Prevention, Early Detection, and Interception最新文献

{"title":"Abstract 651: Analysis of the immune microenvironment to advance breast cancer risk prediction and prevention","authors":"D. Hinerfeld, K. Knutson, D. Radisky, E. Thompson, Y. Asmann, K. McCoy, A. Degnim, J. Carter, S. Winham, M. Cote, J. Laak, M. Sherman","doi":"10.1158/1538-7445.SABCS18-651","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-651","url":null,"abstract":"","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84907797","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 4221: Development and evaluation of cell line-derived FFPE reference material for MSI assay validation","authors":"T. Matsusaka, Eva-Maria Surmann, Sian Constantine, H. Child, J. A. Wickenden","doi":"10.1158/1538-7445.SABCS18-4221","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-4221","url":null,"abstract":"Microsatellite Instability (MSI) is defined by variance in the repeat count of microsatellite motifs and occurs in cells that are deficient in one or more mismatch repair proteins. MSI is present in varying cancer types, but is most commonly found in colorectal, gastric and endometrial cancer. Patients with early stage colorectal cancers that display MSI have a better prognosis and show a better response to chemotherapy compared to those with microsatellite stable tumors. MSI alongside additional markers such as tumor mutational burden is also a positive predictive biomarker for immune checkpoint inhibition Identification of MSI tumors in the diagnostic laboratory is traditionally performed by fluorescent multiplex PCR, evaluating the microsatellite length of two mononucleotide repeats and three dinucleotide repeats (recommended NCI Panel) or a commercially available kit, consisting of five mononucleotide markers alongside IHC staining for the four MMR proteins MSH2, MSH6, MLH1, and PMS2. With the increase in MSI testing related to the recent FDA approval of Keytruda ® , several companies and laboratories are now developing newer and better PCR-based and next-generation sequencing assays to assess MSI. To control for error, we have developed a pair of cell line-derived MSI/MSS reference samples covering the most commonly used MSI biomarkers. MSI/MSS cell lines were mixed at biologically-relevant ratios and processed into FFPE to serve as a whole-process control. Our data support the suitability of this material on a variety of different platforms and with a high degree of consistency throughout various FFPE batches. In conclusion, our cell line-derived reference samples represent a commutable control to support MSI assay development and validation. Citation Format: Takahiro Matsusaka, Eva-Maria Surmann, Sian Constantine, Hannah Child, Julie Wickenden. Development and evaluation of cell line-derived FFPE reference material for MSI assay validation [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 4221.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81013202","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 5064: Sirt6 is a novel tumor suppressor in human urothelial cancer and activated by methysticin","authors":"Dongjun Fu, N. Yokoyama, Mattew Tippin, X. Zi","doi":"10.1158/1538-7445.AM2019-5064","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-5064","url":null,"abstract":"Sirtuin 6 (SIRT6) plays an important role in longevity, metabolism, DNA-repair, and inflammatory response. In human urothelial cancer, a high level of SIRT6 expression predicts a better survival for patients. We found that overexpression of SIRT6 in human muscle-invasive bladder cancer cell line J82 reduced cell migration and invasion, but didn’t reduce the in vitro cell growth. Kava is a traditional psychotropic beverage made from the rhizomes of Piper methysticum G. Forst. Previous epidemiological studies have shown an inverse relationship between cancer incidence and kava consumption in South Pacific Island Nations. We have shown that Methysticin, a major kavalactone in the Kava plant, inhibits the growth, migration and invasion of bladder cancer lines. However, these anti-cancer activities of Methysticin are attenuated in cells with low expression of SIRT6, expression of enzymatically mutant SIRT6 or SIRT6 knockout, which suggested that the anti-cancer activities of Methysticin are at least in part dependent on SIRT6 expression. Molecular modelling indicates that Methysticin docks into the site next to a loop near the acetylated peptide substrate binding site of SIRT6. The Cellular Thermal Shift Assay (CETSA, an in vivo assay) demonstrated that Methysticin significantly decreased heat-induced protein degradation of SIRT6. Treatment of J82 cells with Methysticin also resulted in a dose-dependent reduction of H3K18 acetylation. Taken together, these results suggest that Methysticin acts a novel SIRT6 activator for its anti-bladder activity. Further studies have demonstrated that Methysticin activates the TBK1/IRF3/STING pathway by increasing the protein expression of TBK1 and the phosphorylation of TBK1 and STING, which suggest that Methysticin may be able to enhance anti-tumor immunity. Therefore, our results support further investigation of Methylation for bladder cancer prevention. Note: This abstract was not presented at the meeting. Citation Format: DongJun Fu, Noriko N. Yokoyama, Mattew Tippin, Xiaolin Zi. Sirt6 is a novel tumor suppressor in human urothelial cancer and activated by methysticin [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 5064.