Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-970
Adam K. Aragaki, J. Hoffman-Censits, N. Hahn, D. McConkey, Burles A. Johnson
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.
尽管付出了巨大的努力，但仍然非常需要识别能够准确识别将从免疫检查点抑制剂(ICI)治疗中获得最大临床益处的患者的生物标志物。肿瘤内CD8+ T细胞基因特征(CD8TGS)的高表达、肿瘤突变负担(TMB)和程序性死亡配体1 (PD-L1)的高表达都丰富了多种癌症亚型对ICI治疗的反应。虽然高瘤内B细胞基因表达也与黑色素瘤的ICI反应相关，但它是否对其他癌症具有预测价值尚不清楚。我们分析了来自IMvigor 210晚期尿路上皮癌患者的atezolizumab 2期临床试验的肿瘤RNA测序数据，以研究B细胞基因表达与临床结果之间的潜在关系。两种特征(BCGS/CD8TS或B8T高/高)水平高的肿瘤在所有B8T组中具有最高的总生存率(OS)。令人惊讶的是，具有B8T高/低表达模式的肿瘤亚群与最差的OS相关。此外，B8T细胞特征将高TMB或高PD-L1患者分层为具有不同OS结果的亚群。尽管B8T高/高肿瘤与ICI治疗的男性最佳临床结果相关，但它们与ICI治疗的女性更好的OS无关。相反，B8T高/高肿瘤的女性在非ici治疗的肌肉浸润性膀胱癌中具有最好的临床结果。总的来说，这些数据表明B8T特征可以增强接受ICI治疗的晚期尿路上皮癌患者的OS分层，并且肿瘤免疫微环境的性别特异性差异可能导致不同的结果。引文格式:Adam K. Aragaki, Jean Hoffman-Censits, Noah M. Hahn, David J. McConkey, Burles Avner Johnson。基于肿瘤内B细胞基因特征表达的免疫检查点抑制剂治疗后生存的性别特异性分层[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):摘要第970期。
{"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":null,"pages":null},"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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-1107
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
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.
背景:携带EGFR突变的NSCLC细胞可以通过扩增含有CRKL的染色体片段Chr22q11.2 (Chr22amp)获得对同源TKIs的抗性。这也特别与极光激酶B (AZD2811)抑制剂的敏感性相关，可能由其他Chr22基因介导。此外，对AZD2811的反应发生表型重布线，从野生型(WT)细胞的衰老多倍体到Chr22amp细胞的凋亡。在这里，我们旨在通过磷酸化蛋白质组学途径分析来阐明这一背景下潜在的信号改变。方法:对EGFR突变细胞系PC9和8个TKI耐药衍生物(4个Chr22amp和4个WT)进行分析。通过流式细胞术检测AZD2811 (100nM)和奥西替尼(160nm)的反应动力学。样品(n=3)分别在使用AZD2811 6、24和48 h和使用希莫替尼1 h后制备，并与时间匹配的对照组进行磷酸化蛋白质组学分析。细胞洗涤，尿素溶解，胰蛋白酶消化。磷酸化肽用TiO2富集，并用Orbitrap LC-MS/MS进行分析。计算分析定量了样品中的多肽。KScanTM生物信息学鉴定了Chr22amp和WT之间的差异磷酸肽，通过KSEA、推定下游靶标(PDT)和差异化合物靶标活性标记(CTAM)确定激酶底物谱。结果:ch22amp细胞对AZD2811的单细胞时程分析显示，处理后48 h，约60%的细胞变成了Annexin V+。我们在治疗后6、24和48小时取时间点。我们将磷酸化蛋白质组学分析重点放在了Chr22amp扩增细胞的三个比较上:1)与WT相比的基础信号状态;2)亲代PC9对奥希替尼的信号反应;3)与WT相比，AZD2811改变了信号传导动力学。在基础水平上，Chr22amp具有CK1e, CDK2, p38a底物差异富集，MTOR抑制剂和Aurora B抑制剂调节位点(p结论:在这里，我们发现Chr22amp细胞中显著的通路失调，破坏了EGFR抑制并增强了对AZD2811的敏感性。有趣的是，我们在Chr22amp细胞中检测到基础水平的Aurora B活性增强，以及AZD2811对EGFR通路的惊人影响。引文格式:Arran Dokal, Jordi bertrann - 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。Chr22q11.2扩增的NSCLC细胞的精确磷酸化蛋白质组学分析揭示了不同的信号破坏和对极光激酶B抑制的反应[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):1107。
{"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":null,"pages":null},"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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-1072
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
{"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":null,"pages":null},"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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-44
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
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.
