rajiv , Patel Rajesh , Malekafzali Ashi , Hegde Priti , Ye Weilan , Schmidt Maike
Published: August 2012

EGFL7 is a secreted protein expressed by proliferating endothelial cells in growing vessels during normal organ development. Though expression is generally restricted to a small subset of vessels in the adult, elevated expression has been observed under physiological conditions requiring new blood vessel growth, such as wound healing, pregnancy and tumor growth. EGFL7 facilitates new blood vessel formation by supporting endothelial cell adhesion and migration. In addition, EGFL7 can protect endothelial cells from stress-induced apoptosis, such as hypoxia or potentially growth factor withdrawal. A blocking antibody to EGFL7 (anti-EGFL7) has demonstrated increased survival benefits in preclinical models when combined with a blocking antibody to the pro-angiogenic growth factor VEGFA. Anti-EGFL7 is currently being investigated in Phase II clinical trials in NSCLC and mCRC in combination with bevacizumab and chemotherapy. We present here a comprehensive assessment of Egfl7 expression in a broad range of human solid tumors using in situ hybridization (BC n=150, CRC n=134, RCC n=8, LC n=62, LN mets predom. BC n=27, OV n=25) and quantitative PCR (BC n=92 primary, n=20 LN mets synchronous collection, n=12 distant matched metastasis sequential collection; CRC n=85 primary, n=9 distant matched metastasis sequential collection; NSCLC n=77 primary, n=3 distant matched metastasis sequential collection). Egfl7 is expressed in all tumor types interrogated. With the methods utilized in this study, expression appears to be limited to endothelial cells, with no appreciable tumor cell expression. This data is supported by co-expression analysis in preclinical and clinical samples, showing correlation with vascular markers (n=91 xenograft models CD31 r=0.85, p<0.0001; human tumors CD34 BC r=0.54, p<0.0001; CRC r=0.5, p<0.0001; NSCLC r=0.39, p=0.0003). Comparison with pro-angiogenic growth factors suggests an indication-dependent pattern of co-expression, with strongest correlation being observed in CRC (VEGFA r=0.3, p=0.003; VEGFC r=0.74, p<0.0001; VEGFD r=0.38, p=0.0001). RNA expression in a cohort of archival samples from metastatic CRC, BC and NSCLC patients does not indicate a strong prognostic association between Egfl7 and overall survival. However, analysis of paired primary and metastasis samples indicate a significant upregulation of Egfl7 in distant metastasis of CRC tumors (average fold change 1.8, p=0.0079, n=9 matched pairs), despite little change in the total vascular content as measured by CD34 expression (average fold change 1.06, p=0.77, n=9 matched pairs).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-312. doi:1538-7445.AM2012-LB-312
Abstract LB-322: Cruciferous vegetable intake after diagnosis of breast cancer and survival: a report from the shanghai breast cancer survival study
Authors: Nechuta Sarah J. , Lu Wei , Cai Hui , Zheng Ying , Bao Ping-Ping , Zheng Wei , SHu Xiao Ou
Published: August 2012

BACKGROUND: Cruciferous vegetables are a major source of glucosinolate-derived bioactive compounds, such as isothiocyanates and indoles, which have been shown in animal studies and in vitro to inhibit cancer growth and progression. However, little is known regarding the role of cruciferous vegetables in breast cancer prognosis. Using resources from the Shanghai Breast Cancer Survival, a large population-based prospective cohort study of Chinese breast cancer survivors, we evaluated the association of cruciferous vegetable consumption after cancer diagnosis and breast cancer outcomes with repeated dietary assessments after diagnosis. METHODS: Women with incident breast cancer aged 20-75 years were recruited within 6-months of diagnosis during 2002-2006. In-person baseline interviews collected detailed data on clinic characteristics, socio-demographics, and lifestyle factors. Medical records were used to verify clinical data. The cohort has been followed-up by a combination of in-person follow-up surveys and record linkage to the Shanghai Vital Statistics Registry. Cruciferous vegetable intake (g/day) was reassessed at 18- and 36-months. Cox regression models were used to derive hazard ratios (HR) and 95% confidence intervals (CIs) for the associations of cruciferous vegetables and breast cancer outcomes. Analyses include 4,886 women with stage I-IV breast cancer. RESULTS: After a median follow-up of 5.2 years, 587 deaths (496 breast cancer deaths) and 615 recurrences occurred. Cruciferous vegetable intake increased after diagnosis (mean (SD)=62.5 (44.5) at 6-months and 133.8 (93.3) at 36-months). After adjustment for socio-demographics, clinical characteristics including treatment and tumor characteristics, and lifestyle factors, cruciferous vegetable intake was associated with improved breast cancer survival in a dose-response pattern (P for trend < 0.01). The multivariable hazard ratios (95% confidence intervals) across increasing quartiles (vs. Q1) were 0.73 (0.60-0.90), 0.51 (0.41-0.64), and 0.38 (0.29-0.49) for total mortality; 0.78 (0.62-0.97), 0.53 (0.41-0.68), and 0.38 (0.29-0.51) for breast cancer-specific mortality; 0.79 (0.63-0.98), 0.71 (0.57-0.88), and 0.65 (0.52-0.81) for recurrence. These associations persisted after excluding the first year of observation, although the association for recurrence was no longer statistically significant. CONCLUSION: Cruciferous vegetable intake after breast cancer diagnosis was associated with improved prognosis among Chinese women.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-322. doi:1538-7445.AM2012-LB-322
Abstract LB-324: The cancer risks and life shortening effect of low and very low cholesterol among Asians
Authors: Wen Chi-Pang , Wu Xifeng , Yang Yi Chen , Tsai Min Kuang , Hsu Chung Yi
Published: August 2012

