Experimental and Molecular Therapeutics最新文献

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Abstract 1238: Treating estrogen receptor (ER)-negative and triple-negative breast cancer by targeting STAT3 signaling with putative STAT3 inhibitors 1238:利用STAT3抑制剂靶向STAT3信号通路治疗雌激素受体(ER)阴性和三阴性乳腺癌
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1238
Hyejin Kim, Doerte R. Fricke, Jimin Xu, Haiying Chen, Jia Zhou, Q. Shen
{"title":"Abstract 1238: Treating estrogen receptor (ER)-negative and triple-negative breast cancer by targeting STAT3 signaling with putative STAT3 inhibitors","authors":"Hyejin Kim, Doerte R. Fricke, Jimin Xu, Haiying Chen, Jia Zhou, Q. Shen","doi":"10.1158/1538-7445.AM2021-1238","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1238","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75857930","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}
引用次数: 0
Abstract 1130: First-in-class KAT6A/KAT6B inhibitor CTx-648 (PF-9363) demonstrates potent anti-tumor activity in ER+ breast cancer with KAT6A dysregulation 摘要:一流的KAT6A/KAT6B抑制剂CTx-648 (PF-9363)在KAT6A失调的ER+乳腺癌中显示出强大的抗肿瘤活性
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1130
Shikhar Sharma, Jay Chung, S. Uryu, Amanda M. Rickard, N. Nady, Showkhin Khan, Zhenxiong Wang, Yong Zhang, Haikuo Zhang, P. Kung, E. Greenwald, K. Maegley, P. Bingham, Hieu Lam, Y. E. Bozikis, Hendrik Falk, E. Allan, V. Avery, M. Butler, M. Camerino, Catalina Carrasco-Pozo, S. Charman, Melissa J. Davis, M. Dawson, Dawson Sarah-Jane, M. de Silva, M. Dennis, O. Dolezal, Rachel Lagiakos, G. Lindeman, Laura MacPherson, S. Nuttall, T. Peat, B. Ren, Alexandra E Stupple, Elliot E. Surgenor, Chin Wee Tan, T. Thomas, J. Visvader, A. Voss, F. Vaillant, K. White, J. Whittle, Yuqing Yang, Soroor Hediyeh-zadeh, P. Stupple, I. Street, B. Monahan, T. Paul
{"title":"Abstract 1130: First-in-class KAT6A/KAT6B inhibitor CTx-648 (PF-9363) demonstrates potent anti-tumor activity in ER+ breast cancer with KAT6A dysregulation","authors":"Shikhar Sharma, Jay Chung, S. Uryu, Amanda M. Rickard, N. Nady, Showkhin Khan, Zhenxiong Wang, Yong Zhang, Haikuo Zhang, P. Kung, E. Greenwald, K. Maegley, P. Bingham, Hieu Lam, Y. E. Bozikis, Hendrik Falk, E. Allan, V. Avery, M. Butler, M. Camerino, Catalina Carrasco-Pozo, S. Charman, Melissa J. Davis, M. Dawson, Dawson Sarah-Jane, M. de Silva, M. Dennis, O. Dolezal, Rachel Lagiakos, G. Lindeman, Laura MacPherson, S. Nuttall, T. Peat, B. Ren, Alexandra E Stupple, Elliot E. Surgenor, Chin Wee Tan, T. Thomas, J. Visvader, A. Voss, F. Vaillant, K. White, J. Whittle, Yuqing Yang, Soroor Hediyeh-zadeh, P. Stupple, I. Street, B. Monahan, T. Paul","doi":"10.1158/1538-7445.AM2021-1130","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1130","url":null,"abstract":"KAT6A is a lysine histone acetyltransferase (HAT) of the MYST family of HATs. KAT6A, and its paralog KAT6B, have been shown to acetylate histone H3K23Ac and regulate diverse biological processes, including transcription, cell-cycle progression, stem cell maintenance and development. Molecular dysregulation of KAT6A has been observed in several cancers, including amplifications in breast, lung, ovarian cancer along with oncogenic fusions in AML. In breast cancer, KAT6A is amplified as part of the 8p11 amplicon in 10-15% of the patient population, which correlates with a worse clinical outcome in the estrogen receptor+ (ER+) subtype. Here we present identification of a first-in-class potent KAT6A/KAT6B tool inhibitor CTx-648 (PF-9363), that possesses high selectivity versus other MYST family members (KAT7, KAT5, KAT8) and other KATs, demonstrating anti-tumor activity in breast cancer. Using genetic and pharmacological approaches, we have demonstrated several ER+ breast cancer cell lines including KAT6A amplified and over-expressing models, are dependent on KAT6A