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78304666","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 3333: Potential of kava in reducing lung cancer risk, tobacco use, and associated disparities","authors":"Chengguo Xing, Yi Wang, N. Fujioka, S. Narayanapillai, Junxuan Lu","doi":"10.1158/1538-7445.AM2019-3333","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-3333","url":null,"abstract":"Tobacco use is the primary risk factor for lung cancer, the leading cause of cancer deaths in the US. Quitting, however, is challenging due to the addictive nature of nicotine. Thus, preventing lung carcinogenesis in conjunction with smoking cessation may be necessary. Racial disparities also exist - African American (AA) smokers, with the same level of tobacco consumption, are at the highest risk of developing lung cancer. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one key carcinogen in tobacco for human lung cancer risk and its differential uptake in AA and CA smokers may contribute to the disparity. AA smokers also have the lowest success rate in quitting. Kava is a daily beverage to help people relax and improve the quality of sleep. It is commercially available in US as a dietary supplement. Epidemiological data suggest that kava consumption may reduce cancer risk. Its relaxing property may help reduce tobacco dependence/use. Our preclinical data showed that kava completely blocked NNK induced tumorigenesis in A/J mice with enhancing NNK detoxification and reducing DNA damage as the potential mechanism. Building upon these, a pilot pre- and post- one-week kava trial was performed among smokers (n = 21). The results showed that kava was well-tolerated with high compliance and there were no signs of adverse effects when rigorous safety measures were implemented. Excitingly, the results suggested that one-week kava intake helped smokers 1) reduce tobacco use; 2) reduce the amounts of urinary DNA adducts; and 3) increase urinary excretion of NNAL. Specifically, urinary Total Nicotine Equivalent (TNE), the sum of nicotine N-oxide, total nicotine, cotinine, and 3-HO-cotinine, was used to estimate tobacco use and one-week kava use led to a 29.8% reduction in TNE (p 40% (p Note: This abstract was not presented at the meeting. Citation Format: Chengguo Xing, Yi Wang, Naomi Fujioka, Sreekanth Narayanapillai, Junxuan Lu. Potential of kava in reducing lung cancer risk, tobacco use, and associated disparities [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 3333.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82383142","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 2432: Prevalence of depression and other chronic diseases among uninsured cancer survivors: A free clinic study","authors":"Sayeef Mirza, S. Rahman, M. MacDonald, A. Towne, Katherine Robinson, Amber Todd, Wei Wang, D. Wathington","doi":"10.1158/1538-7445.SABCS18-2432","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-2432","url":null,"abstract":"","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"100 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76068502","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 2429: Social Support as a Moderator in the Relationship between Intrusive Thoughts and Psychological Symptoms among Spanish-speaking Latinas with Breast Cancer","authors":"C. Escalera, A. Nápoles, Jasmine Santoyo-Olsson, C. Ortiz","doi":"10.1158/1538-7445.SABCS18-2429","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-2429","url":null,"abstract":"Background: Intrusive thoughts are associated with higher levels of psychological symptoms and impaired quality of life in the year after breast cancer treatment. To our knowledge, no studies have examined social support as a potential moderator between intrusive thoughts about breast cancer and psychological symptoms among Latinas. This study aims to assess the moderating effects of different dimensions of social support on the association between intrusive thoughts and psychological symptoms among Spanish-speaking Latina breast cancer survivors. Methods: Analyses were performed using baseline data from a randomized control trial of a stress management intervention delivered to 151 Spanish-speaking Latinas with non-metastatic breast cancer. Survey measures on intrusive thoughts, four dimensions of social support (emotional/information, tangible, affectionate, and positive social interaction), and psychological symptoms (depression, anxiety, and somatization) were obtained at baseline via a structured survey. Information on age, time since diagnosis, breast cancer treatment, surgery type, breast cancer stage, history of depression and marital status was obtained via medical records review and served as covariates. Generalized linear models were used to investigate bivariate and multivariate associations and to explore moderation effects of the four dimensions of social support. Results: In the bivariate models, intrusive thoughts were associated with more depressive (β=0.024, p=0.0014), anxiety (β=0.047, p Citation Format: Cristian Escalera, Anna Maria Napoles, Jasmine Santoyo-Olsson, Carmen Ortiz. Social Support as a Moderator in the Relationship between Intrusive Thoughts and Psychological Symptoms among Spanish-speaking Latinas with 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 2429.