Cancer Clinical Studies Research Articles

PWE-168 Omega-3 fatty acid infusion reduces gastrointestinal toxicity and prevents thromboembolism in patients with advanced oesophagogastric cancer treated with palliative platinum based chemotherapy: Abstract PWE-168 Table 1

<h3>Introduction</h3> The omega-3 fatty acids, EPA and DHA have proven anticancer activity in laboratory and clinical cancer studies. This clinical trial evaluated whether adding omega-3 fatty acids to palliative platinum based chemotherapy influenced the outcome of patients with oesophagogastric cancer compared to those given chemotherapy alone <h3>Method</h3> 21 participants in the 1st stage of a phase II single arm trial received palliative chemotherapy, intravenous (IV) epirubicin (50mg/m²) and oxaliplatin (130mg/m²) every 21 days, oral capecitabine (1250mg/m²) daily for 21 days and IV omega-3 fatty acids (2ml/Kg/4 h) (Omegaven® Fresenius-Kabi). The Omegaven infusion was given immediately after the chemotherapy on days 1, 8 and 15 of each cycle (intervention). Clinical outcomes were compared to outcomes in 37 patients treated with chemotherapy alone (control). Toxicities were graded using the CTCAE v4.03. Clinical response rate was assessed by RECIST v1.1 criteria. <h3>Results</h3> Fifty-six patients eligible participants were screened for inclusion, 35 were excluded principally because of poor performance status. Twenty one patients were enrolled in the study, 20 received at least one treatment and they form the basis of this report. The radiological response and toxicity of the intervention and control groups are indicated (Table 1). The mean baseline and 7 day post treatment triglyceride levels were 1.7 mmol/l (95% CI 1.6- 1.79) and 1.66 mmol/l (95% CI 1.56–1.75) respectively. The highest recorded triglyceride level was 4.84 mmol/l. No patient experienced fat overload syndrome or grade 3/4 hypertriglyceridemia. Mean platelet counts were 217 X109/l in the intervention group (95% CI 207–226 X109/l) compared to 332 X109/l in the control group (95% CI 316–348 X109/l). <h3>Conclusion</h3> Compared to patients treated with chemotherapy alone, those treated with supplementary omega-3 fish oils had reduced chemotherapy related toxicity, notably fewer gastrointestinal and thromboembolic adverse effects. Omega-3 fatty acids have the potential to ameliorate the toxicity associated with chemotherapeutic agents. <h3>Disclosure of interest</h3> A. Eltweri Grant/ Research Support from: Fresenius-Kabi, A. Thomas Grant/ Research Support from: Fresenius-Kabi, A. Dennison Grant/ Research Support from: Fresenius-Kabi, M. Metcalfe Grant/ Research Support from: Fresenius-Kabi, D. Bowrey Grant/ Research Support from: Fresenius-Kabi, Nutricia

ERRγ target genes are poor prognostic factors in Tamoxifen-treated breast cancer.

BackgroundOne-third of estrogen (ER+) and/or progesterone receptor-positive (PGR+) breast tumors treated with Tamoxifen (TAM) do not respond to initial treatment, and the remaining 70% are at risk to relapse in the future. Estrogen-related receptor gamma (ESRRG, ERRγ) is an orphan nuclear receptor with broad, structural similarities to classical ER that is widely implicated in the transcriptional regulation of energy homeostasis. We have previously demonstrated that ERRγ induces resistance to TAM in ER+ breast cancer models, and that the receptor’s transcriptional activity is modified by activation of the ERK/MAPK pathway. We hypothesize that hyper-activation or over-expression of ERRγ induces a pro-survival transcriptional program that impairs the ability of TAM to inhibit the growth of ER+ breast cancer. The goal of the present study is to determine whether ERRγ target genes are associated with reduced distant metastasis-free survival (DMFS) in ER+ breast cancer treated with TAM.MethodsRaw gene expression data was obtained from 3 publicly available breast cancer clinical studies of women with ER+ breast cancer who received TAM as their sole endocrine therapy. ERRγ target genes were selected from 2 studies that published validated chromatin immunoprecipitation (ChIP) analyses of ERRγ promoter occupancy. Kaplan-Meier estimation was used to determine the association of ERRγ target genes with DMFS, and selected genes were validated in ER+, MCF7 breast cancer cells that express exogenous ERRγ.ResultsThirty-seven validated receptor target genes were statistically significantly altered in women who experienced a DM within 5 years, and could classify several independent studies into poor vs. good DMFS. Two genes (EEF1A2 and PPIF) could similarly separate ER+, TAM-treated breast tumors by DMFS, and their protein levels were measured in an ER+ breast cancer cell line model with exogenous ERRγ. Finally, expression of ERRγ and these two target genes are elevated in models of ER+ breast cancer with hyperactivation of ERK/MAPK.ConclusionsERRγ signaling is associated with poor DMFS in ER+, TAM-treated breast cancer, and ESRRG, EEF1A2, and PPIF comprise a 3-gene signaling node that may contribute to TAM resistance in the context of an active ERK/MAPK pathway.