enzymatic function. Epigenomic profiling studies using bulk and nascent RNA-seq combined with ATAC-seq revealed CTx-648 leads to downregulation of a specific set of genes involved in ESR1 pathway, cell cycle and stem cell pathways. In vivo target validation studies showed strong anti-tumor activity of CTx-648 in several ER+ breast cancer cell line and patient-derived xenograft models, including models harboring endocrine therapy resistance ESR1 mutations, highlighting promise for this novel therapy in ER+ breast cancer population. Based on the strength of the pre-clinical data, a selective KAT6 inhibitor (PF-07248144) is now commencing a Phase 1 clinical study in Advanced or Metastatic Solid Tumors. Citation Format: Shikhar Sharma, Jay Chung, Sean Uryu, Amanda Rickard, Natalie Nady, Showkhin Khan, Zhenxiong Wang, Yong Zhang, Haikuo Zhang, Pei-Pei Kung, Eric Greenwald, Karen Maegley, Patrick Bingham, Hieu Lam, Ylva E. Bozikis, Hendrik Falk, Elizabeth Allan, Vicky M. Avery, Miriam S. Butler, Michelle A. Camerino, Catalina Carrasco-Pozo, Susan A. Charman, Melissa J. Davis, Mark A. Dawson, Dawson Sarah-Jane, Melanie de Silva, Matthew L. Dennis, Olan Dolezal, Rachel Lagiakos, Geoffrey J. Lindeman, Laura MacPherson, Stewart Nuttall, Thomas S. Peat, Bin Ren, Alexandra E. Stupple, Elliot Surgenor, Chin Wee Tan, Tim Thomas, Jane E. Visvader, Anne K. Voss, Francois Vaillant, Karen L. White, James Whittle, Yuqing Yang, Soroor Hediyeh-Zadeh, Paul A. Stupple, Ian P. Street, Brendon J. Monahan, Thomas Paul. First-in-class KAT6A/KAT6B inhibitor CTx-648 (PF-9363) demonstrates potent anti-tumor activity in ER+ breast cancer with KAT6A dysregulation [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 1130.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74438784","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}
引用次数: 7
Abstract 1427: Sensitizing HL60 acute myeloid leukemia cells to decitabine with pterostilbene 摘要1427:紫檀芪使HL60急性髓性白血病细胞对地西他滨敏感
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1427
Cayla Boycott, B. Stefańska
{"title":"Abstract 1427: Sensitizing HL60 acute myeloid leukemia cells to decitabine with pterostilbene","authors":"Cayla Boycott, B. Stefańska","doi":"10.1158/1538-7445.AM2021-1427","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1427","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74644995","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}
引用次数: 0
Abstract 1445: A nuclear localizing peptide that targets glioblastoma 1445:一种靶向胶质母细胞瘤的核定位肽
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1445
Calvin D. Lewis, A. Singh, V. Kapoor, D. Hallahan
{"title":"Abstract 1445: A nuclear localizing peptide that targets glioblastoma","authors":"Calvin D. Lewis, A. Singh, V. Kapoor, D. Hallahan","doi":"10.1158/1538-7445.AM2021-1445","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1445","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73016999","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}
引用次数: 0
Abstract 1280: New generation of STING agonists: Development and characterization of a novel series of systemic immunomodulators with improved potency 1280:新一代STING激动剂:开发和表征一系列新的系统性免疫调节剂,具有更高的效力
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1280
Maciej K. Rogacki, S. Chmielewski, J. Mazurek, M. Zawadzka, K. Wnuk-Lipinska, K. Kuś, Katarzyna Wójcik-Jaszczyńska, Aleksandra Poczkaj, Łukasz Dudek, Wojciech Schonemann, Urszula Głowniak-Kwitek, M. Leś, Marek Wronowski, T. Mahajan, U. Kulesza, Magdalena Zastawna, David Synak, Karol Zuchowicz, Karolina Gluza, K. Banaszak, Karolina Wiatrowska, Izabela Strojny, M. Gładysz, J. Jablonska, Ewelina Gabor-Worwa, Monika Dobrzańska, Raghuram S. Tangirala, P. Littlewood, K. Brzózka