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"122 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90272523","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 4218: Validation of a new blood-based biomarker strategy for the early detection of lung cancer","authors":"M. Kammer, Amanda K. Kussrow, S. Antic, R. Nguyen, Heidi Chen, D. Bornhop, P. Massion","doi":"10.1158/1538-7445.AM2019-4218","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-4218","url":null,"abstract":"Rationale: The management of indeterminate pulmonary nodules (IPNs) remains a challenging problem. Our new assay methodology, the Free Solution Assay (FSA), measured by the Compensated Interferometric Reader (CIR), consisting of a diode laser, capillary and CCD, provides 40-fold lower limits of quantitation (LOQ) than ELISA for known candidate serum protein biomarkers, while speeding assay development, accuracy, and sensitivity. We hypothesized that lowering the LOQ of previously investigated biomarkers can increase the biomarker discriminatory power, enabling patients in an intermediate risk group (15-80%) to be reclassified into a low ( 80) risk group. Methods: In this retrospective case-control study, FSA-CIR was used to measure the serum concentration of CYFRA 21-1 in two patient cohorts, a training cohort (N=274) of patients with IPNs collected at Vanderbilt University Medical Center and an external validation cohort (N=103) collected at the University of Pittsburgh Medical Center. Patient malignancy was determined by tissue biopsy or 2-year follow-up CT scan showing no signs of nodule growth. Baseline risk for cancer was calculated using nodule size. The added value of CYFRA 21-1 was assessed by comparing the difference in risk for lung cancer after incorporating CYFRA 21-1 into the model. Results: The limit of detection (LOD) of 6pg/mL and an average LOQ for standards was determined to be 60pg/mL. Patient samples in the training cohort were found to have CYFRA 21-1 concentrations ranging 100 pg/mL to 10 ng/mL, with a median of 0.79 (0.28-1.22, interquartile range) ng/mL in the control population and 1.90 (1.33-3.35) ng/mL in the case population, providing a ROC-AUC of 0.86 across three histological subtypes (adenocarcinoma, squamous cell carcinoma, and small cell lung cancer). The CYFRA 21-1 + nodule size risk model correctly reclassified 28 (25%) [DB1] of intermediate-risk benign nodules into the low-risk group and 28(24%) of intermediate-risk malignant nodules into the high-risk group. The independent validation cohort’s controls had a median of 0.35 (0.20-0.56) ng/mL, while cases had 0.97(0.66-1.22) ng/mL, providing a ROC-AUC of 0.84 and correct reclassification of 12(34%) of intermediate-risk benign nodules and 6(15%) of intermediate-risk malignant nodules. The CYFRA 21-1 + nodule size risk model correctly classified 90.6% in the low-risk group and 87.0% in the high-risk group. Conclusions: FSA-CIR measurements requiring only a few microliters of serum allowed for reclassification of patients in the intermediate risk group in both the training and validation cohorts. The results suggest that CYFRA 21-1 measured by FSA-CIR represents a strong candidate biomarker for risk stratification of patients with IPNs. Citation Format: Michael N. Kammer, Amanda K. Kussrow, Sanja L. Antic, Rina Nguyen, Heidi Chen, Darryl J. Bornhop, Pierre P. Massion. Validation of a new blood-based biomarker strategy for the early detection of lung cancer [abstrac","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"341 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75365010","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 2728: Cholecystokinin receptor antagonist proglumide reverses nonalcoholic steatohepatitis and prevents hepatocellular carcinoma","authors":"V. Ciofoaia, S. Nadella, H. Cao, Matthew Huber, Robin D. Tucker, N. Shivapurkar, B. Kallakury, A. Kroemer, Jill P. Smith","doi":"10.1158/1538-7445.SABCS18-2728","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-2728","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":"81991745","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 3326: Mucositis, candidiasis, and associations with the oral microbiome in treatment naive patients with oropharyngeal cancer","authors":"C. Pierce, S. Hogue, Shirlene Paul, B. Hong, Wildson Vieira da Silva, Maria F. Gomez, A. Giuliano, J. Caudell, G. Weinstock","doi":"10.1158/1538-7445.AM2019-3326","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-3326","url":null,"abstract":"Purpose: Oropharyngeal cancer (OPC) incidence continues to increase dramatically in the US. Accumulating evidence suggests that oral microbiota (communities of microorganisms that reside in the oral cavity) may influence cancer treatment-related toxicities. We sought to examine the composition and diversity of oral microbiota in OPC patients prior to treatment, and identify associations between oral microbiota and subsequent development of oral mucositis (inflammation of mucous membranes) and candidiasis (fungal infection