Background: Attention has been focused on the increased risk of high cholesterol, but the effect of low cholesterol remains unclear and receives little attention. Method: The study cohort, 537,430 adults in Taiwan who went through a medical screening program between 1996 and 2008, was followed up for an average of 8.5 years for mortality and cancer incidence, with 18,745 deaths and 17,714 cancer cases identified. Low and very low cholesterol or LDL were defined as < 180 and <160, or <110 and <90 mg/dL, respectively. Cox proportionate model was used for hazard ratio (HR) calculation, by controlling for all relevant risk factors (Age, gender, BMI, smoking, drinking, blood pressure, blood sugar, physical activity and anemia) Results: One out of four (24.6%) had low cholesterol and 7.5% had very low cholesterol, in contrast to 10.4% with high cholesterol. Increases in all cancer mortality were found for those with low cholesterol (HR:1.41, with 95% 1.3-1.5) and very low cholesterol (HR: 1.58 with 95% 1.4-1.7), with 180-239 mg/dL as reference. Similar results were seen for cancer incidence. The increase came prominently from liver cancer (HR:2.86), and the increases remained after all deaths or all cancer incidences within the first 3 years were excluded (HR: 1.31), or after HBV carriers were excluded (HR: 1.33). All cancer mortality increased by 1% for every unit decrease of cholesterol across all levels. With 60% increase in all-cause mortality, the life span of very low cholesterol was shortened by 5-6 years. Conclusion: Found in 1/4 of adult Asians, subjects with low cholesterol (<180 mg/dL), a level commonly reached by those taking statins or on vegetarian diet, had approximately 50% increase in cancer risks. The inverse relationship existed across all levels of cholesterol, with 10% increase for every 10-unit decrease. Those with very low cholesterol had their life span shortened by 5-6 years. While reverse causation with pre-clinical cancer cases could be responsible, the fact that the cancer risks remained after excluding first three years of cancer implied low cholesterol is an independent risk factor or risk marker for all cancer. In this Asian community, low cholesterol should receive as much attention as high cholesterol.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-324. doi:1538-7445.AM2012-LB-324
Abstract LB-326: Elucidating significant genetic associations between genes and lung cancer
Authors: D'Amelio Anthony M. , Etzel Carol J.
Published: August 2012

