Prevention, Early Detection, and Interception最新文献

{"title":"Abstract 648: Effects of bazedoxifene and lapatinib in the prevention of estrogen receptor positive (ER+) and negative (ER-) mammary cancers","authors":"C. Grubbs, Altaf Mohammed, S. Sei, R. Shoemaker","doi":"10.1158/1538-7445.SABCS18-648","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-648","url":null,"abstract":"","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90368849","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 4225: Is biomarker-driven precision medicine possible by using high dimensional augmented intelligence assisted analysis of cancer immune responses","authors":"C. Krieg, L. Cardenas, S. Guglietta, John M. Wrangle, M. Rubinstein, M. Robinson","doi":"10.1158/1538-7445.AM2019-4225","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-4225","url":null,"abstract":"Checkpoint inhibitors have significantly accelerated cancer treatment but still a majority of patients do not respond. Biomarker driven patient stratification early to the right immunotherapeutic might enhance response and patient survival. Here we used high-dimensional mass cytometry (CyTOF) combined with machine-learning bioinformatics for the in-depth characterization of immune responses before and during anti-PD-1 immunotherapy. CyTOF allows us to monitor protein expression of 34 markers on a single cell while running 20 samples simultaneously. The analysis is data driven, can be adapted to high throughput approaches and can model arbitrary trial designs such as batch effects and paired designs and is quantitative over millions of events. Using CyTOF as a precision medicine tool we could predict response to anti-PD-1 using liquid blood biopsies. Biobanked peripheral blood mononuclear cells (PBMCs) from 51 patients with stage IV melanoma before and after 12 weeks of anti-PD-1 therapy was analyzed. We observed a clear T cell response on therapy. The most evident difference in responders before therapy was an enhanced frequency of CD14+ CD16+HLA-DRhi classical monocytes. We validated our results using conventional flow and found a clear correlation of enhanced monocyte frequencies before therapy initiation with clinical response such as lower hazard and extended progression-free and overall survival. In a second study we used CyTOF to monitor immune response in 21 non small cell lung cancer (NSCLC) patients that initially responded and then progressed under anti-PD-1 to a novel combination immunotherapy of anti-PD-1 plus an IL-15 super-agonist (ALT-803). In this phase Ib clinical study a response in the CD8+ T cell compartment was observed. Unexpected our high dimensional unbiased analysis was able to detect and characterize a strong expansion of innate tumor-reactive effector NK cells starting around day 4 of therapy. Taken together, our unbiased artificial intelligence driven immune workflow might support patient selection prior to therapy, and serve as a novel tool for precision medicine to select the right drug combination and identify new drug-able cell populations. Citation Format: Carsten Krieg, Luis Cardenas, Silvia Guglietta, John Wrangle, Mark Rubinstein, Mark Robinson. Is biomarker-driven precision medicine possible by using high dimensional augmented intelligence assisted analysis of cancer immune responses [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 4225.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73812895","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 5088: Silibinin inhibits UVB-induced promotion and progression of microscopic basal cell carcinoma formation via targeting bone morphogenic protein 2","authors":"Cynthia M. Rigby, G. Deep, A. Jain, D. Orlicky, C. Agarwal, K. Raina, R. Agarwal","doi":"10.1158/1538-7445.AM2019-5088","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-5088","url":null,"abstract":"Non-melanoma skin cancers (NMSCs) account for about half of all malignancies diagnosed annually in the United States. Around 80% of NMSCs are basal cell carcinoma (BCC) and 20% are squamous cell carcinoma (SCC). Whereas the efficacy of several chemopreventive agents has been examined and reported against both BCC and SCC, a majority of these studies have focused on the test agent’s activity in a long-term setting to determine the amount of tumors formed. Notably, the studies evaluating the efficacy of chemopreventive agents during early stage/s of BCC development are lacking. Accordingly, utilizing the well-established patched (Ptch)+/- mouse model of UVB-induced BCC formation, we excised skin samples from UVB exposed mice prior to tumor formation to study the promotion/progression of BCC and to determine the target/s of silibinin, a well-known skin cancer (SCC) chemopreventive agent, in tumor growth inhibition. Ptch+/- and Ptch+/+ mice were irradiated with UVB 240mJ/cm2 3 times per week with or without topically applied silibinin 5 times per week. As early as one month, we found that UVB exposure significantly increased the number of mast cells in Ptch+/- mice by about 48% (P Citation Format: Cynthia M. Rigby, Gagan Deep, Anil K. Jain, David J. Orlicky, Chapla Agarwal, Komal Raina, Rajesh Agarwal. Silibinin inhibits UVB-induced promotion and progression of microscopic basal cell carcinoma formation via targeting bone morphogenic protein 2 [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 5088.