Experimental and Molecular Therapeutics最新文献

{"title":"Abstract 970: Gender-specific stratification of survival following immune checkpoint inhibitor therapy based on intratumoral expression of a B cell gene signature","authors":"Adam K. Aragaki, J. Hoffman-Censits, N. Hahn, D. McConkey, Burles A. Johnson","doi":"10.1158/1538-7445.AM2021-970","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-970","url":null,"abstract":"Despite intensive efforts there is still a great need to identify biomarkers that can accurately identify patients who will obtain the most clinical benefit from immune checkpoint inhibitor (ICI) therapy. High intratumoral CD8+ T cell gene signature (CD8TGS) expression, tumor mutational burden (TMB), and programmed death ligand 1 (PD-L1) expression all enrich for response to ICI treatment across multiple cancer subtypes. Although high intratumoral B cell gene expression also correlated with ICI response in melanoma, whether it adds predictive value in other cancers is unknown. We analyzed tumor RNA sequencing data from the IMvigor 210 phase 2 clinical trial of atezolizumab in patients with advanced urothelial carcinoma to examine potential relationships between B cell gene expression and clinical outcomes. Tumors with high levels of both signatures (BCGS/CD8TS or B8T high/high) had the highest overall survival (OS) of all B8T groups. Surprisingly, the subset of tumors with B8T high/low expression patterns were associated with the worst OS. Moreover, the B8T cell signature stratified patients with high TMB, or high PD-L1, into subsets with differential OS outcomes. Whereas the B8T high/high tumors were associated with the best clinical outcomes in ICI treated men, they were not associated with better OS in ICI treated women. Conversely, women with B8T high/high tumors had the best clinical outcomes in non-ICI treated muscle invasive bladder cancer. Collectively, these data suggest that the B8T signature can enhance OS stratification in patients with advanced urothelial carcinoma who were treated with ICI therapy, and that sex-specific differences in the tumor immune microenvironment may drive disparate outcomes. Citation Format: Adam K. Aragaki, Jean Hoffman-Censits, Noah M. Hahn, David J. McConkey, Burles Avner Johnson. Gender-specific stratification of survival following immune checkpoint inhibitor therapy based on intratumoral expression of a B cell gene signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 970.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79305163","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 1107: Precision phosphoproteomic analysis in Chr22q11.2 amplified NSCLC cells reveals distinct signaling corruption and response to Aurora kinase B inhibition","authors":"Arran Dokal, J. Bertran-Alamillo, E. Wilkes, H. Lewis, A. Giménez-Capitán, C. Greenhalgh, Ruth Osuntola, Maruan Higazi-Vega, Shona Ellison, V. Rajeeve, G. Fabbri, U. Polanska, J. E. Pease, Pedro Rodriguez-Cutillas, J. Urosevic, M. Molina-Vila, D. Britton, Jon Travers","doi":"10.1158/1538-7445.AM2021-1107","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1107","url":null,"abstract":"Background: NSCLC cells carrying EGFR mutations can gain resistance to cognate TKIs through amplification of Chr22q11.2 (Chr22amp), a chromosome segment containing CRKL. This also specifically associates with exquisite sensitivity to inhibitors of Aurora Kinase B (AZD2811), potentially mediated by other Chr22 genes. Furthermore, a phenotypic rewiring occurs in the response to AZD2811, from a senescent polyploidy in wildtype (WT) cells to apoptosis in Chr22amp cells. Here, we aimed to elucidate the underlying signaling alterations in this background by phosphoproteomic pathway analysis. Methods: The EGFR mutant cell line PC9 and 8 TKI resistant derivatives were profiled (4 Chr22amp and 4 WT). Kinetics of response to AZD2811 (100nM) and osimertinib (160 nM) were identified by flow cytometry. Samples (n=3) were prepared for phosphoproteomics, after 6, 24, and 48 h AZD2811 and 1 h osimertinib, with time matched controls. Cells were washed and lysed in urea, then digested with trypsin. Phosphorylated peptides were enriched with TiO2 and analyzed by Orbitrap LC-MS/MS. Computational analyses quantified peptides across samples. KScanTM bioinformatics identified differential phosphopeptides between Chr22amp and WT to determine kinase substrate profiles by KSEA, putative downstream targets (PDT) and differential compound target activity markers (CTAM). Results: Single cell time-course analysis of phenotypic response to AZD2811 in Chr22amp cells showed that >60% of cells become Annexin V+ by 48 h post-treatment. We took earlier timepoints of 6, 24 and 48 h post treatment. We focused the phosphoproteomic analysis on three comparisons of Chr22amp amplified cells to: 1) the basal signaling state compared to WT; 2) the signaling response to osimertinib in parental PC9; and 3) the altered kinetics of signaling in response to AZD2811 compared to WT. At the basal level, Chr22amp had CK1e, CDK2, p38a substrates differentially enriched, and MTOR inhibitor and Aurora B inhibitor modulated sites (p Conclusions: Here, we identified significant pathway deregulation in Chr22amp cells that subverted EGFR inhibition and enhanced sensitivity to AZD2811. Intriguingly, we detected enhanced Aurora B activity in Chr22amp cells at basal levels, and surprising impact of AZD2811 on the EGFR pathway. Citation Format: Arran Dokal, Jordi Bertran-Alamillo, Edmund Wilkes, Hilary Lewis, Ana Gimenez-Capitan, Calum Greenhalgh, Ruth Osuntola, Maruan Higazi-Vega, Shona Ellison, Vinothini Rajeeve, Giulia Fabbri, Urszula Polanska, J. Elizabeth Pease, Pedro Rodriguez-Cutillas, Jelena Urosevic, Miguel Angel Molina-Vila, David Britton, Jon Travers. Precision phosphoproteomic analysis in Chr22q11.2 amplified NSCLC cells reveals distinct signaling corruption and response to Aurora kinase B inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1107.