Prevention, Early Detection, and Interception最新文献

{"title":"Abstract LB-245: 9cis-retinoid UAB30 by inhibiting aberrant fatty acid metabolism protects against UVB-induced skin inflammation and carcinogenesis","authors":"M. Kashyap, M. Waseem, Changzhao Li, Mohd S Iqbal, V. Atigadda, C. Elmets, M. Athar","doi":"10.1158/1538-7445.SABCS18-LB-245","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-LB-245","url":null,"abstract":"","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89253922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 1618: Breast cancer screening in low and lower - middle income country : A program in Vietnam","authors":"V. Dang, T. Dao, T. Tran, H. Tran","doi":"10.1158/1538-7445.SABCS18-1618","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-1618","url":null,"abstract":"","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"208 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89330244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 5085: Molecular analysis of chemopreventive effects of grape antioxidants resveratrol and quercetin in transgenic adenocarcinoma of the mouse prostate","authors":"C. Singh, M. Ndiaye, G. Chhabra, Charlotte A. Mintie, N. Ahmad","doi":"10.1158/1538-7445.AM2019-5085","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-5085","url":null,"abstract":"Prostate cancer (PCa) is one of the most frequently diagnosed cancers of the male population and current treatments are insufficient to fully manage this neoplasm. Therefore, identification of novel mechanism-based approaches are needed for PCa management. Earlier, we demonstrated that a combination of the grape antioxidants resveratrol and quercetin impart superior anti-proliferative responses in multiple human PCa cell lines, as well as a significant anti-tumor response in transgenic adenocarcinoma of the mouse prostate (TRAMP) (Cancer Res 75(15 Suppl):2801). The rationale of the study was based on the fact that i) both resveratrol and quercetin are naturally present in several plants ii) quercetin improves bioavailability of resveratrol by inhibiting its sulfation, and iii) separately, both agents have shown potential for management of PCa in previously published studies. This study extended our previous work and determined the mechanisms of chemopreventive effects of resveratrol-quercetin combination employing a mouse PCa RT² Profiler PCR array that profiles 84 key PCa-related genes. For this, we employed tumor tissues generated in a chemoprevention protocol where TRAMP mice were given AIN76A diet supplemented with resveratrol (600 mg/kg), quercetin (60 mg/kg), or a combination of both. PCR array analysis found significant modulation (≥2-fold) in 14, 15, and 10 genes in the quercetin, resveratrol, and combination groups, respectively. To explore the involved gene networks using Ingenuity Pathway Analysis (IPA), we selected total 22 genes with ≥2-fold change in any one group and ≥1.5-fold change in other group(s). IPA analysis identified that resveratrol-quercetin modulated genes supported the cumulative actions of increased apoptosis, as well as inhibition of cell viability/proliferation, hyperplasia, vasculogenesis, and angiogenesis. Further, IPA predicted inhibition of major PCa promoting upstream signaling molecules viz. Pi3k, Vegf, Csf2, Ca2+, and Pth. This PCR array also identified decreased levels of Igf1, Egfr, Egr3, and Il6, which are known to support PCa progression, as well as found increased levels of Nkx3-1, which is a tumor suppressor in PCa. Furthermore, IPA exploration identified a gene network where decreased Igf1 emerged as a central regulatory player, interacting with most of the resveratrol-quercetin modulated genes. Additionally, employing IHC, immunoblot, and RT-qPCR analyses, we found marked decrease in the levels of cell proliferation markers Ki67 and PCNA, oxidative stress biomarker 4-HNE, EMT marker vimentin, and prosurvival marker Bcl2. These results suggest that this natural combination of grape polyphenols may be useful as a chemopreventive regimen for PCa. Further detailed studies including clinical trials are needed to determine the translational significance of our findings. Citation Format: Chandra K. Singh, Mary A. Ndiaye, Gagan Chhabra, Charlotte