{"title":"Abstract 1280: New generation of STING agonists: Development and characterization of a novel series of systemic immunomodulators with improved potency","authors":"Maciej K. Rogacki, S. Chmielewski, J. Mazurek, M. Zawadzka, K. Wnuk-Lipinska, K. Kuś, Katarzyna Wójcik-Jaszczyńska, Aleksandra Poczkaj, Łukasz Dudek, Wojciech Schonemann, Urszula Głowniak-Kwitek, M. Leś, Marek Wronowski, T. Mahajan, U. Kulesza, Magdalena Zastawna, David Synak, Karol Zuchowicz, Karolina Gluza, K. Banaszak, Karolina Wiatrowska, Izabela Strojny, M. Gładysz, J. Jablonska, Ewelina Gabor-Worwa, Monika Dobrzańska, Raghuram S. Tangirala, P. Littlewood, K. Brzózka","doi":"10.1158/1538-7445.AM2021-1280","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1280","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"106 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73062567","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}
引用次数: 0
Abstract 1061: Characterization of synergistic selinexor combinations with dexamethasone, pomalidomide, elotuzumab, and daratumumab in primary MM cells 摘要/ Abstract摘要:selinexor与地塞米松、泊马度胺、elotuzumab和daratumumab联合在原发MM细胞中的协同作用
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1061
P. Sudalagunta, M. Meads, R. Canevarolo, Maria C. Silva, C. Cubitt, Gabriel Deavila, R. Alugubelli, C. Logothetis, Amit Kulkarni, Qi Zhang, O. Hampton, C. Walker, Y. Landesman, K. Shain, A. Silva
{"title":"Abstract 1061: Characterization of synergistic selinexor combinations with dexamethasone, pomalidomide, elotuzumab, and daratumumab in primary MM cells","authors":"P. Sudalagunta, M. Meads, R. Canevarolo, Maria C. Silva, C. Cubitt, Gabriel Deavila, R. Alugubelli, C. Logothetis, Amit Kulkarni, Qi Zhang, O. Hampton, C. Walker, Y. Landesman, K. Shain, A. Silva","doi":"10.1158/1538-7445.AM2021-1061","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1061","url":null,"abstract":"Introduction. Multiple myeloma (MM) is an all but incurable plasma cell malignancy without predictive biomarkers for approved therapies. Selinexor (SELI), a nuclear export inhibitor targeting exportin 1 (XPO1), is approved with dexamethasone (DEX) with promising SELI-combination studies ongoing. We investigated SELI combinations ex vivo to identify synergistic combinations and companion biomarkers. Methods. We established a platform to perform parallel RNA/exome sequencing and ex vivo drug sensitivity assessment on CD138+ cells from MM patient bone marrow aspirates. At the time of this analysis, 844 different samples with clinical, WES and RNA sequencing data were treated ex vivo with the following agents: SELI (n=75), DEX (192), pomalidomide (POM, 268), elotuzumab (ELO, 21), daratumumab (DARA, 117), SELI+DEX (22), SELI+POM (20), SELI+ELO (21), SELI+DARA (27). Cells were cultured with autologous macrophages, stroma, collagen matrix and patient-derived serum. Cell death (LD50 and AUC) was assessed through digital image analysis. Sequencing was performed through ORIEN/AVATAR. Links between non-synonymous mutations in coding genes and cell death were calculated using T-tests with multiple test correction. Results. Our analysis identified SELI+DEX (number of samples=60, p<1E-9), SELI+POM (57, p<0.001) and SELI+ELO (55, p<0.01) as the most synergistic combinations (BLISS model). SELI+DARA showed synergy in 23 out of 50 samples tested. Notably, both direct drug toxicity and phagocytosis were observed. RNAseq found gene expression associations with drug resistance/response. In turn, gene set enrichment analysis (GSEA) showed that SELI resistance was associated with expression of cell adhesion, inflammatory cytokines, and EMT pathways, while the MYC targets were associated with SELI sensitivity. SELI+ELO resistance was associated with expression of hedgehog signaling pathway, while expression of ribosomal subunits was associated with sensitivity. SELI+POM resistance was linked with lysosome and cell adhesion molecules, while sensitivity