Cooling-Induced ER Stress is Good for Your Brain

Cooling-Induced ER Stress is Good for Your Brain

Comparing Platforms for Messenger RNA Expression Profiling of Archival Formalin-Fixed, Paraffin-Embedded Tissues

Archival formalin-fixed, paraffin-embedded (FFPE) tissue specimens represent a readily available but largely untapped resource for gene expression profiling-based biomarker discovery. Several technologies have been proposed to cope with the bias from RNA cross-linking and degradation associated with archival specimens to generate data comparable with RNA from fresh-frozen materials. Direct comparison studies of these RNA expression platforms remain rare. We compared two commercially available platforms for RNA expression profiling of archival FFPE specimens from clinical studies of prostate and ovarian cancer: the Affymetrix Human Gene 1.0ST Array following whole-transcriptome amplification using the NuGen WT-Ovation FFPE System V2, and the NanoString nCounter without amplification. For each assay, we profiled 7 prostate and 11 ovarian cancer specimens, with a block age of 4 to 21 years. Both platforms produced gene expression profiles with high sensitivity and reproducibility through technical repeats from FFPE materials. Sensitivity and reproducibility remained high across block age within each cohort. A strong concordance was shown for the transcript expression values for genes detected by both platforms. We showed the biological validity of specific gene signatures generated by both platforms for both cohorts. Our study supports the feasibility of gene expression profiling and large-scale signature validation on archival prostate and ovarian tumor specimens using commercial platforms. These approaches have the potential to aid precision medicine with biomarker discovery and validation.

Su1959 Omega-3 Fatty Acid Infusion Reduces Gastrointestinal Toxicity and Prevents Thromboembolism in Patients With Advanced Esophagogastric Cancer Treated With Palliative Platinum Based Chemotherapy

Introduction The omega-3 fatty acids, EPA and DHA have proven anticancer activity in laboratory and clinical cancer studies. This clinical trial evaluated whether adding omega-3 fatty acids to palliative platinum based chemotherapy influenced the outcome of patients with oesophagogastric cancer compared to those given chemotherapy alone Method 21 participants in the 1st stage of a phase II single arm trial received palliative chemotherapy, intravenous (IV) epirubicin (50mg/m 2 ) and oxaliplatin (130mg/m 2 ) every 21 days, oral capecitabine (1250mg/m 2 ) daily for 21 days and IV omega-3 fatty acids (2ml/Kg/4 h) (Omegaven® Fresenius-Kabi). The Omegaven infusion was given immediately after the chemotherapy on days 1, 8 and 15 of each cycle (intervention). Clinical outcomes were compared to outcomes in 37 patients treated with chemotherapy alone (control). Toxicities were graded using the CTCAE v4.03. Clinical response rate was assessed by RECIST v1.1 criteria. Results Fifty-six patients eligible participants were screened for inclusion, 35 were excluded principally because of poor performance status. Twenty one patients were enrolled in the study, 20 received at least one treatment and they form the basis of this report. The radiological response and toxicity of the intervention and control groups are indicated (Table 1). The mean baseline and 7 day post treatment triglyceride levels were 1.7 mmol/l (95% CI 1.6- 1.79) and 1.66 mmol/l (95% CI 1.56–1.75) respectively. The highest recorded triglyceride level was 4.84 mmol/l. No patient experienced fat overload syndrome or grade 3/4 hypertriglyceridemia. Mean platelet counts were 217 X109/l in the intervention group (95% CI 207–226 X109/l) compared to 332 X109/l in the control group (95% CI 316–348 X109/l). Conclusion Compared to patients treated with chemotherapy alone, those treated with supplementary omega-3 fish oils had reduced chemotherapy related toxicity, notably fewer gastrointestinal and thromboembolic adverse effects. Omega-3 fatty acids have the potential to ameliorate the toxicity associated with chemotherapeutic agents. Disclosure of interest A. Eltweri Grant/ Research Support from: Fresenius-Kabi, A. Thomas Grant/ Research Support from: Fresenius-Kabi, A. Dennison Grant/ Research Support from: Fresenius-Kabi, M. Metcalfe Grant/ Research Support from: Fresenius-Kabi, D. Bowrey Grant/ Research Support from: Fresenius-Kabi, Nutricia