Introduction: To further understand and elucidate the genetic risk factors for Lung Cancer (LC) will substantially improve cancer prevention, screening programs, and treatment options for this insidious disease. However, our previous attempts to increase the discriminatory power in an existing risk model with the inclusion of SNPs identified via GWAS have not been very successful. In this analysis, we reassess the increase in discriminatory power by including haplotypes based on existing GWAS-identified SNPs and additional single SNPs. Methods: Cases included 1154 histological-confirmed Caucasian lung cases from MD Anderson Cancer Center in Houston, Texas, and controls included 1137 individuals recruited through the Kelsey-Seybold Clinics in Houston, Texas. Genetic information from both populations was selected for 157 SNPs that exist in the Texas GWAS and were part of the top 200 SNPs as determined by a previously published meta-analysis of 10 different lung cancer GWAS datasets (Landi et al. 2009). Plink and Haploview were used to determine the top SNPs and top haplotype blocks respectively. Then, univariate logistic regression was used to determine the best genetic model for the top SNPs. Joint logistic risk model regression was used to determine haplotype risk for each individual haplotype block. Finally, multivariate logistic regression was used to develop the final extended model that included the original set of risk factors from the Spitz model plus additional haplotypes and SNPs. We evaluated increase in discriminatory power by evaluated change in the area under the receiver-operating characteristic curve and the net reclassification index. Results: The discriminatory power for the original Spitz model was 66.1% (95% CI = 0.638-0.683). With the inclusion of only single SNPs in to the model, the discriminatory power increased by 4.5% to 70.6% (95% CI = 0.684-0.727, p-value = <0.0001). Adding the top 6 haplotypes further increased the discriminatory power to 71.9% (95% CI = 0.697-0.739). The net reclassification index results show that this increase in discriminatory power is evident for both cases (23.47%) and controls (23.43%). Conclusions: Inclusion of genetic variants into an established epidemiologic risk model can substantially increase the discriminatory power; however, selection and modeling of these variants needs to be carefully done.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-326. doi:1538-7445.AM2012-LB-326
Abstract LB-331: Polymorphisms in inflammation pathway genes and endometrial cancer
Authors: Delahanty Ryan J. , Xiang Yong-Bing , Spurdle Amanda , Beeghly-Fadiel Alicia , Long Jirong , Thompson Deborah , Tomlinson Ian , Yu Herbert , Lambrechts Diether , Dörk Thilo , Goodman Marc T. , Salvesen Helga B. , Lu Wei , Cai Qiuyin , Zheng Wei , Shu Xiao Ou
Published: August 2012

Experimental and epidemiological evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. To investigate this hypothesis, we carried out a two-stage study to evaluate single nucleotide polymorphisms (SNPs) in inflammatory pathway genes in association with endometrial cancer risk. In stage 1, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 830 endometrial cancer cases and 2,322 controls using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage 1 SNPs significantly associated with endometrial cancer (P<0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. We then selected one SNP from each of the 24 loci for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in the stage 2 sample, which consisted of eight additional studies including 4,890 endometrial cancer cases and 5,403 controls. Four of the 21 SNPs in or near the FABP1, CXCL3, MSR1, and MMP9 genes were significantly associated with endometrial cancer in the combined data sets. The allelic odds ratios were 0.90 (0.82-0.97) for FABP1, 1.17 (1.05-1.31) for CXCL3, 0.86 (0.78-0.96) for MSR1, and 0.90 (0.85-0.95) for MMP9. The SNPs in CXCL3 and MMP9 were significantly associated with endometrial cancer in both the discovery and replication samples. Of these findings, the association for the MMP9 promoter polymorphism rs3918249 (P=0.00047) remained significant after adjustment for the total number of comparisons. These findings suggest that genetic polymorphisms in the MMP9 gene and possibly in or near the FABP1, CXCL3, and MSR1 genes may contribute to genetic susceptibility to endometrial cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-331. doi:1538-7445.AM2012-LB-331
Abstract LB-340: High pain prevalence is reported by patients with head and neck cancer: systematic review
Authors: Macfarlane Tatiana V. , Wirth Tanja , Ranasinghe Sriyani
Published: August 2012

Background: Pain is a major symptom in patients with cancer; however information on head and neck cancer (HNC) related pain is limited. Aim: To investigate the prevalence of pain and associated factors among patients with HNC. Materials and Methods: The systematic review used a wide searching strategy to December 2011. Cancers of the oral mucosa, oropharynx, hypopharynx and larynx were included in this review with pain as main outcome. The review was restricted to full research reports of observational studies published in English. A checklist was used to assess the quality of selected studies. Results: There were 82 studies included in the review and most of them (84%) were conducted in the past ten years. Studies were relatively small, with a median of 80 patients (IQR 44, 154). The quality of reporting was variable, for example only 67% of the articles stated the study design and none of the papers justified sample size. The majority of the papers (84%) did not report efforts that were taken to address potential sources of bias and 35% did not specify the participation rate. Most studies (77%) used self-administered quality of life questionnaires, where pain was a component of the overall scale. Only 32 studies reported pain prevalence in HNC patients (combined estimate from meta-analysis 49%, 95% CI 41% - 57%), in contrast to levels of pain (scale 0-100: mean 55, 95% CI 51 - 59 based on 12 studies). Only 55 studies (67%) considered associated factors, mostly tumour- or treatment-related. Three out of ten studies reported higher levels of pain at older ages and three out of twelve found higher levels in women. There was no consistent evidence of an association with smoking and alcohol. Conclusion: The study has shown high levels of pain prevalence and some factors associated with higher levels of pain. There is a need for higher quality studies in a priority area for the care of patients with HNC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-340. doi:1538-7445.AM2012-LB-340
Abstract LB-343: Defining mechanisms of endocrine resistance in breast cancer using whole exome sequencing
Authors: Chandiramani Natasha , Levano Kelly S. , Peterson Esther A. , Kenny Paraic A.
Published: August 2012