A. Mintie, Nihal Ahmad. Molecular analysis of chemopreventive e","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89477832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB-248: A novel multiplex assay for detection and quantitation of fatty acid synthase (FASN) in serum or plasma samples","authors":"N. Venkateswaran, W. Nelson","doi":"10.1158/1538-7445.SABCS18-LB-248","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-LB-248","url":null,"abstract":"Many cancers overexpress FASN which catalyzes the final synthetic step of de novo fatty acid synthesis pathway. FASN has been considered as a potential drug target for several decades now. Many publications provide evidence of the elevated FASN with aggressive tumors, but still, there are very few inhibitors of FASN that have successfully been utilized as therapeutics in the clinical arena. An accurate measurement of FASN in association with tumor-specific markers in solid tumors and serum may help to propel forward the therapeutic significance of FASN inhibitors. With this objective in mind, we are currently working on the development of a multiplex assay for detection and quantitation of FASN and Cripto-1 in serum samples. We have optimized a magnetic fluorescent bead based multiplex sandwich immunoassay for detection and quantitation of FASN and Cripto-1 (CR-1) in human serum and plasma samples. We selected Cripto-1 to pair with FASN because it is an EGF-like domain carrying growth factor associated with a number of different types of human carcinomas. We use two different monoclonal antibodies for FASN and one for CR-1 as capture antibodies covalently coupled to magnetic fluorescent beads and a mixture of two biotin-labeled detection antibodies in this assay. The streptavidin-phycoerythrin (SAPE) conjugate is used to report the positive capture of a target in this assay. We have also included various internal controls in this assay to monitor the assay performance and assure quality of the reagents used in each well. The dynamic range of this assay was determined to be 100pg/mL to 100 ng/mL using recombinant FASN and Cripto-1 from commercial sources. The R2 values were 0.98 and above for each of the analytes and recovery of each standard were between 90 % and 125%. We spiked recombinant FASN and Cripto-1 in normal human serum and plasma at different concentrations and spike recovery was between 70 % and 130 %. We further evaluated this assay with some commercially obtained clinical samples. This presentation includes detailed results of this study. Citation Format: Neeraja Venkateswaran, William M. Nelson. A novel multiplex assay for detection and quantitation of fatty acid synthase (FASN) in serum or plasma samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-248.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87896725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB-247: 9cis-retinoic UAB30 inhibits UVB-induced pro-inflammatory cytokines/chemokines signaling via targeting Bromodomain-4","authors":"M. Waseem, M. Kashyap, Changzhao Li, Sandeep Chaudhary, D. Chandrashekar, V. Atigadda, S. Varambally, C. Elmets, M. Athar","doi":"10.1158/1538-7445.SABCS18-LB-247","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-LB-247","url":null,"abstract":"BET bromodomain-containing protein 4 (BRD4), an epigenome reader works as an oncogene for several cancer types including those that develop in the skin. BRD4 inhibitors have been shown to have antitumor efficacy in multiple cancer models. Additional studies demonstrate the involvement of BRD4 in onsetting inflammation which is a key component of the pathogenesis of cancers including in the development of tumor growth conducive microenvironment. Here we show that a recently developed non-hyperlipidemic retinoid X receptors (RXR) agonist 9cUAB30 besides its anticancer properties also reduces UVB-induced inflammation in a murine model. The molecular mechanism underlying anti-inflammatory effect of 9cUAB30 is complex that involves epigenetic modulation of histones. Orally administered 9cUAB30 reduces BRD4 expression and its downstream signaling. 