Infection and integration of high-risk human papillomavirus in HPV-associated cancer cells

High-risk human papillomaviruses (HPV) have been associated with many human cancers in clinical studies. Integration of HPV into the human genome is a suspected etiological factor in the induction of some HPV-associated cancers. The characteristics of HPV integration in certain HPV-integrated cancer cells remain unclear. In this study, ten HPV-associated carcinoma cell lines were evaluated for the presence, genotype, and integration status of HPV by nested polymerase chain reaction. The HPV genome did not insert in the genome of a mammary cancer cell line (MCF7), adrenal neuroblastoma cell line (NH-6), or three esophageal carcinoma cell lines (KYSE150, KYSE450 and KYSE140). HPV type 18 DNA did infect cell lines of tongue cancer (Tca83), hepatocellular carcinoma (Hep G2), and lung carcinoma (A549), but the HPV type 18 genes were not transcribed into mRNA. However, HPV type 18 integrated into the genomes of the esophageal carcinoma cell lines EC9706 and EC109, and the integration sites for both cell lines were in loci 8q24, which is a gene desert area adjacent to fragile sites. We speculate that HPV transcripts are more likely to integrate near highly susceptible fragile sites. This study suggests that HPV integration is still a significant issue that needs to be fully examined and can possibly be used as individualized biomarkers for the early diagnosis of HPV-related cancers.

Circulating tumor cells in lung cancer: detection methods and clinical applications.

Circulating tumor cells (CTCs) are tumor cells that have disseminated from primary and metastatic sites, and circulate in the bloodstream. Advanced immunological and molecular-based methods can be used to detect and analyze the cells with the characteristics of tumor cells, and can be detected and analyzed in the blood of cancer patients. The most commonly used methods in lung cancer combine the processes of immunomagnetic enrichment and immunocytochemical detection, morphology-based enrichment coupled with reverse transcriptase polymerase chain reaction (RT-PCR), and RT-PCR alone. CTC analysis is considered a liquid biopsy approach for early diagnosis, risk stratification, evaluation of curative efficacy, and early detection of lung cancer relapse. In this review, we discuss the present techniques for analyzing CTCs, and the restrictions of using these methods in lung cancer. We also review the clinical studies in lung cancer and discuss the underlying associations between these studies and their future applications to this disease.

Near Infrared Fluorescence Imaging for early detection, monitoring and improved intervention of diseases involving the joint

Joints consist of different tissues, such as bone, cartilage and synovium, which are at risk for multiple diseases. The current imaging modalities, such as magnetic resonance imaging, Doppler ultrasound, X-ray, computed tomography and arthroscopy, lack the ability to detect disease activity before the onset of anatomical and significant irreversible damage. Optical in vivo imaging has recently been introduced as a novel imaging tool to study the joint and has the potential to image all kinds of biological processes. This tool is already exploited in (pre)clinical studies of rheumatoid arthritis, osteoarthritis and cancer. The technique uses fluorescent dyes conjugated to targeting moieties that recognize biomarkers of the disease. This review will focus on these new imaging techniques and especially where Near Infrared (NIR) fluorescence imaging has been used to visualize diseases of the joint. NIR fluorescent imaging is a promising technique which will soon complement established radiological, ultrasound and MRI imaging in the clinical management of patients with respect to early disease detection, monitoring and improved intervention.

Synovial sarcoma: recent discoveries as a roadmap to new avenues for therapy.