About 70% of breast cancers are estrogen receptor positive (ER+) and current treatments target either ER activity (Tamoxifen and Fulvestrant) or the production of estrogen (aromatase inhibitors). These treatments have led to significant increases in disease-free and overall survival, but after initial response to these agents, many ER+ cancers progress to endocrine resistance. There have been several attempts to understand the molecular mechanisms that lead to acquired resistance, but a clear understanding is still lacking. We hypothesize that endocrine resistant cells in the tumor arise by acquiring compensatory somatic mutations, and that some of these driver mutations responsible for resistance are in oncogenes or tumor suppressor genes. To test this we performed whole exome sequencing on three of MCF7 breast cancer cell sublines that are resistant to either tamoxifen, fulvestrant or exemestane - drugs commonly used in the clinic to treat ER+ breast cancers. An Illumina TruSEQ adaptor-based exonic library was prepared using genomic DNA from the resistant and control cell lines, and multiplexed on an Illumina HiSeq 2000 sequencer (100bp paired-end reads). Reads were aligned to human genome build 19 using BWA, variants were called using SAMTools, somatic mutations in endocrine cell lines were determined with VarScan, and amino acid changes were annotated using ANNOVAR. We have identified several non-synonymous mutations in cancer-relevant genes and are currently working to validate these targets. Studying these genes will increase our understanding of how tumors overcome the requirement for estrogen signaling and ultimately, we hope that comparing tumor profiles of patients with endocrine resistance disease will lead to therapeutics targeted to these secondary mutational lesions.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-343. doi:1538-7445.AM2012-LB-343
Abstract LB-347: Identify signaling responses to MEK inhibitor AZD6244 in lung cancer cells with proteomics reverse phase protein array
Authors: Dai Bingbing , Liu Wenbin , Heymach John V. , Byers Lauren A. , Wang Jing , Coombes Kevin R. , Fang Bingliang , Roth Jack A.
Published: August 2012

AZD6244 is small-molecule inhibitor that targets the MAPK pathway, and is currently in phase I/II clinical evaluation. While some efficacy of these agents has been observed in phase I/II clinical trials, one of the hurdles of targeted therapy is the intrinsic and acquired resistance mediated by complex feedback pathways. Identifying downstream effectors required for cellular response to MEK inhibitors will help us understand the mechanism of resistance, possibly leading to the development of direct therapeutic targets. Explore the signaling responses after treatment with MEK inhibitors will also allow us to identify signaling feedback loops and cross talks. We used reverse phase protein array (RPPA) technology to determine which downstream effectors of MEK/ERK pathways critical for cell growth inhibition or apoptosis induced by MEK inhibitors, and to identify which signaling pathways are inhibited or activated when the pathways is blocked. RPPA is a antibody-based quantitative assay used to analyze nanoliter amounts of sample for 200 proteins to determine expression levels and protein modifications such as phosphorylation or cleavage. Experiments were carried out in 5 resistant and 5 sensitive cell lines with the MEK inhibitor, AZD6244. Cells were treated at different time points (0, 6, 12, 24, 48, and 72 hours) and with various dosages (0, 0.3, 1, 3 and 10 µM). Cell lysates were collected and quantified for RPPA assays. The data was analyzed for the presence of clusters based on differential protein expression by using available methods with a statistical software package (StatSoft, Tulsa, OK). Significantly changed proteins were analyzed with Ingenuity Pathway Analysis (IPA). Proteins Data from RPPA was further validated by using Western blotting with the same antibody used in the RPPA assay. The results showed that inhibition of MEK/ERK could activate multiple signaling pathways including AKT, SRC, STAT3 and IGF1R. Activation of those signaling pathway through signaling cross talk and feedbacks may involved in the intrinsic and acquitted resistance to MEK inhibitor. We also indentified a penal of molecules, such as BIM, P27, p53 and JNK were specifically induced only in the sensitive cells. Those molecules might be the mediators of MEK inhibitor induced cell apoptosis. The results will be helpful in understanding of the signaling cross talks and feedbacks and in the exploration of mechanisms of sensitivity and resistance to the treatment with MEK inhibitors in lung cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-347. doi:1538-7445.AM2012-LB-347
Abstract LB-354: A novel orally-bioavailable small-molecule inhibitor of Stat3 regresses human breast and lung cancer xenografts
Authors: Yue Peibin , Zhang Xiaolei , Page Brent DG , Zhao Wei , Paladino David , Gunning Patrick T. , Turkson James
Published: August 2012