with Candida yeast). Methods: 60 newly diagnosed, treatment naive, OPC patients were recruited from Moffitt Cancer Center (2015-2017). Patients provided mouthwash-based oral gargles before starting chemoradiation or radiation. DNA was isolated using the QIAGEN DNeasy PowerSoil kit, and the V1-V3 region of the bacterial 16S rRNA gene was sequenced. An operational taxonomic unit table was generated and Ribosomal Database Project Classifier used to assign taxonomy. The development of oral mucositis (no/mild vs. severe) and candidiasis (no vs. yes) during treatment was abstracted from medical records. Comparisons of bacterial relative abundance (Mann Whitney U), alpha diversity (Chao1, Shannon, and Simpson), and beta diversity (Bray-Curtis) were performed in R and its extension (Phyloseq). Results: Of 60 OPC patients, 65% were stage IV, 48% tonsillar and 42% base of tongue, and 40% never smokers. Pre-treatment levels of genus Klebsiella and class Gammaproteobacteria were significantly greater in the oral cavity of patients who had no/mild mucositis vs. those who developed severe mucositis (p Conclusions: Microbiome profiling may hold promise as a prognostic biomarker of treatment-related toxicities. Several potentially predictive taxa were identified to be differentially abundant in OPC patients who subsequently developed oral mucositis or candidiasis. Future analyses will evaluate the role of oral microbial resilience (the rate of recovery after disturbance) using oral specimens collected 3 mo. after treatment. Translational research focused on understanding how oral microbiota influence local immune and inflammatory responses may aid in the development of microbiota-based interventions to minimize adverse events. Citation Format: Christine M. Pierce, Stephanie Hogue, Shirlene Paul, Bo-Young Hong, Wildson Vieira da Silva, Maria F. Gomez, Anna R. Giuliano, Jimmy J. Caudell, George M. Weinstock. Mucositis, candidiasis, and associations with the oral microbiome in treatment naive patients with oropharyngeal 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 3326.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82070367","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 2731: A novel PDE10/beta-catenin inhibitor, MCI-048, suppresses lung tumorigenesis to block metastasis","authors":"B. Zhu, Verónica Ramírez‐Alcántara, Antonio Ward, K. Berry, A. Keeton, M. Boyd, Y. Maxuitenko, Xi Chen, G. Piazza","doi":"10.1158/1538-7445.AM2019-2731","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-2731","url":null,"abstract":"We previously reported that phosphodiesterase 10A (PDE10) is overexpressed during early stages of lung cancer and is essential for lung tumor cell growth. Here we characterize a novel PDE10 inhibitor, MCI-048, that was identified by screening a library of indene compounds. MCI-048 potently inhibited the growth and induced apoptosis of multiple human lung cancer cell lines expressing PDE10, while normal human airway epithelial cells lacking PDE10 expression were appreciably less sensitive. The mechanism of action of MCI-048 involves PDE10 inhibition, cGMP elevation, PKG activation, and phosphorylation of β-catenin at key residues that induce ubiquitination and proteosomal degradation of the oncogenic pool of β-catenin in cytoplasm to suppress the translocation of active β-catenin to the nucleus and Lef/Tcf-mediated transcription of genes encoding for proteins such as c-myc, cyclin D, and survivin, which are essential for tumor cell proliferation and survival. Pharmacokinetic and tissue distribution studies revealed a unique feature of MCI-048 to accumulate at high concentrations in lungs relative to plasma and other tissues. To assess the potential of MCI-048 for the treatment of lung cancer and blocking metastasis, we tested the drug in two mouse models of lung cancer involving either orthotopic implantation of KRAS mutant A549 lung tumor cells or the chemical carcinogen, urethane. Oral administration of MCI-048 significantly inhibited tumor growth and extended survival in the orthotopic model using two different protocols to either treat the primary tumor or metastasis. Similarly, MCI-048 significantly reduced tumor burden as measured by both surface counting and histopathological analysis in the urethane-induced model of lung tumorigenesis. Biochemical analysis showed that MCI-048 reduced levels of urethane-induced active Ras-GTP and PDE10 levels, as well as other oncogenic markers, including pEGFR and c-Myc. Both mouse models revealed that MCI-048 was well tolerated with no discernable toxicity, thus supporting preclinical development for the treatment of lung cancer. Funding provided by NCI grants R21CA182941, R01CA131378, R01CA148817, R01CA197147, and R01CA155638. Citation Format: Bing Zhu, Veronica Ramirez-Alcantara, Antonio Ward, Kristy Berry, Adam B. Keeton, Michael R. Boyd, Yulia Maxuitenko, Xi Chen, Gary A. Piazza. A novel PDE10/beta-catenin inhibitor, MCI-048, suppresses lung tumorigenesis to block metastasis [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 2731.","PeriodicalId":20357,"journal":{"name":"Prevention, Early Detection, and Interception","volume":"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":"82831061","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}