Oncogenesis in synovial sarcoma is driven by the chromosomal translocation t(X,18; p11,q11), which generates an in-frame fusion of the SWI/SNF subunit SS18 to the C-terminal repression domains of SSX1 or SSX2. Proteomic studies have identified an integral role of SS18-SSX in the SWI/SNF complex, and provide new evidence for mistargeting of polycomb repression in synovial sarcoma. Two recent in vivo studies are highlighted, providing additional support for the importance of WNT signaling in synovial sarcoma: One used a conditional mouse model in which knockout of β-catenin prevents tumor formation, and the other used a small-molecule inhibitor of β-catenin in xenograft models. Synovial sarcoma appears to arise from still poorly characterized immature mesenchymal progenitor cells through the action of its primary oncogenic driver, the SS18-SSX fusion gene, which encodes a multifaceted disruptor of epigenetic control. The effects of SS18-SSX on polycomb-mediated gene repression and SWI/SNF chromatin remodeling have recently come into focus and may offer new insights into the basic function of these processes. A central role for deregulation of WNT-β-catenin signaling in synovial sarcoma has also been strengthened by recent in vivo studies. These new insights into the the biology of synovial sarcoma are guiding novel preclinical and clinical studies in this aggressive cancer.

Chemokine receptor-specific antibodies in cancer immunotherapy: achievements and challenges.

The 1990s brought a burst of information regarding the structure, expression pattern, and role in leukocyte migration and adhesion of chemokines and their receptors. At that time, the FDA approved the first therapeutic antibodies for cancer treatment. A few years later, it was reported that the chemokine receptors CXCR4 and CCR7 were involved on directing metastases to liver, lung, bone marrow, or lymph nodes, and the over-expression of CCR4, CCR6, and CCR9 by certain tumors. The possibility of inhibiting the interaction of chemokine receptors present on the surface of tumor cells with their ligands emerged as a new therapeutic approach. Therefore, many research groups and companies began to develop small molecule antagonists and specific antibodies, aiming to neutralize signaling from these receptors. Despite great expectations, so far, only one anti-chemokine receptor antibody has been approved for its clinical use, mogamulizumab, an anti-CCR4 antibody, granted in Japan to treat refractory adult T-cell leukemia and lymphoma. Here, we review the main achievements obtained with anti-chemokine receptor antibodies for cancer immunotherapy, including discovery and clinical studies, proposed mechanisms of action, and therapeutic applications.

Global Oct4 target gene analysis reveals novel downstream PTEN and TNC genes required for drug-resistance and metastasis in lung cancer.

Overexpression of Oct4, a stemness gene encoding a transcription factor, has been reported in several cancers. However, the mechanism by which Oct4 directs transcriptional program that leads to somatic cancer progression remains unclear. In this study, we provide mechanistic insight into Oct4-driven transcriptional network promoting drug-resistance and metastasis in lung cancer cell, animal and clinical studies. Through an integrative approach combining our Oct4 chromatin-immunoprecipitation sequencing and ENCODE datasets, we identified the genome-wide binding regions of Oct4 in lung cancer at promoter and enhancer of numerous genes involved in critical pathways which promote tumorigenesis. Notably, PTEN and TNC were previously undefined targets of Oct4. In addition, novel Oct4-binding motifs were found to overlap with DNA elements for Sp1 transcription factor. We provided evidence that Oct4 suppressed PTEN in an Sp1-dependent manner by recruitment of HDAC1/2, leading to activation of AKT signaling and drug-resistance. In contrast, Oct4 transactivated TNC independent of Sp1 and resulted in cancer metastasis. Clinically, lung cancer patients with Oct4 high, PTEN low and TNC high expression profile significantly correlated with poor disease-free survival. Our study reveals a critical Oct4-driven transcriptional program that promotes lung cancer progression, illustrating the therapeutic potential of targeting Oc4 transcriptionally regulated genes.