9cUAB30 mediated inhibition of BRD4 is also evidenced by the downregulation of acetylated histones such as H3K27ac, H3K18ac, H3K9ac, H4K8ac and H4K5ac. This is further confirmed by RNAseq data that show UVB-mediated alterations in multiple BRD4 target genes are attenuated by 9cUAB30 treatment. Furthermore, the BRD4 regulated cytokines such as IL6, IL12a, IL19, IL23, IL27, and IL33 which are induced by UVB, are attenuated by 9cUAB30 treatment. However, UVB induced additional multiple cytokines/chemokines. 9cUAB30 treatment was also successful in diminishing their levels significantly. These data support the notion that 9cUAB30 acts by targeting additional inflammation regulating pathways besides those regulated by BRD4 dependent epigenetic modulation. These initial effects in the tumor adjacent skin could be seen even in the SCCs and BCCs which progress from these early benign lesions suggesting that BRD4 mediated signaling is important during the entire pathogenesis of highly malignant cutaneous lesions. This is further confirmed by in vitro investigation employing Squamous cell carcinoma A431 and SCC13 cells in culture. Further evidence that 9cUAB30 acts via dampening BRD4 regulated pathways comes from genetic studies employing the knockdown and forced expression approaches. Our data also demonstrate that 9cUAB30 dependent majority of anti-inflammation and EMT blocking effects are mediated by targeting BRD4- NFkB /BRD4-Twist axis. In summary 9cUAB30 elaborates anti-inflammatory effects by targeting BRD4 regulated chromatin remodeling. Citation Format: Mohammad Waseem, Mahendra P. Kashyap, Changzhao Li, Sandeep C. Chaudhary, Darshan S. Chandrashekar, Venkatram R. Atigadda, Sooryanarayana Varambally, Craig A. Elmets, Mohammad Athar. 9cis-retinoic UAB30 inhibits UVB-induced pro-inflammatory cytokines/chemokines signaling via targeting Bromodomain-4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-247.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"67 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88670111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 4212: A pilot clinical trial to study the effects of Angelica gigas dietary supplement (CognI.Q) on human immune cells (NCT03630328)","authors":"Deepkamal N. Karelia, J. Haley, T. Schell, D. Hershock, Junjia Zhu, Cheng Jiang, Junxuan Lu, Jinhui Zhang","doi":"10.1158/1538-7445.AM2019-4212","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-4212","url":null,"abstract":"Korean Angelica gigas Nakai (AGN)-containing products are marketed as dietary supplements for memory improvement, pain relief and women’s health especially for menopausal symptom management. Decursin (D) and its isomer decursinol angelate (DA) are the major marker compounds in the ethanol extract of AGN root. In rodent models, we and others have shown that D/DA are rapidly converted to decursinol (DOH) after gavage or i.p. injection. Our multi-omic analyses of the TRAMP neuroendocrine carcinomas suggest immune enhancement by AGN. We have published a 20-subject single dose-PK study (NCT02114957) in men and women volunteers in Amarillo, TX (age 21-58 years) with AGN dietary supplement CognI.Q (purchased from Quality of Life Laboratories). For dosage, each person swallowed 4 vegicaps (800 mg AGN) at time 0, the recommended daily dose by manufacturer. The human AUC0-48h for DOH (27579 h.nmol/L) is much higher than for DA (335 h.nmol/L) and D (37 h.nmol/L), supporting extensive conversion from D/DA to DOH (Zhang, J. et al, PLOS One, 2015). Significantly, as secondary endpoint parameters, the neutrophil counts in these human subjects were increased by 71% at 24h post-dose vs. pre-dose. The natural killer cell (NK) mRNA signature in their peripheral blood mononuclear cells (PBMC) was increased by 60~90%. Neutrophils (myeloid lineage) fight against bacterial infection whereas NK cells (lymphoid lineage) not only kill virus-infected cells but also recognize and kill cancer cells, serving as a crucial innate immune surveillance against malignancy in our body. Therefore, we hypothesize that daily intake of AGN dietary supplement (CognI.Q) increases the number and/or activities of neutrophils and NK cells, and in turn may boost human innate immune function against bacterial and viral infections as well as cancer risk. As an initial effort to test our hypothesis, the goal of this pilot clinical trial is to delineate the CognI.Q supplement-specific