Constitutive activation of STAT3, a member of the Signal Transducer and Activator of Transcription (STAT) family of proteins, occurs with a high frequency in diverse human tumors and is a molecular abnormality promoting carcinogenesis and tumor progression. Although STAT3 has been targeted for anticancer drug development, there is presently no STAT3 drug in the clinic. To identify potent therapeutics for tumors harboring constitutively-active STAT3, the key dimerization step in STAT3 activation was targeted in small-molecule drug development. A novel, orally bio-available small-molecule inhibitor has been identified that binds STAT3 SH2 domain with a KD of 504 nM. BP-1-102 blocks constitutively-active STAT3 signaling and selectively inhibits growth, survival, migration and invasion of diverse STAT3-dependent tumor cells in vitro. BP-1-102-mediated inhibition of aberrantly-active STAT3 in tumor cells suppresses the expression of c-Myc, Cyclin D1, Bcl-xL, Survivin, and vascular endothelial growth factor (VEGF). Further, treatment with BP-1-102 of breast cancer cells harboring aberrantly-active STAT3 disrupts STAT3-NFκB cross-talk and blocks the phosphorylation of focal adhesion kinase and paxillin, while enhancing E-cadherin expression. Intravenous or oral administration of BP-1-102 furnishes micromolar or microgram levels in tumor tissues and inhibits growth of human breast and lung tumor xenografts. Data together identify BP-1-102 as a small-molecule STAT3 inhibitor with a great potential for clinical development. The oral bioavailability represents a substantial advancement in the discovery of small-molecule STAT3 inhibitors as novel anticancer drugs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-354. doi:1538-7445.AM2012-LB-354
Abstract LB-356: Micelle-encapsulated thiostrepton: an effective nanomedicine for inhibiting tumor growth
Authors: Wang Ming , Gartel Andrei
Published: August 2012

The thiazole antiobiotic, thiostrepton, has been found to suppress the expression of FOXM1, the oncogenic forkhead transcription factor overexpressed in cancer cells. Thiostrepton has also been shown to induce cell death in cancer cells through a proteasome inhibitory mechanism. As thiostrepton is highly hydrophobic, encapsulation into nano-sized delivery vehicles not only aides its solubilization but also improves its targeting for tumors in vivo. This is achieved by encapsulating thiostrepton into the interior of an amphiphilic micelle, composed from an assembly of lipid-PEG (polyethylene glycol) conjugates. In this study, we examined the anti-tumor effects of micelle-thiostrepton in both subcutaneous xenograft models (HepG2 liver cancer, Capan-2 pancreatic cancer and MDA-MB-231 breast cancer) and endogenous liver tumor models (DEN/PB-induced adenocarcinomas). In the case of the xenograft tumor-bearing mice, biodistribution studies showed micelle-thiostrepton to accumulate into both the liver (30% of injected dose) and the xenograft tumors (60% of injected dose) from 4 hours post-administration. In the endogenous liver cancer models, micelle-thiostrepton accumulated into the liver only, allowing a high concentration of tumor-associated thiostrepton drug. Continuous administration of micelle-thiostrepton at doses of 40mg/kg, 3 times a week for 30 days retarded the growth rate of all subcutaneous tumors and reduced the occurrence of adenocarinomas in endogenous liver cancer models. Immunoblotting and immunohistochemical staining revealed that treatment with micelle-thiostrepton inhibited the expression of the oncogenic transcription factor FOXM1 in tumors, a reduction of which generally coincides with suppressed cell proliferation and increased cell death. Furthermore, it was found that the reduced tumor growth rate of thiostrepton-treated tumors was indeed related to increased apoptosis, as indicated by the elevated expression of cleaved caspase-3 in such tumors samples. Our data suggest that the thiazole antibiotic/proteasome inhibitor thiostrepton, when formulated into nanoparticles, may be highly suited as a nanomedicine for treating cancer, particularly that of liver cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-356. doi:1538-7445.AM2012-LB-356
Abstract LB-357: Identification of a new inhibitor of the Golgi system, targeting ADP-ribosylation Factor 1 (Arf1) with potential for cancer therapy
Authors: Ohashi Yoshimi , Iijima Hiroshi , Yamaotsu Noriyuki , Yamazaki Kanami , Sato Shigeo , Okamura Mutsumi , Sugimoto Kenji , Dan Shingo , Hirono Shuichi , Yamori Takao
Published: August 2012