Clinical Outcomes in Elderly Patients with Advanced Non-small Cell Lung Cancer: Results from ARIES, a Bevacizumab Observational Cohort Study

AimsRetrospective analyses from first-line clinical studies in advanced non-small cell lung cancer (NSCLC) have reported conflicting results on progression-free survival (PFS) and overall survival benefits with the addition of bevacizumab to chemotherapy in elderly patients. Here we report effectiveness and safety outcomes by age subgroup for patients with NSCLC in the ARIES observational cohort study. Materials and MethodsARIES enrolled patients with advanced non-squamous NSCLC who received first-line bevacizumab-containing treatment per physician's choice. Kaplan–Meier estimates were used to calculate medians and 95% confidence intervals for PFS and overall survival for patients aged <65, ≥65, <75 and ≥75 years. ResultsIn total, 1967 patients receiving first-line treatment with bevacizumab and chemotherapy were enrolled. The median PFS and overall survival values were 6.4 (95% confidence interval = 6.0–6.8) and 14.2 (95% confidence interval = 12.7–15.2) months for patients aged <65 years, respectively, and 6.8 (95% confidence interval = 6.3–7.0) and 12.1 (95% confidence interval = 11.4–13.1) months for patients ≥65 years, respectively. For patients <75 years, the median PFS and overall survival values were 6.6 (95% confidence interval = 6.3–6.9) and 13.5 (95% confidence interval = 12.6–14.5) months, respectively, and 6.6 (95% confidence interval = 5.9–7.1) and 11.6 (95% confidence interval = 10.0–12.5) months, respectively, for patients ≥75 years. Incidence proportions of bevacizumab-associated adverse events were generally similar across all age groups. ConclusionsData from the ARIES study suggest that treatment with bevacizumab in combination with chemotherapy is a viable first-line treatment option for elderly bevacizumab-eligible patients with advanced non-squamous NSCLC.

Paving the Road to Clinical Trial Participation: Removing Road Blocks and Directing Patients Toward Novel Therapies

Paving the Road to Clinical Trial Participation: Removing Road Blocks and Directing Patients Toward Novel Therapies

Empowering Promotores de Salud as partners in cancer education and research in rural southwest Kansas.

To describe community-based participatory processes used to develop promotore training on cancer research, and to assess the feasibility of training promotores from rural communities to disseminate cancer research information. Prospective, cohort design. Rural communities in the state of Kansas. 34 Spanish-speaking promotores attended an information session; 27 enrolled and 22 completed training. With input from a community advisory board, the authors developed a leadership and cancer curriculum and trained Spanish-speaking promotores to disseminate information on cancer research. Promotores completed pretraining and post-training surveys in Spanish to assess demographic characteristics and changes in knowledge of cancer, cancer treatment and cancer research studies, and intent to participate in cancer research. Cancer knowledge, awareness of cancer clinical trials, interest in participating in cancer clinical research studies. Compared to pretraining, after training, promotores were more likely to correctly define cancer, identify biopsies, describe cancer stages, and report ever having heard of cancer research studies. Completion rates of the training and willingness to participate in cancer research were high, supporting the feasibility of training promotores to deliver community-based education to promote cancer research participation. Nursing professionals and researchers can collaborate with promotores to disseminate cancer education and research among underserved rural Latino communities in Kansas and elsewhere. Members of these communities appear willing and interested in improving their knowledge of cancer and cancer clinical trials.

Hyperpolarized 13C-Magnetic Resonance Spectroscopy

Myocardial metabolic abnormalities have been demonstrated widely in diverse cardiac diseases. Metabolic impairment may be secondary to the underlying pathophysiological mechanism; however, in most conditions, it could be considered a direct cause, or at least a cofactor, in the functional abnormalities of the heart. Article see p 895 A more complete understanding of the myocardial metabolic changes associated with cardiac diseases may lead to pharmacological studies and potentially new metabolic-targeted drugs. In heart failure, agents that act through the optimization of cardiac metabolism may be particularly attractive as they could potentially work without exerting negative hemodynamic effects; this would allow for their addition to current therapies.1 It has been demonstrated that shifting the metabolic substrate of the heart from fatty acids to carbohydrate oxidation can improve pump function and delay the progression of heart failure.2 That said, in spite of the initial enthusiasm over drugs that showed promising metabolic effects in vitro, few clinical benefits have been unequivocally demonstrated. A robust imaging technique, which would allow the direct assessment of metabolism in vivo, is essential to understanding the metabolic changes and the effectiveness of pharmacological drugs. Unfortunately, nuclear medicine techniques, such as positron emission tomography and single photon emission computed tomography, are unable to detect the metabolized tracers and distinguish between different downstream metabolites.3 Magnetic resonance spectroscopy (MRS) with hyperpolarized 13C-enriched substrates is a promising imaging technique for the evaluation of cardiac metabolism in vivo. Because the natural amount of 13C in biological tissue is low, a sufficient signal:noise ratio for 13C-MRS is obtained by increasing the polarization level (hyperpolarization) of these compounds. Currently, dynamic nuclear polarization is the most widely used hyperpolarization technique for 13C-enriched molecules and this enables an increased signal:noise ratio of ≈10 000-fold.4 13C-MRS allows for a …