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75099680","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 1614: Coconut kernel extract as a novel chemopreventive agent that target cancer stemness","authors":"Sandhya Sorra, Joyeeta Talukdar, G. Gogoi, Hong Li, D. Baishya, Bikul Das","doi":"10.1158/1538-7445.SABCS18-1614","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-1614","url":null,"abstract":"","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"79 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79763040","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 5091: Inhibition of mutagenicity of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ( PhIP) by aqueous extract (crude) and organic extract (pulegone) ofCalamintha nepeta.","authors":"Yanlingxue Wan, R. Hayes, Joshua Li, K. Ferrer, Padma T. Uppula, B. Y. Wong","doi":"10.1158/1538-7445.SABCS18-5091","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-5091","url":null,"abstract":"","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79634346","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 650: Gut microbiota population may be used to predict chemotherapeutic responsiveness in triple negative breast cancer","authors":"Alaa Bawaneh, Adam S. Wilson, Kenysha Y. J. Clear, A. Chiba, K. Cook","doi":"10.1158/1538-7445.AM2019-650","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-650","url":null,"abstract":"Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and predominately affects young and minority women. TNBC is characterized by a high recurrence rate, with about 34% of TNBC patients relapsing around 2.6 years. This type of breast cancer lacks targeted therapy options and is limited to chemotherapy treatment options. The purpose of our study was to determine whether gut microbiota populations correlate with chemotherapeutic responsiveness and may be a predictive biomarker of outcome. Moreover, we want to determine the impact of targeting the microbiome on chemotherapy efficacy. In this study, 8-week old female BALB/c mice were injected with TNBC 4T1-luciferase cells into their L4/5 mammary fat pad. Once tumors developed, mice were either untreated (control group), treated with 1 x weekly 2.5 mg/kg IV doxorubicin (DOX), or treated with doxorubicin + antibiotics (mixture of streptomycin, ampicillin, and colistin in the drinking water to ablate host bacterial populations). Tumors were collected at the end of the study. Fecal samples were collected at time point 0 weeks (T0; before therapy when tumors were approximately 100 mm3) and time point 4 weeks (T4; after treatment). We subdivided the doxorubicin treated group into DOX-responders (tumors stopped growing or shrank) or DOX-nonresponders (tumors continued to grow on treatment). Tumors from the DOX-responders and DOX + antibiotics groups were significantly smaller and mice from these groups displayed reduced lung weight, suggesting decreased lung metastatic burden. 16S-bacterial sequencing analysis was performed on breast tumor tissue and feces. We demonstrate that at T0, elevated fecal Ruminococcus correlates with DOX-nonresponsiveness. Furthermore, at T4, we show increased fecal abundance of Oscillospira and Bacteroidales are associated with better therapeutic outcome. Protein analysis of primary 4T1 breast tumor tissue indicate a significant elevation of apoptosis (cleaved caspase-3 protein levels) in DOX-responders and DOX + antibiotic treated mice. We also stained breast tumor tissue and lung tissue for bacteria to confirm presence of microbiota by immunohistochemistry. Taken together our data demonstrates that chemotherapy efficacy is modulated by the microbiome. Moreover, fecal microbiota populations could be used as a predictive biomarker of chemotherapeutic responsiveness and suggests that modulation of the gut microbiome through dietary or probiotic interventions may affect therapeutic outcomes. Citation Format: Alaa Bawaneh, Adam S. Wilson, Kenysha YJ Clear, Akiko Chiba, Katherine L. Cook. Gut microbiota population may be used to predict chemotherapeutic responsiveness in triple negative breast 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 650.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81170116","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 3313: Plasma levels of MMP7 are significantly increased in patients with colorectal cancer compared to benign disease colon pathology","authors":"H. S. Kumara, D. N. Gamage, N. Mitra, Carl S Winkler, Sandhu K. Jaspreet, Xiaohong Yan, V. Cekic, H. Miyagaki, N. Gandhi, R. Whelan","doi":"10.1158/1538-7445.SABCS18-3313","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-3313","url":null,"abstract":"","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80042377","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 1606: The ethyl ester forms of the n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid decrease the proliferation, invasion, and matrixmetalloproteinase activity of colorectal cancer cells","authors":"Eric Pfister, M. Lane","doi":"10.1158/1538-7445.SABCS18-1606","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-1606","url":null,"abstract":"","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82483011","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 5074: Optimizing erlotinib plus sulindac dosing regimens in a preclinical model of FAP","authors":"A. Ulusan, P. Rajendran, W. Dashwood, Altaf Mohammed, S. Sei, P. Brown, Eduardo Vilar-Sánchez, R. Dashwood","doi":"10.1158/1538-7445.AM2019-5074","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-5074","url":null,"abstract":"Introduction Colorectal cancer (CRC) involves sporadic cases and hereditary syndromes, such as familial adenomatous polyposis (FAP). In FAP patients, surgical intervention often is coupled to prevention strategies using nonsteroidal anti-inflammatory drugs. However, none of the current therapeutic options is fully effective. A recent trial in FAP patients combined standard of care Sulindac (SUL) treatment with daily Tarceva/erlotinib (ERL), and had good efficacy in reducing adenomatous polyp burden. Toxicity concerns, however, raised questions over the combination strategy for long-term prevention (Samadder et al. 2016). Using the Apc‐mutant