was tied to ribosome, spliceosome and RNA polymerase. GSEA also identified G2M, MTORC1, MYC targets, E2F and glycolysis as biomarkers for the SELI+DARA synergistic subgroup. WES also identified mutations associated with SELI sensitivity. Mutation of BCL7A, a protein involved in chromatin remodeling, was associated with sensitivity, and mutation of CEP290, which encodes a microtubule binding protein, was associated with resistance (p<0.05). Both BCL7A and CEP290 contain predicted nuclear export sequences, suggesting they are XPO1 cargoes. Conclusions. We observed ex vivo synergy between SELI and DEX, POM, ELO and DARA, and identified expression signatures and mutations associated with response to these agents. Ongoing analysis of additional samples is being performed to validate these results. Citation Format: Praneeth Reddy Sudalagunta, Mark B. Meads, Rafael Renatino Canevarolo, Maria Coelho Silva, Christopher Cubitt, Gab","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73201598","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}
引用次数: 0
Abstract 1323: Novel autophagy inhibitor to treat pancreatic cancer 摘要1323:新型自噬抑制剂治疗胰腺癌
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1323
Mythili Ramachandran, Zhao Ma, Yuanpei Li
{"title":"Abstract 1323: Novel autophagy inhibitor to treat pancreatic cancer","authors":"Mythili Ramachandran, Zhao Ma, Yuanpei Li","doi":"10.1158/1538-7445.AM2021-1323","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1323","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73210547","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}
引用次数: 0
Abstract 1188: Reclassification of ER+ (luminal A/luminal B1 minus ER low)-like and ER- like breast tumors based on proteomic/gene and clinical outcome signatures 摘要:基于蛋白质组学/基因和临床结局特征的ER+ (luminal A/luminal B1 - ER low)样和ER-样乳腺肿瘤的重新分类
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1188
Guisong Wang, Punit Shah, R. Searfoss, Leigh Fantacone-Campbell, J. Hooke, B. Deyarmin, Rebecca N. Zingmark, S. Somiari, Jianfang Liu, L. Kvecher, Bradley J. Mostoller, Lori A. Sturtz, Praven-Kumar Raj-Kumar, E. Granger, L. Vahdat, M. Cutler, C. Bountra, R. Sarangarajan, Hai Hu, M. Kiebish, A. Kovatich, N. Narain, C. Shriver
{"title":"Abstract 1188: Reclassification of ER+ (luminal A/luminal B1 minus ER low)-like and ER- like breast tumors based on proteomic/gene and clinical outcome signatures","authors":"Guisong Wang, Punit Shah, R. Searfoss, Leigh Fantacone-Campbell, J. Hooke, B. Deyarmin, Rebecca N. Zingmark, S. Somiari, Jianfang Liu, L. Kvecher, Bradley J. Mostoller, Lori A. Sturtz, Praven-Kumar Raj-Kumar, E. Granger, L. Vahdat, M. Cutler, C. Bountra, R. Sarangarajan, Hai Hu, M. Kiebish, A. Kovatich, N. Narain, C. Shriver","doi":"10.1158/1538-7445.AM2021-1188","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1188","url":null,"abstract":"Introduction: Classification of breast cancer can incorporate immunohistochemical (IHC) detection of ER/PR/HER2/KI67 to stratify the subtypes. High throughput proteomics analysis allows for the expansion of biomarker discovery within the subtypes. We evaluated a cohort of 109 tumors characterized as ER+ (Luminal A and Luminal B1; HER2+ and ER low (1-10%) cases were excluded) compared to ER-/HER2- tumors. Utilizing an integrated bioinformatics approach, we developed a proteomic marker signature to reclassify tumors into ER+(like) and ER-(like) tumors. CPTAC (Proteomic)/TCGA (RNAseq) datasets and larger METBRIC and GSE96058 cohorts were used to validate this marker signature. The selected biomarkers demonstrated significant differences impacting survival outcome. Methods: Clinical IHC subtyping of core biopsies was used to select a cohort of patients with ER+/HER2- and ER-/HER2- primary tumors from flash-frozen surgical samples. The positive/negative status of ER/PR/HER2 