Abstract C85: Community-based participatory research leads to sustainable lifestyle intervention program for reducing breast cancer risk among African American and Latina women

Abstract Minority women are underrepresented in clinical research, which impedes progress in understanding and eliminating health disparities. Reducing health disparities is an important goal of public health community. Recent data suggests that community-based participatory research (CBPR) which systematically involves the affected communities in each stage of the research process-inception, planning, recruitment, conduct and education is the key to reducing health disparities. Between 2001 and 2005 approximately 10,000 invasive and 2,000 in situ breast cancer cases were reported in Region 5 of the San Bernardino County women in California. Although data reveals that the age adjusted incidence rate of 23.7 for in situ breast cancer cases in the Region 5 population is lower than the state-wide rate of 27.3, the number of in situ cases in the area rose from 9.6 in 1988 to 24.8 in 2007. Obesity rates for African American (AA) and Latina adults in the San Bernardino County are 34%. The emergence of the obesity epidemic worldwide has been associated with increases in metabolic syndrome, breast cancer, and type 2 diabetes in the industrialized countries. The proposed pilot study used a CBPR method to study women's perceptions, beliefs and attitudes towards participating in a clinical breast cancer study that involved blood. Methods: A community-based participatory mixed-methods approach, including a 6-month lifestyle intervention education program was employed. Participants were recruited using purposive convenience sampling that evaluated educational program designed to increase women's knowledge of positive attitudes and participation in breast cancer clinical studies and simple changes in lifestyle that result in reduced risk for breast cancer. To evaluate the effectiveness of the educational intervention, we used knowledge, attitudes, behavior, and perception-based questionnaire, and in-depth interviews to assess changes before and after the educational experience. Results: Fifty eight women that included 36 African American and 22 Latina women participated in the educational program, out of which twenty five women were recruited into the lifestyle intervention program that required providing blood to test for metabolic syndrome and risk for breast cancer. All the women in the intervention study were willing to provide blood for the study. Seventy six percent of the women in the lifestyle intervention program were either obese or experienced metabolic syndrome. At the end of six months, 78% of the women who participated in the study reduced their body fat by 2% change, by reducing dietary fat consumption. Approximately 93% of the women increased servings of fruits and vegetables in their diet and engaged in some form of exercise after their enrollment into the study. This program is currently sustained by community support groups, after the end of the grant. The project director meets with the women once a month and monitors their life style changes. Conclusion: Community-based participatory research projects that engage community partners through the entire process of research planning and conduct may result in effective sustainable projects that will result in resilient communities. Funding supported by Kaiser Permanente Fontana Community Benefit Grant. Citation Format: Padma Pauline Tadi Uppala, Padma Pauline Tadi Uppala, Loistine Herndon, Hildemar Dos Santos, Amanda Dupre, Persila Mohammadnia, Maheswari Senthil. Community-based participatory research leads to sustainable lifestyle intervention program for reducing breast cancer risk among African American and Latina women. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C85. doi:10.1158/1538-7755.DISP13-C85

The perceived information in obtained from the informed consent in Iranian patients with cancer in clinical studies.

Objective:One of the basic issues in clinical studies is to receive the informed consent; that is to say, all the activities applied in patient’s involvement in the information, decision-making, ability and volunteering in diagnosis, cure and care. In as much as most cancer patients require information about their individual needs, the present study is conducted to determine the perceived information from the informed consent of clinical studies in cancer patients.Methods:This is a descriptive study. Fifty cancer patients hospitalized for participating in the clinical study was chosen according to the convenience sampling. Tools used in this research included the questionnaire (individual and social features) and the check list about patient’s right and cancer patient’s information before and after receiving informed consent in clinical studies (10 items on a Likert rating scale). To validate the study, content and formal validation was used. Data in this research were analyzed using descriptive statistics (frequency, mean and standard deviation) and the software of SPSS 16.Result:In general, the mean of the scores obtained from cancer patients’ perceived information before completing the informed consent of the clinical studies was 14±3.5 and after consent of the clinical studies was 16±2.4. The cancer patients’ perceived information before and after consent of the clinical studies was weak.Conclusions:Based on the findings of the present study, the rate of the information the cancer patients received, before completing the informed consent form, was low, but after completing the informed consent form this rate was again low. Therefore, conducting similar and wider studies is recommended to unveil the factors affecting perceiving information and how to promote the quality of the informed consent in other hospitals in Iran.