innate immune enhancement activity in healthy men. We will use a double-blinded, placebo-controlled and crossover trial design so that each man will serve as his own comparison for the immune cell responses to CognI.Q and placebo. Supplement period of 3 weeks will be interspersed with a 2 week washout period. We expect to detect an increase in both neutrophil and NK cell counts compared to placebo. Positive data from our proposed trial will be the first of its kind to support enhancement in healthy US residents of these innate immune cells by an AGN dietary supplement. Detailed study design and interim study analysis will be discussed at the meeting. Citation Format: Deepkamal N. Karelia, Jeremy S. Haley, Todd D. Schell, Diane Hershock, Junjia Zhu, Cheng Jiang, Junxuan Lu, Jinhui Zhang. A pilot clinical trial to study the effects of Angelica gigas dietary supplement (CognI.Q) on human immune cells (NCT03630328) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar ","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76491201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB-246: Apoptotic mechanisms ofVernonia amydalinadelile in the prevention of prostate cancer","authors":"C. Yedjou, Solange S Tchounwou, William K Johnson, Sylvianne Njiki, P. Tchounwou","doi":"10.1158/1538-7445.AM2019-LB-246","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-LB-246","url":null,"abstract":"Prostate cancer is one of the common cancers in males and its incidence keeps increasing globally. Approximately 81% of prostate cancer is diagnosed during the early stage of the disease. The treatment options for prostate care include surgery, radiotherapy, and chemotherapy, but these treatments often have side effects that may result in a poor quality of life such as impotence or decreased bowel function. Our central goal is to test the apoptotic mechanisms of Vernonia amydalina Delile (an edible medicinal plant that is relatively inexpensive, non-toxic, and virtually without side effects) for the prevention of prostate cancer using human adenocarcinoma (PC-3) cells as a test model. To address our specific goal, PC-3 cells were treated with Vernonia amydalina Delile (VAD). Cell viability was determined by the MTT assay and cell morphology was analyzed by acridine orange and propidium iodide (AO/PI) dye using the fluorescent microscope. Cell cycle arrest and cell apoptosis were evaluated by Flow Cytometry assessment. Nucleosomal DNA fragmentation was detected by DNA laddering. Data obtained from the AO/PI dye assessment indicated that VAD significantly reduced the number of live cells in a dose-dependent manner, showing a gradual increase in the loss of viability in VAD-treated cells. A similar result was obtained by the MTT assay. We observed a significant increase in DNA damage in VAD-treated cells compared to the control group. Flow cytometry data demonstrated that VAD induced apoptosis in treated cells compared to the control cells. These results suggest that induction of cell death, cell cycle arrest, and cell apoptosis are involved in the therapeutic efficacy of VAD as anticancer candidate towards the prevention and/or treatment of prostate cancer. Citation Format: Clement G. Yedjou, Solange S. Tchounwou, William K. Johnson, Sylvianne Njiki, Paul B. Tchounwou. Apoptotic mechanisms of Vernonia amydalina delile in the prevention of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-246.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"104 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77418465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 5072: Targeting the mTOR/TORC Pathway for the prevention of er-negative and triple-negative breast cancer","authors":"A. Mazumdar, Jamal L Hill, Yun Zhang, L. Bollu, A. Contreras, Michelle I Savage, S. Sei, Altaf Mohammed, P. Brown","doi":"10.1158/1538-7445.SABCS18-5072","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-5072","url":null,"abstract":"Background: Women with “triple-negative breast cancer” (TNBC), are currently treated with chemotherapy, and have a very poor prognosis. TNBC tumors also frequently have p53 and BRCA1 gene mutations. Dysregulation of PI3K-mTOR pathway has been commonly associated with ER-negative breast cancers with poor prognosis. The