was defined using updated ASCO 2020 guidelines. Ki-67 status was determined using the 2011 St. Gallen9s International Expert Consensus recommendations. Proteomic analysis was performed using Thermo Q-Exactive+ LC MS/MS analysis. Differential analysis was applied to select the significantly altered proteins between ER+ and ER- cases, Univariate survival analysis was engaged to filter informative protein/genes using TCGA RNA-Seq data. Nearest centroid analysis was deployed to define the classifier to predict novel molecular subtypes. Results/Conclusions: We selected 34 proteins/genes from 164 significantly differentially expressed proteins for further analysis. The centroid model constructed with the 34 proteins defined 2 groups: ER+(like) and ER-(like). An additional 4 groups were defined across subtypes: luminal tumors classified both by IHC and marker signature (LL), luminal tumors classified by IHC but marker signature more like triple negative (LT), triple negative tumors classified by IHC but marker signature more like luminal (TL), and triple negative classified by both IHC and marker signature (TT). This marker signature segregated close to 5000 tumors across CPTAC, TCGA, METABRIC and GSE96058 cohorts. Survival analysis in these groups of patients revealed differences in radiation, hormone/radiation, hormone therapy, and hormone/radiation/chemotherapy treatments. In summary using proteomics data we identified a 34 gene/protein marker signature, validated in large external cohorts and exhibited impact on survival and response to therapy. Further, this signature was enriched in metabolism and microenvironmental associated factors that could represent novel targets or development combination strategies based on this signature. Citation Format: Guisong Wang, Punit Shah, Rick Searfoss, Leigh Fantacone-Campbell, Jeffrey A. Hooke, Brenda Deyarmin, Rebecca N. Zingmark, Stella Somiari, Jianfang Liu, Leonid Kvecher, Bradley Mostoller, Lori A. Sturtz, Praven-Kumar Raj-Kumar, Elder Grang","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75413814","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}
引用次数: 0
Abstract 1380: Synergistic effect of the combination of XPO1 and mTORC1/2 inhibition for the treatment of triple-hit DLBCL 摘要1380:XPO1与mTORC1/2联合抑制治疗三击型DLBCL的协同效应
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1380
Bing-Xu Hou, Aihua Wang, Bo Shan, J. Mei
{"title":"Abstract 1380: Synergistic effect of the combination of XPO1 and mTORC1/2 inhibition for the treatment of triple-hit DLBCL","authors":"Bing-Xu Hou, Aihua Wang, Bo Shan, J. Mei","doi":"10.1158/1538-7445.AM2021-1380","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1380","url":null,"abstract":"Background Double/triple-hit lymphoma is an aggressive form of DLBCL with particularly poor outcome. XPO1 (exportin 1) is a well characterized nuclear export protein which is overexpressed in multiple tumor types. XPO1 exports many tumor-suppressor proteins and thus acts as a protooncogene by removing tumor suppressor protein and growth regulatory factors from the nucleus, where they are active, to the cytoplasm. First-in-class, single agent oral XPO1 inhibitor, Selinexor (ATG-010), was recently approved for the treatment of patients with DLBCL (de novo or transformed from follicular NHL) after at least two prior therapies. mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2) are critical mediators of the PI3K-AKT pathway. Signaling by the PI3K/AKT/mTOR pathway is frequently deregulated in NHL. Inhibition of mTOR has shown preclinical and clinical efficacy in treating DLBCL. This study tested the antitumor effects induced by the combination of the XPO1 inhibitor, Selinexor and the dual mTORC1/2 kinase inhibitor, ATG-008 (Onatasertib) on triple-hit DLBCL cells, DoHH2. Methods Firstly, the in vitro 50% inhibition