Abstract 4526: BIBF1120, an investigational triple angiokinase inhibitor, in combination with inhibitors of mTOR signaling shows potent antitumor activity in preclinical models of sarcoma

Abstract BIBF1120 (Nintedanib), an investigational potent small molecule angiokinase inhibitor, selectively binds to and blocks receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptor, (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR). Nintedanib has shown promising results in preclinical as well as clinical studies of non-small cell lung cancer, colorectal, ovarian cancer and other solid tumors. We tested the in vitro anti-proliferative activity of BIBF1120 in a panel of sarcoma cell lines including malignant peripheral nerve sheath tumor (MPNST), synovial (SYO-I), Ewing's (CHP100), osteo (SaOS2) and liposarcoma (LS141). Our results indicate that when compared to other potent RTK inhibitors such as Imatinib and Pazopanib, BIBF1120 is highly efficient at nanomolar to low micromolar concentrations in blocking proliferative activity of sarcoma cell lines, specifically, SYO-I and MPNST, which are highly dependent on PDGFR signaling. Western blot analysis to test the efficacy of BIBF1120 confirmed significant blockade of RTK signaling pathways. Ras activation and/or activation of mitogen activated protein kinase (MAPK) pathway has been shown to be critical in sarcomas including MPNST and synovial sarcomas. Unlike Imatinib and Pazopanib, BIBF1120 also blocked MAPK signaling pathway as demonstrated by p-ERK1/2 blockade. In addition to the RTKs, mTOR (mammalian Target of Rapamycin) protein plays a key role in AKT activation and downstream survival signaling. Combination of RTK blockade by BIBF1120 and mTOR blockade by TORC1 inhibitor rapamycin resulted in significantly stronger inhibition of in vitro cellular proliferation compared to single agent treatments. Taken together, our data strongly supports further clinical research of BIBF1120 in sarcoma. Combining potent inhibitors of tyrosine kinase signaling, MAPK signaling and inhibitors of mTOR pathway such as rapamycin could provide a new therapeutic approach in this disease. Citation Format: Parag P. Patwardhan, Elgilda Musi, Kathryn S. Ivy, Natalie Giovino, Gary K. Schwartz. BIBF1120, an investigational triple angiokinase inhibitor, in combination with inhibitors of mTOR signaling shows potent antitumor activity in preclinical models of sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4526. doi:10.1158/1538-7445.AM2014-4526

Abstract 451: A novel algorithm for prioritizing candidate genes driving malignant transformation of MCF10F cells and basal-like breast cancer

Abstract We have developed a model of malignant transformation of MCF10F cells to identify the temporal acquisition of changes in genome structure and gene expression that correspond to the progressive transformed phenotype culminating in tumorigenesis. Genomic DNA and total RNA were isolated from MCF10F, trMCF (MCF10F transformed by 70 nM 17-beta estradiol), bsMCF (trMCF selected by Boyden chamber, tumorigenic), bcMCF (clones of bsMCF), and caMCF (cells from tumors of bsMCF grown in SCID mice). The molecular changes accompanying this progression were interrogated using high resolution methods of analysis for loss of heretozygosity (LOH), chromosome copy number (CCN) and gene expression profiles. The observed genomic changes, along with the tumor phenotype of a poorly differentiated adenocarcinoma, indicate an underlying mechanism common to basal-like breast cancer development in women. As examples, similarities were found at chromosomes 4 and 5 between this ER negative cell model and the basal-like tumors, and progression was accompanied by changes in gene expression consistent with epithelial mesenchymal transition. Here we describe an algorithm for prioritizing candidate oncogenes and tumor suppressor genes. Venn analysis of CCN and gene expression (Venn_input, &amp;gt; 1100 genes) was input into GeneIndexer, a text mining tool, and queried by key words or genes that were selected for relevance to breast cancer and then neutralized for gene-by-word correlation bias. The sum of the output cosine values for the Venn_input list was then used to prioritize candidate genes of interest in relation to breast cancer (Venn_output), and further, in relation to their first appearance during the progression of cell transformation. To determine the relevance of these genes to clinical breast cancer, the Venn_output list was used to perform hierarchical cluster analysis of several clinical studies of breast cancer. Of interest, the prioritized 113 genes identified only the basal-like subtype in four separate clinical sample sets and one set of 51 breast cancer cell lines. Further analysis using a support vector machine technique to train and query these same data predicted the tumor class (basal/non basal) with a sensitivity range of 71-87 percent, and a specificity range of 77-100 percent. These results support the use of this approach for combining complex data for the prioritization of candidate genes, and indicate that this model of malignant cell transformation recapitulates many key aspects of basal breast cancer. Citation Format: Sangjun Lee, Behrouz Madahian, Carrie Sutter, Charles Dickens, Irma Russo, Jose Russo, Ramin Homayouni, Thomas Sutter. A novel algorithm for prioritizing candidate genes driving malignant transformation of MCF10F cells and basal-like breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 451. doi:10.1158/1538-7445.AM2014-451