[Background] ADP-ribosylation factor 1 (Arf1) plays a major role in mediating vesicular transport. Brefeldin A (BFA), a known inhibitor of the Arf1-guanine nucleotide exchange factor (GEF) interaction, is highly cytotoxic. Therefore, interaction of Arf1 with ArfGEF is an attractive target for cancer treatment. However, BFA and its derivatives have not progressed beyond the pre-clinical stage of drug development because of their poor bioavailability. Here, we aimed to identify novel inhibitors of the Arf1-ArfGEF interaction that display potent antitumor activity in vivo but with a chemical structure distinct from that of BFA. [Results] We exploited a panel of 39 cell lines (termed JFCR39) coupled with a drug sensitivity data base and COMPARE algorithm, resulting in the identification of a possible novel Arf1-ArfGEF inhibitor, (2E,4E)-5-((1S,2S,4aR,6R,7S,8S,8aS)-7-hydroxy-2,6,8-trimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)-2-methyl-N-(pyridin-3-ylmethyl)penta-2,4-dienamide (AMF-26), which differed structurally from BFA. By using a pulldown assay with GGA3-conjugated beads, we demonstrated that AMF-26 inhibited Arf1 activation. Subsequently, AMF-26 induced Golgi disruption, apoptosis, and cell growth inhibition. AMF-26 did not inhibit the phosphorylation of Akt and Erk. Computer modeling/molecular dynamics (MD) simulation suggested that AMF-26 bound to the contact surface of the Arf1-Sec7 domain where BFA bound. AMF-26 affected membrane traffic, including the cis-Golgi and trans-Golgi networks, and the endosomal systems. Furthermore, using AMF-26 and its derivatives, we demonstrated that there was a significant correlation between cell growth inhibition and Golgi disruption. In addition, orally administratedAMF-26(83mg/kgofbodyweight;5 days) induced complete regression of human breast cancer BSY-1 xenografts in vivo. [Conclusion] AMF-26 is a novel anticancer drug lead that inhibits the Golgi system, targeting Arf1 activation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-357. doi:1538-7445.AM2012-LB-357
Abstract LB-358: Heme oxygenase-1 and carbon monoxide arrest tumor growth via modulation of cellular respiration
Authors: Wegiel Barbara , Gallo David , Czismadia Eva , Cunningham Kellie , Seth Pankaj , Persson Jenny , Helczynski Leszek , Otterbein Leo
Published: August 2012

Heme oxygenase-1 (HO-1) and carbon monoxide (CO) are endogenous cytoprotective molecules yet their role in tumor growth, metastasis, cell death and DNA damage has not been elucidated. HO-1 expression was assessed in prostate cancer biopsies from 482 patients and strong nuclear staining, indicative of loss of enzymatic activity was observed in moderately differentiated tumors. Employing prostate cancer (PCa) as our model we treated PCa cells with the chemotherapeutics camptothecin or doxorubicin and observed an increase in cytosolic HO-1 activity that correlated with increased cell death. Overexpression of HO-1 or exogenous pretreatment with CO increased tumor cell sensitivity to chemotherapeutics one thousand fold. In contrast, CO blocked chemotherapeutic-induced cell death of normal prostate epithelial cells. In vivo, CO exposure of mice with established PC3 xenografts resulted in complete growth arrest and sensitization of tumors to doxorubicin with mitotic blockade and enhanced apoptosis of the tumor cells. Exposure to CO showed similar effects in a model of PC3 orthotopic tumors with significant inhibition in markers of invasion. Further, CO blocked development of PIN and prostate tumors in the model of TRAMP mice with concomitant targeting of mitochondria. Further, CO inhibited growth of lung adenocarcinoma in the inducible KRas model of carcinogenesis. Collectively, our data demonstrate the importance of cellular localization of HO-1 in human PCa progression and importantly that CO in part, regulates cellular sensitivity to DNA damaging agents and offers a novel therapeutic adjuvant for the treatment of cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-358. doi:1538-7445.AM2012-LB-358
Abstract LB-362: The MEK inhibitor selumetinib (AZD6244 - ARRY-142886) prevents lung metastasis in a triple-negative breast cancer (TNBC) xenograft model
Authors: Bartholomeusz Chandra , Ali Dadbin , Saso Hitomi , Kondo Kimie , Smith Paul , Hortobagyi Gabriel N. , Ueno Naoto T.
Published: August 2012