mTOR inhibitor everolimus is used to treat ER-positive tumors that have become resistant to anti-estrogen therapy. We hypothesized that targeting mTOR may prevent development of ER-negative and BRCA1-mutant breast cancers and asked whether the mTOR inhibitor everolimus exhibited tumor preventive efficacy in several mouse models of breast cancer. Methods: p53-null mammary gland donor mice were transplanted into cleared fat pads of p53 wild-type mice. BRCA/p53-deficient mice: We produced BRCA1 mice by breeding males and females. All mice were separated into two groups 1) Control and 2) everolimus. MMTV-erbB2 and p53 null mammary gland mice were treated with everolimus (5mg/kg, by oral gavage). BRACA1 mice were given 2mg/kg and 5mg/kg 2X a week of everolimus. All of these mice spontaneously developed mammary tumors within 12 months. Mice were observed daily, toxicity and the percentage of tumor free mice were recorded. Tumor incidence and time to tumor formation was visualized using Kaplan- Meier curves and analyzed using the generalized Wilcoxon test. Results: In MMTV-erbB2 mice everolimus reduced tumor incidence and was associated with an increase in median survival time from 240 days to 410 days. At 365 days, when all mice in control group died, only half of the mice treated with everolimus had developed tumors (p=0.0001). Everolimus also reduced tumor incidence in p53 null mammary gland mice. At 420 days, 50% of the control mice developed mammary tumors compare to only 7 % of the everolimus treated mice (p=0.04). Everolimus also reduced tumor incidence in BRCA1 mice. At 262 days, when 13 (out of 18) (72%) of the control mice developed mammary tumors compare to only 7 (out of 18) (38%) in everolimus treated group developed tumors (p=0.02). Long term treatment (>150 days) of everolimus was associated with mild toxicity that includes slight weight loss ( Conclusions: The mTOR inhibitor everolimus prevented mammary tumorigenesis in all three mouse models. Our results suggest that everolimus can be an effective cancer preventive drug and that further studies with reduced everolimus dose alone or in combination with other targeted therapies are warranted. In the future, clinical trials of the everolimus should be considered for the prevention of breast cancer in high-risk patients. Supported by NCI PREVENT Cancer Preclinical Drug Development Program (HHSN-2612015000-18I (PB)). Citation Format: Abhijit Mazumdar, Jamal Hill, Yun Zhang, Lakshmi Reddy Bollu, Alejandro Contreras, Michelle Savage, Shizuko Sei, Altaf Mohammed, Powel Brown. Targeting the mTOR/TORC Pathway for the prevention of er-negative and triple-negative breast cancer [abstr","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"160 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84818513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 3325: EGFR mutation and protein expression analysis in sinonasal inverted papilloma and squamous cell carcinoma","authors":"V. N. Cabal, M. Ménendez, S. Potes-Ares, B. Vivanco, L. Suárez-Fernández, C. Riobello, R. García-Marín, F. López, J. Llorente, M. Hermsen","doi":"10.1158/1538-7445.AM2019-3325","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-3325","url":null,"abstract":"Introduction Inverted sinonasal papilloma has been demonstrated to be precursor to a subset of sinonasal squamous cell carcinoma and to carry frequent mutations in EGFR exon 20. The aim of this study was to evaluate EGFR mutation and protein expression as risk marker for malignant transformation of inverted papillomas. Experimental procedures The total number of samples studied was 41 inverted papillomas (ISP) and 32 squamous carcinomas (SCC). We defined patients with one single ISP, with multiple ISP (ISP-ISP) or ISP with malignant transformation (ISP-transformed). In addition, we classified SCC related with ISP (SCC-ISP) and those without relation (SCC de novo). EGFR exon 20 was amplified by PCR and analyzed by Sanger sequencing using the ABI PRISM 3100 and 3730 Genetic Analyzer, (Applied Biosystems, Foster City CA). Immunohistochemistry was performed on an automatic staining workstation (Dako Autostainer Plus; DakoCytomation, Glostrup, Denmark) using the antibody anti-pEGFR clone D7A5 (Cell Signaling Technology, Cambridge, UK). Results