Abstract 3647: Treatment of glioblastoma through the controlled localized production of IL-12 by the RheoSwitch Therapeutic System® Platform

Abstract Challenges in developing immunotherapies against glioblastoma include the immune-privileged status of the CNS and the physiological processes that contribute to the suppression of immune responses in the brain. The localized controlled production of IL-12 in the tumor may increase cytotoxic T cell infiltrate and subsequently reduce tumor vascularity and tumor volume, resulting in a prolongation of survival. We have developed an adenoviral vector, Ad-RTS-mIL-12 (AD), administered intratumorally under the control of the RheoSwitch Therapeutic System® (RTS®) expression platform. Gene expression and subsequent IL-12 protein production is controlled by the oral administration of the small molecule activator ligand veledimex (AL). We have shown the the safety and biologic activity of this system in both nonclinical and clinical studies in melanoma and breast cancer. Based upon these favorable results we chose to study the activity of RTS-mIL-12 delivered intratumorally by an adenoviral vector-based approach in an orthotopic murine glioma model. The ability of AL to cross the blood brain barrier was assessed in both naive and orthotopic GL-261 tumor bearing C57B6 mice. The results in mice demonstrated that AL brain tissue levels increased from 25325 to 47868 ng*h/g in naïve mice at doses of 225- 450 mg/m2 p.o. administered on either QD or BID schedules while, as anticipated, the levels of AL in brain tissue increased in the tumor bearing mice. At 450 mg/m2/day BID p.o. increased brain tissue AL levels in GL261 mice increased by approximately 6 fold from 324±51 ng/g in normal mice to 1950±573 ng/g at Day 3 and were sustained through 14 days of continuous dosing (1150±212 ng/g). Based on these findings we assessed the effects of AD + AL on survival in the orthotopic GL261 syngeneic mouse glioma model where each animal received 1 x 105 GL261 glioma cells via intracranial injection on Day 0. In this study AD was administered intratumorally at 1 x 1010 vp/animal on Day 5. AL was administered via gavage at doses of 450-1200 mg/m2/day for 14 consecutive days on a BID schedule. In addition, bevacizumab 30mg/m2 biwkx3 and dexamethasone 6mg/m2/day BID x14 days were studied. AD + AL demonstrated a dose-related increase in survival benefit without exhibiting an adverse safety profile. At Day 100 with (study termination), 45, 50 and 68% of the animals that received doses of 450, 900 or 1200mg/m2/day, respectively, were alive. In contrast, the median survival in the vehicle control groups was 18 days, while in the bevacizumab and dexamethasone groups the median survival was 22 and 24 days, respectively. Additional studies in this model are ongoing to determine the optimal dose and schedule. This novel regulated immunotherapeutic approach could potentially be translated into an effective clinical regimen for the treatment of glioblastoma. Citation Format: John A. Barrett, Hongliang Cai, Francois Lebel, Kay R. Meshaw, Tami Zmetra, Jonathan Lewis. Treatment of glioblastoma through the controlled localized production of IL-12 by the RheoSwitch Therapeutic System® Platform. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3647. doi:10.1158/1538-7445.AM2014-3647