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84396410","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 1072: Combination screening of DNA damaging agents temozolomide and trabectedin with inhibitors of DNA repair using a complex spheroid model with a panel of patient-derived and established tumor cell lines","authors":"N. Coussens, R. Parchment, J. Moscow, L. Doyle, R. Delosh, J. Laudeman, R. Reinhart, C. Ogle, T. Silvers, T. Dexheimer, Joel Morris, B. Teicher, J. Doroshow","doi":"10.1158/1538-7445.AM2021-1072","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1072","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84427186","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 44: The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer","authors":"Lawrence Snyder, J. Flanagan, Y. Qian, S. Gough, M. Andreoli, M. Bookbinder, G. Cadelina, J. Bradley, E. Rousseau, J. Chandler, Ryan R. Willard, J. Pizzano, C. Crews, A. Crew, J. Houston, Marcia Dougan Moore, R. Peck, I. Taylor","doi":"10.1158/1538-7445.AM2021-44","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-44","url":null,"abstract":"ARV-471, an estrogen receptor (ER) alpha PROTAC® protein degrader, is a hetero-bifunctional molecule that facilitates the interactions between estrogen receptor alpha and an intracellular E3 ligase complex, leading to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with a half-maximal degradation concentration (DC50) of ~ 1 nM. PROTAC® mediated ER degradation decreases the expression of classically regulated ER-target genes and inhibits cell proliferation of ER-dependent cell lines (MCF7, T47D). Additionally, ARV-471 degrades clinically relevant ESR1 variants (Y537S and D538G) and inhibits growth of cell lines expressing those variants. In an immature rat uterotrophic model, ARV-471 degrades rat uterine ER and demonstrates no agonist activity. Daily, oral-administration of single agent ARV-471 (3, 10, and 30 mpk) leads to significant anti-tumor activity of estradiol-dependent MCF7 xenografts and concomitant tumor ER protein reductions of >90% at study termination. Moreover, when a CDK4/6 inhibitor is combined with ARV-471 in the MCF7 model, even more pronounced tumor growth inhibition is observed (131% TGI), accompanied by significant reductions in ER protein levels. In an ESR1 Y537S, hormone-independent patient-derived xenograft model, ARV-471 at 10 mpk completely inhibited growth and also significantly reduced mutant ER protein levels. Taken together, the preclinical data of ARV-471 supports its continued development as a best-in-class oral ER PROTAC® protein degrader. These preclinical data supported the clinical development of ARV-471 for the treatment of patients with breast cancer. The discovery, chemical structure and initial clinical data of ARV-471 will be presented. Citation Format: Lawrence B. Snyder, John J. Flanagan, Yimin Qian, Sheryl M. Gough, Monica Andreoli, Mark Bookbinder, Gregory Cadelina, John Bradley, Emma Rousseau, Julian Chandler, Ryan Willard, Jennifer Pizzano, Craig M. Crews, Andrew P. Crew, John Houston, Marcia Dougan Moore, Ron Peck, Ian Taylor. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 44.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85025224","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 1078: Hypoxic microenvironment promotes resistance to targeted therapies in HER2-overexpressing breast cancer involving epithelial-to-mesenchymal transition features","authors":"Virginia Judith Wolos, I. J. Tapia, Marianela Abrigo, E. Lacunza, E. Joffe, G. Fiszman","doi":"10.1158/1538-7445.AM2021-1078","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1078","url":null,"abstract":"Trastuzumab and trastuzumab emtansine (T-DM1) targeted therapies are the main choice for the treatment of HER2-overexpressing breast cancer patients. However, de novo or acquired resistance is still the major obstacle in clinical practice. It has been shown that several pathways, including HER2, can lead to HIF-α stabilization in breast cancer cells. Thus, the purpose of our study was to analyse the effect of hypoxia in acquired resistance to anti-HER2 therapies. We used HER2-overexpressing BT-474 and non-overexpressing MCF-7 human breast cancer cell lines. As an acute hypoxia model, we added CoCl2 (100 µM) to cell culture medium. The hypoxic status of the cells was evaluated by a Western blot analysis, showing a peak of HIF-1α expression after 6 hours of CoCl2 exposure. This result correlated with VEGF induction, as measured by RT-qPCR (p Citation Format: Virginia Judith Wolos, Ivana Jaqueline Tapia, Marianela Abrigo, Ezequiel Lacunza, Elisa Dora Bal de Kier Joffe, Gabriel Leon Fiszman. Hypoxic microenvironment promotes resistance to targeted therapies in HER2-overexpressing breast cancer involving epithelial-to-mesenchymal transition features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1078.