Patients with TNBC are negative for estrogen receptor, progesterone receptor, and HER2 expression, and have a very poor prognoses because tumors often metastasize, leading to death. Preventing metastasis as well as inhibiting the tumor growth, is crucial to improving the prognosis of TNBC. We previously showed that patients with ERK2-overexpressing TNBC were at higher risk of death than those with low-ERK2-expressing tumors. Interestingly, when we treated the TNBC cells lines MDA-MB-231 and SUM-149 with the MEK1/2 ATP uncompetitive kinase inhibitor (selumetinib) at concentrations of 0.1 and 1.0 μM, it did not reduce cell viability in a two-dimensional (2D) cell culture. However, in a three-dimensional (3D) cell culture model, selumetinib changed the mesenchymal phenotype of TNBC to an epithelial phenotype. Cells undergoing epithelial-mesenchymal transition are well known to potentially contribute to the metastatic process and have increased ability to form mammospheres. Thus, we hypothesized that targeted inhibition of the MEK-ERK pathway by selumetinib may prevent lung metastasis in TNBC. In the present study, we observed that SUM-149 cells treated with selumetinib (0.1, 1.0 μM) exhibited cell-cycle arrest at G1 but did not exhibit apoptosis indicated by an increased proportion of cells at sub-G1 phase. Both SUM-149 and MDA-MB-231 cells treated with selumetinib exhibited significant inhibition of anchorage-independent growth, an indicator of in vivo tumorigenicity (P<0.005). In addition, in SUM-149 cells and MDA-MB-231, treatment with selumetinib (0.01, 0.1,1.0 and 10μM) suppressed formation of mammospheres in a dose-dependent manner. Next, to determine the role of the MEK-ERK pathway in the prevention of TNBC metastasis, we used a metastatic TNBC animal model established with MDA-MB-231-LM2-4175 (lung metastatic subpopulation) cells transfected with a luciferase gene that were injected intravenously into the tail vein of mice. We observed that mice treated with selumetinib had significantly fewer lung metastases than did control mice injected with a vehicle (P<0.05, 2-sided t test.) These findings support a crucial role for the MAPK pathway in metastasis and suggest that ERK pathway might provide clinical benefit by preventing metastasis. Targeted inhibition of the MEK-ERK pathway with selumetinib may be a novel approach to treatment of TNBC metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-362. doi:1538-7445.AM2012-LB-362
Abstract LB-37: Cancer patient navigators of Georgia (CPNG) advocate for cancer survivors
Authors: Patterson Angie
Published: August 2012

The Georgia Cancer Coalition (GCC) is a not-for-profit organization that seeks to unite government agencies, academic institutions, civic groups, healthcare organizations and survivors to reduce the number of cancer deaths in Georgia and to move Georgia to the top ranks of cancer care in the nation. The Georgia Society for Clinical Oncology (GASCO) partnered with the GCC and was awarded a grant from the American Society for Clinical Oncology (ASCO) to determine the interest in formulating a statewide multi-disciplinary organization for people who help cancer patients navigate the healthcare system. A survey was conducted and results from eighty navigators representing 25 cities demonstrated an organizational need. The Cancer Patient Navigators of Georgia (CPNG) was founded as a unique statewide organization of individuals who serve people with all types of cancer, at all stages, in all types of settings, with a diversity of education and training (from lay navigators to nurse navigators and social work navigators). CPNG's mission is to connect, educate and share best practices among patient navigators in Georgia, so that together we can successfully reduce barriers and increase access to services specifically related to cancer. The steering team developed a logo, by-laws, officers, working committees, electronic newsletters and a website, with a members-only section for social networking. Membership currently tops 230. A recent social networking survey had 100 respondents. We have conducted three annual meetings with attendance of each meeting exceeding 100. The GCC received a private gift of $250,000 to expand the patient navigation efforts in Georgia. One component of the gift is sponsoring the first Integrative Oncology conference to be held in Georgia on January 20, 2012 for the members of Cancer Patient Navigators of Georgia. In conclusion, the initial survey indicating an organizational need to create a statewide multi-disciplinary organization for people who help cancer patients navigate the healthcare system was the beginning of the Cancer Patient Navigators of Georgia (CPNG).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-37. doi:1538-7445.AM2012-LB-37
Abstract LB-377: Promoter methylation of the DAPK1 CLL predisposition gene is associated with chronic lymphocytic leukaemia risk
Authors: Candiloro Ida , Mikeska Thomas , Giles Graham , Severi Gianluca , Dobrovic Alexander
Published: August 2012