ARV-471是雌激素受体(ER) α PROTAC®蛋白降解物，是一种异源双功能分子，促进雌激素受体α与细胞内E3连接酶复合物之间的相互作用，导致雌激素受体通过蛋白酶体泛素化和随后的降解。ARV-471在雌激素受体阳性的乳腺癌细胞株中对雌激素受体有较强的降解作用，一半最大降解浓度(DC50)约为1 nM。PROTAC®介导的内质网降解降低经典内质网靶基因的表达，抑制内质网依赖细胞系的细胞增殖(MCF7, T47D)。此外，ARV-471可降解临床相关的ESR1变体(Y537S和D538G)，并抑制表达这些变体的细胞系的生长。在未成熟大鼠子宫萎缩模型中，ARV-471可降解大鼠子宫内质网，且无激动剂活性。每日口服单药ARV-471(3,10和30mpk)可导致雌二醇依赖性MCF7异种移植物的显著抗肿瘤活性，并在研究结束时伴随肿瘤ER蛋白降低>90%。此外，当CDK4/6抑制剂与ARV-471在MCF7模型中联合使用时，观察到更明显的肿瘤生长抑制(131% TGI)，并伴有内质网蛋白水平的显著降低。在ESR1 Y537S，激素不依赖的患者来源的异种移植模型中，ARV-471在10 mpk时完全抑制生长，并显著降低突变ER蛋白水平。综上所述，ARV-471的临床前数据支持其作为同类最佳口服ER PROTAC®蛋白降解剂的持续发展。这些临床前数据支持了ARV-471用于治疗乳腺癌患者的临床开发。本文将介绍ARV-471的发现、化学结构和初步临床数据。引文格式:Lawrence B. Snyder、John J. Flanagan、钱一民、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。口服生物可利用雌激素受体降解PROTAC的ARV-471的发现用于治疗乳腺癌患者[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):摘要第44期。
{"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":null,"pages":null},"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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-1078
Virginia Judith Wolos, I. J. Tapia, Marianela Abrigo, E. Lacunza, E. Joffe, G. Fiszman
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.
曲妥珠单抗和曲妥珠单抗emtansine (T-DM1)靶向治疗是治疗her2过表达乳腺癌患者的主要选择。然而，新发或获得性耐药仍然是临床实践中的主要障碍。研究表明，包括HER2在内的几种途径可导致乳腺癌细胞中HIF-α的稳定。因此，我们研究的目的是分析缺氧在抗her2治疗获得性耐药中的作用。我们使用过表达her2的BT-474和非过表达MCF-7的人乳腺癌细胞系。作为急性缺氧模型，我们在细胞培养液中加入100µM的CoCl2。Western blot检测细胞缺氧状态，结果显示CoCl2暴露6小时后HIF-1α表达达到峰值。通过RT-qPCR测量，该结果与VEGF诱导相关(p引文格式:Virginia Judith Wolos, Ivana jacqueline Tapia, Marianela Abrigo, Ezequiel Lacunza, Elisa Dora Bal de Kier Joffe, Gabriel Leon Fiszman)。缺氧微环境促进her2过表达乳腺癌对靶向治疗的耐药，涉及上皮到间质转化特征[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):摘要第1078期。
{"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":null,"pages":null},"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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-1214
A. Takano, Y. Miyagi, Y. Daigo
{"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":null,"pages":null},"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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-1355
T. Ghosh, Teeratas Kansom, Suman Mazumder, Joshua Davis, Ahmed S. Alnaim, Aedan Bird, P. Opanasopit, A. Mitra, Robert Arnold
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.
背景:前列腺癌(PCa)是美国男性非皮肤癌死亡的第二大原因，其中许多进展为侵袭性转移性去势抵抗性PCa (mCRPC;前列腺癌对雄激素剥夺无反应)。紫杉烷(TX)常规处理;多西他赛(DTX)或卡巴他赛(CBZ)仅能略微提高生存率。穿心莲内酯类似物19-叔丁基二苯基硅基-8,7-环氧穿心莲内酯(3A.1)已显示出对多种癌症的抗癌活性。在本研究中，我们研究了3A的作用。1单独或联合DTX和CBZ治疗侵袭性前列腺癌模型。方法:用CBZ、DTX和3A处理雄激素受体阴性(AR-ve) mCRPC细胞株。1在较宽的浓度范围内单药或联合用药，并测定体外细胞毒性。采用Chou-Talalay9s联合指数(CI)定理确定了紫杉烷的协同作用，并预测了紫杉烷的剂量减少。通过mRNA测序评估单药和联合用药对基因表达谱(GEP)的治疗后影响。差异表达基因(DEGs)和3A的分子通路。采用DESeq2、edgeR和Ingenuity pathway analysis (IPA)鉴定其作用机制和药物协同作用。免疫印迹法证实顶端DE基因的蛋白表达。细胞周期分析、划痕/伤口愈合和COMET检测用于功能验证顶级治疗相关基因。结果:暴露于3A;1在mCRPC中表现出剂量和时间依赖性的抗肿瘤活性。所有3A的CI值。1+ TX组合小于0.5，说明有协同作用。共处理3A。在前列腺腺癌患者(PRAD-TCGA)中，TRA2B和SF1基因与较差的Gleason评分和淋巴结转移状态相关。结论:上述结果提示3A;1可能有助于提高紫杉烷类药物治疗侵袭性前列腺癌的抗癌效果。引文格式:Taraswi Mitra Ghosh, Teeratas Kansom, Suman Mazumder, Joshua Davis, Ahmed Alnaim, Aedan Bird, P Opanasopit, Amit K. Mitra, Robert Arnold。一种新型穿心莲内酯类似物(3A.1)通过上调热休克蛋白和下调mat2a介导的细胞迁移和侵袭，与紫杉烷衍生物协同作用于侵袭性转移性前列腺癌[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):1355。
{"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":null,"pages":null},"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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-1223
David J. Elzi, William Bauta, S. Lai, T. Das, Shweta Mogare, V. I. Rebel
{"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":null,"pages":null},"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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-1011
Michael W Caminear, B. Harrington, C. Annunziata
{"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":null,"pages":null},"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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-1481
E. Venetsanakos, Mike Preigh, J. Hou, M. Cox, J. Bender, S. Blackman
{"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":null,"pages":null},"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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：