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"108 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86002471","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 1214: Identification of URST1 as a prognostic biomarker and therapeutic target for lung cancer","authors":"A. Takano, Y. Miyagi, Y. Daigo","doi":"10.1158/1538-7445.AM2021-1214","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1214","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77044583","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 1355: A novel andrographolide analogue (3A.1) synergizes with Taxane derivatives in aggressive metastatic prostate cancers through upregulation of heatshock proteins and downregulation of MAT2A-mediated cell migration and invasion","authors":"T. Ghosh, Teeratas Kansom, Suman Mazumder, Joshua Davis, Ahmed S. Alnaim, Aedan Bird, P. Opanasopit, A. Mitra, Robert Arnold","doi":"10.1158/1538-7445.AM2021-1355","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1355","url":null,"abstract":"BACKGROUND: Prostate cancer (PCa) is the 2nd leading cause of non-cutaneous cancer deaths among men in the USA with many progressing to aggressive metastatic castration resistant PCa (mCRPC; PCa unresponsive to androgen deprivation). Conventional treatment with taxanes (TX; docetaxel (DTX) or cabazitaxel (CBZ)) increases survival rates only slightly. The andrographolide analog, 19-tert-butyldiphenylsilyl-8,7-epoxy andrographolide (3A.1) has shown anticancer activity against various cancers. In this study, we investigated the effect of 3A.1 alone and in combination with DTX and CBZ against models of aggressive PCa. METHODS: Androgen receptor negative (AR-ve) mCRPC cell lines were treated with CBZ, DTX and 3A.1 as single-agent or combination over a broad concentration range, and in vitro cytotoxicity was determined. Chou-Talalay9s combination index (CI) theorem was used to determine synergism and predicted dose reduction of taxanes. Post-treatment effect of single-agent and combination regimens on gene expression profile (GEP) was assessed using mRNA sequencing. Differentially expressed genes (DEGs) and molecular pathways involved in 3A.1 mechanism of action and drug synergy were identified using DESeq2, edgeR and Ingenuity pathway analysis (IPA). Protein expression of top DE genes was confirmed by immunoblotting. Cell cycle analysis, scratch/wound healing, and COMET assays were used to functionally validate the top treatment-associated genes. RESULTS: Exposure to 3A.1 alone exhibited a dose- and time-dependent antitumor activity in mCRPC. CI values of all 3A.1+ TX combinations were less than 0.5, indicating synergism. Co-treatment of 3A.1 with TX reduced the required dose of DTX by 9.5 to 18-folds (p 0.7) genes, TRA2B and SF1, were associated with worser Gleason score and nodal metastasis status in prostate adenocarcinoma patients (PRAD-TCGA). CONCLUSION: These results suggest that 3A.1 may be useful in increasing the anticancer efficacy of taxanes to treat aggressive prostate cancer. Citation Format: Taraswi Mitra Ghosh, Teeratas Kansom, Suman Mazumder, Joshua Davis, Ahmed Alnaim, Aedan Bird, P Opanasopit, Amit K. Mitra, Robert Arnold. A novel andrographolide analogue (3A.1) synergizes with Taxane derivatives in aggressive metastatic prostate cancers through upregulation of heatshock proteins and downregulation of MAT2A-mediated cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1355.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80957166","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 1223: Simultaneous knockdown of CD320 and LRP2 receptors is selectively toxic to cancer cells but not normal cells","authors":"David J. Elzi, William Bauta, S. Lai, T. Das, Shweta Mogare, V. I. Rebel","doi":"10.1158/1538-7445.AM2021-1223","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1223","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"87 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81245611","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 1011: Disulfiram superior to ALDH1A1 inhibitor analogs in targeting ovarian cancer stem cells","authors":"Michael W Caminear, B. Harrington, C. Annunziata","doi":"10.1158/1538-7445.AM2021-1011","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1011","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81970121","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 1481: DAY101, a potent pan-RAF inhibitor with activity in preclinical models harboring MAPK pathway alterations beyond BRAF V600E mutation","authors":"E. Venetsanakos, Mike Preigh, J. Hou, M. Cox, J. Bender, S. Blackman","doi":"10.1158/1538-7445.AM2021-1481","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1481","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"67 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85400184","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}