polyposis in rat colon (Pirc) model as a mimic of human FAP, we sought to optimize the dosing regimens for SUL+ERL for an improved safety profile, while retaining efficacy in the GI tract. Methods In a short-term pharmacodynamic biomarker study, rats (n=7) were fed AIN control diet or AIN diet containing 250 ppm SUL, either alone or in combination with ERL, given by oral gavage at 6 or 12 mg/kg (daily), 21 mg/kg (twice weekly), or 42 mg/kg (once weekly). Colon and small intestine (SI) polyps were resected at 0.5, 1, 2, 3, 7, 10, and 14 days after dosing, and assessed by immunoblotting (IB) or RT-qPCR for changes in pErk/Erk, pAkt/Akt, and other biomarkers. In a follow-up efficacy study, rats (n=10) were given SUL, ERL, or ERL+SUL using dosing regimens that were dictated by recovery times for pErk in the biomarker study. Colon and SI polyps were recorded at necropsy for location, incidence, multiplicity, and volume. Tumors and adjacent normal tissues were taken for histopathology and molecular analyses. Results The biomarker study revealed that pErk was inhibited in Pirc colon polyps for up to 10 days after discontinuing ERL treatment, with full recovery on or around day 14. Nuclear β-catenin, c-Myc, Mmp-7 and Cyclin D1 also were attenuated by ERL+SUL in colon polyps. In the efficacy study, results accrued via endoscopy at 3, 4 and 5 months were remarkably consistent with data obtained during final necropsy, at 6 months. Compared to AIN controls, multiple ERL+SUL groups exhibited significant suppression of polyps in the colon (78-98% inhibition, p Conclusions These studies have the potential to define safe and effective dosing strategies for SUL+ERL, improving efficacy against colon and SI polyps, while circumventing toxicity and resistance. Outcomes from the current work, plus an ongoing one-year toxicity/resistance trial in Pirc, should be directly translatable to the clinical management of FAP patients exhibiting similar pathology and phenotype. Supported by NCI Contract Number HHSN261201500018I, Task Order HHSN26100004. Citation Format: Ahmetmursel Ulusan, Praveen Rajendran, Wan-Mohaiza Dashwood, Altaf Mohammed, Shizuko Sei, Powel H. Brown, Eduardo Vilar-Sanchez, Roderick H. Dashwood. Optimizing erlotinib plus sulindac dosing regimens in a preclinical model of FAP [abstract]. In: Proceedings of the America","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83104195","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 662: Impact of chemotherapy on the intestinal microbiome and epithelial barrier in PDX models of lung cancer","authors":"Cindy Pensec, D. Guenot, L. Calvet, C. Mignard, O. Duchamp, T. Carton, S. Leuillet, H. Blottière, F. Vacon","doi":"10.1158/1538-7445.AM2019-662","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-662","url":null,"abstract":"Introduction In the field of lung cancer treatments, significant progresses have been realized during last decade, such as targeted therapies and immunotherapies. Nevertheless, chemotherapy remains the gold standard for cancer. Pemetrexed is a chemotherapeutic agent commonly used in advanced lung cancer. This drug has a broad-spectrum effect that can induce significant side effects in patients. However, the impact of pemetrexed on gut microbiota and gastrointestinal inflammation in PDX mice remains unknown, although the role of the microbiota in carcinogenesis and modulation of efficacy or toxicity of chemotherapy agents has been demonstrated. The aim of this new study was to explore the impact of pemetrexed on the gut microbiota and the integrity of intestinal epithelial barrier and inflammation markers of PDX models following treatment. Methods Upon establishment of the PDX model, mice were treated with pemetrexed for 2 weeks. Stool specimens were collected at 3 time-points: before, after and one week after treatment. Gut microbiota composition was studied by 16S rRNA gene sequencing. The colon integrity of the epithelial barrier was evaluated by a histological examination, a permeability measurement and a selected cytokines expression. In parallel, body weight was recorded and tissues were sampled for assessment of toxicity and inflammation. Results Pemetrexed induced a significant body weight loss after each treatment cycle reflecting toxicity as known in clinical results. We have found that pemetrexed and tumor induced several modifications on microbiota composition, and the more important perturbation was the significant increase of the relative abundance of Enterobacteriaceae. A significant alteration of epithelial barrier integrity associated with early inflammation and infiltration of leukocytes into mucosal tissues was observed following treatment. Moreover, we have shown that pemetrexed effect on the microbiota was reproducible on several models of lung PDX models of lung carcinoma, and that dysbiosis seem proportional to the effectiveness of chemotherapy. Conclusion This work is a preliminary approach, that confirms the relationship between microbiota and chemotherapy. A better understanding of gut microbiota alterations induced by chemotherapy could help reduce side effects. It is essential to expand our knowledge about the chemotherapy impact on microbiota in order to minimize the side effects, avoid infection complications, and improve therapy efficiency. Citation Format: Cindy Pensec, Dominique Guenot, Loreley Calvet, Caroline Mignard, Olivier Duchamp, Thomas Carton, Sebastien Leuillet, Herve M. Blottiere, Francoise Le Vacon. Impact of chemotherapy on the intestinal microbiome and epithelial barrier in PDX models of lung 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 662.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"42 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89272617","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}