were evaluated by two experienced investigators (BV and MM). Results We found EGFR exon 20 mutations in 62% (8/13) ISP, 58% (7/12) ISP-ISP, 63% (10/16) ISP-transformed, 54% (7/13) SCC-ISP and 5% (1/19) SCC de novo. Protein expression of pEGFR was detected in 56% (5/9) ISP, 75% (6/8) ISP-ISP, 47% (7/15) ISP-transformed, 42% (5/12) SCC-ISP and 71% (10/14) SCC de novo. We observed an inverse correlation between EGFR exon 20 mutation and pEGFR expression (p=0.034). Overall survival was significantly better for SCC-ISP compared with SCC de novo (2-year survival 54% and 29% respectively; p=0.030). Conclusions EGFR exon 20 mutations occurred in a high frequency, both for cases with single or multiple ISP and for ISP-transformed, making it a characterizing genetic abnormality for ISP in general. This result also means that the presence of a EGFR exon 20 mutations is not of value as a risk marker for malignant progression. Among the SCC, EGFR exon 20 mutations were notably less and pEGFR expression more frequent in SCC de novo compared to SCC-ISP, suggesting that the EGFR signaling pathway is important in both types of SCC, albeit activated in a different manner. Patients with SCC-ISP had a more favorable clinical course, however, neither EGFR exon 20 mutations nor pEGFR expression demonstrated prognostic value. Nevertheless, EGFR exon 20 mutations can be targeted with specific inhibitors and may be of value for adjuvant therapy for SCC as well as ISP that are difficult to manage. Citation Format: Virginia N. Cabal, Marta Menendez, Sira Potes-Ares, Blanca Vivanco, Laura Suarez-Fernandez, Cristina Riobello, Rocio Garcia-Marin, Fernando Lopez, Jose Luis Llorente, Mario Hermsen. EGFR mutation and protein expression analysis in sinonasal inverted papilloma and squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85137633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 5081: Leelamine is a novel inhibitor of fatty acid synthesis in prostate cancer","authors":"Krishna B Singh, Shivendra V. Singh","doi":"10.1158/1538-7445.SABCS18-5081","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-5081","url":null,"abstract":"Increased beta-oxidation of fatty acids to meet energy demand is a rather unique characteristic of a subset of human prostate cancers. A safe and effective intervention for inhibition of fatty acid synthesis is still a clinically unmet need. We have shown previously that leelamine (LLM), a phytochemical derived from pine tree bark, suppresses expression and activity of full-length androgen receptor (AR) and its splice variants in vitro and in vivo in preclinical models of prostate cancer. Because AR is implicated in regulation of fatty acid metabolism, the present study was undertaken to determine the effect of LLM on this metabolic pathway. Treatment of a castration-resistant (22Rv1) as well as an androgen-responsive (LNCaP) human prostate cancer cell line with LLM (2.5 and 5 µmol/L) resulted in downregulation of key fatty acid synthesis enzyme proteins including ATP citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and sterol regulatory element-binding protein 1 (SREBP1). LLM treatment also decreased intracellular levels of total free fatty acids and neutral lipid droplets in LNCaP and 22Rv1 cells. Consistent with the in vitro results, we also observed a significant decrease in ACLY and SREBP1 protein expression and number of neutral lipid droplets in vivo in tumor tissue sections of 22Rv1 xenografts after intraperitoneal administration of LLM (9.1 mg/kg bw/ day, 5 times/week) compared to controls. Studies are in progress to determine if overexpression of AR and/or SREBP1 confers protection against fatty acid synthesis inhibition by LLM. In conclusion, it is reasonable to postulate that suppression of AR-SREBP1 regulated fatty acid metabolism is an important mechanism in prostate cancer inhibition by LLM. This study was supported by the grant RO1 CA101753 awarded by the National Cancer Institute. Citation Format: Krishna B. Singh, Shivendra V. Singh. Leelamine is a novel inhibitor of fatty acid synthesis in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5081.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90666581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}