The pro-apoptotic gene DAPK1 has been identified as a hereditary cancer gene in some cases of chronic lymphocytic leukaemia (CLL). The causative mutation acts to increase the probability of methylation of the DAPK1 gene. Moreover, DAPK1 promoter methylation has been demonstrated to occur in nearly all cases of CLL, leading to down-regulation of the gene. We hypothesized that DAPK1 methylation thus underlies most cases of CLL and that predisposition to CLL might be associated with predisposition to methylate the DAPK1 gene. We thus accessed a large epidemiological cohort in which blood had been collected from participants who were then followed up indefinitely. This enabled us to compare methylation at the DAPK1 promoter in peripheral blood leukocyte DNA taken from individuals who developed CLL and control individuals who did not develop cancer. A quantitative MSP-based approach was used to analyse three regions within the 1.3kb promoter CpG island; (i) 5′ of exon 1 and at the 5′ end of the island. (ii) 3′ of exon 1 and in the centre of the island and (iii) 5′ of exon 2 and at the 3′ end of the island. No significant difference was found at the 5′ or the 3′ends of the island. However, when the central region (immediately after exon 1) was examined, the difference between the cases and controls was highly significant (p = 0.004). These results strongly support an important role for DAPK1 methylation in the early pathogenesis of CLL. Whilst methylation at the central part of the CpG island is not known to regulate any transcript, it may be an important first step in the CLL process as a seeding event. This hypothesis is supported by the fact that methylation at either end of the promoter was more likely if methylation was also present in the centre (p= 0.02 for controls and 0.006 for cases).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-377. doi:1538-7445.AM2012-LB-377
Abstract LB-39: Kidney cancer association fighting back togethe
Authors: Fahy Maria T.
Published: August 2012

The Kidney Cancer Association's (KCA) vision since its creation by founder Eugene P. Schonfeld, PhD has been The Elimination of Death and Suffering from Renal Cancers and to pursue A World Without Kidney Cancer. The Kidney Cancer Association has grown in the last 21 years to be an amazing organization that included over 55,000 people in more than 100 countries, The KCA is organization that pursues its worldwide vision through education, research and advocacy with a three person staff which is assisted by a dedicated group of professionals and other individuals who serve on a governing board, or a medical advisory board, or performs a host of other duties that allows the KCA to play an important role in the advances that have made in the diagnosis, treatment and follow up of renal cancers during the past two decades. As an independent advocate and daughter who lost her father to kidney cancer, Team Chema was born. With the help and support of KCA, Team Chema will be involved in bringing information about the latest research and best practices to the places that have cultural and language barriers that hinder cancer prevention and treatment. Team Chema is dedicated to supporting patients, organizing fundraising events and creating awareness.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-39. doi:1538-7445.AM2012-LB-39
Abstract LB-40: How patient advocacy can positively impact clinical research
Authors: Schroer Grace E.
Published: August 2012

The Bladder Cancer Advocacy Network (BCAN) was the first national patient advocacy group to focus on blader cancer. Since its establishment in 2005, BCAN has put forth a number of programs designed to advance the three goals of our mission; raising awareness of bladder cancer, providing education and support to the bladder cancer community and advancing bladder cancer research. As part of BCAN's mission to advance to advance research, they has sought to encourage collaboration among physicians and research who are dedicated to the study of bladder cancer and its prevention, diagnosis and treatment by hosting an annual scientific Think Tank meeting.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-40. doi:1538-7445.AM2012-LB-40