concentration (IC50) of two compounds was determined in DoHH2 cell line using CellTiter-Glo luminescent cell viability assay. The synergy effect of compound ATG-008 in combination with ATG-010 were evaluated by combination index (CI). The synergy effect is calculated by the Chou-Talalay Method [1]. The CI score ranging from 0.1-0.9 suggests very strong to slight synergism. The in vivo combination of the drugs were tested in DoHH2 CDX mouse model. The tumor bearing mouse were treated with vehicle control, Selinexor (5mg/kg, MWF), ATG-008 (10mg/kg, QD) or the combination for 21 days. The tumor size was measured twice a week and tumor growth inhibition (TGI) was evaluated compared with vehicle control group. Results Potent in vitro and in vivo anti-tumor efficacy and synergy has been observed for the combination of the two drugs. The in vitro IC50 for DOHH-2 cell line were 0.85µM and 0.08µM for ATG-008 and Selinexor, respectively. Synergy has been observed for most combo concentrations tested with the strongest synergism observed for ATG-008 (1.7µM) + Selinexor (0.16µM). The combination index was 0.48. In the DoHH2 CDX in vivo study, the mono therapy of ATG-008 showed 41% TGI at day 19 after grouping (p value Conclusions Strong synergism has been observed for the combination of XPO1 and mTORC1/2 inhibition by Selinexor and ATG-008, respectively, suggesting promising therapeutic strategies for double/triple-hit lymphoma patients that warrants further investigation. [1]Chou TC. Cancer Res. 2010 Jan 15;70(2):440-6. Citation Format: Bing Hou, Aihua Wang, Bo Shan, Jay Mei. Synergistic effect of the combination of XPO1 and mTORC1/2 inhibition for the treatment of triple-hit DLBCL [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(1","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75494416","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}
引用次数: 0
Abstract 1208: Identifying a novel glycolytic inhibitor for treatment of aggressive prostate cancer 摘要1208:鉴定一种治疗侵袭性前列腺癌的新型糖酵解抑制剂
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1208
Tanya Stoyanova
{"title":"Abstract 1208: Identifying a novel glycolytic inhibitor for treatment of aggressive prostate cancer","authors":"Tanya Stoyanova","doi":"10.1158/1538-7445.AM2021-1208","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1208","url":null,"abstract":"Among men, prostate cancer is the second leading cause of cancer-associated mortality, with advanced disease remaining a major clinical challenge. Chalcones are a major class of widely occurring natural products that are intermediates in plant flavonoid isoflavonoid synthesis. They are characterized by an α,β-unsaturated carbonyl structure with two aromatic rings and commonly act as free-radical scavengers. Herein, we describe a chalcone derivative, SU086, as an anticancer agent for prostate cancer. Proteomic and metabolomic profiling demonstrate that SU086 impairs glycolysis, a critical pathway for cancer growth and survival. SU086 inhibited prostate cancer cell growth, migration, and invasion in vitro. Moreover, SU086 significantly delayed the tumor growth of cell line-derived xenograft models of CRPC as well as patient-derived xenografts (PDXs) in vivo, and the proliferation of primary human prostate cancer patient-derived tissues ex vivo. Furthermore, SU086 strongly synergized with standard of care second-generation anti-androgens, enzalutamide and abiraterone, in inhibiting prostate cancer cell growth in vitro and tumor growth in vivo. Our study identifies SU086 alone or in combination therapy settings as a novel treatment for aggressive prostate cancer. We demonstrate that SU086 represents a highly effective therapeutic strategy for both AR-sensitive and AR-insensitive prostate cancers and may potentially be applicable across multiple cancer types. Citation Format: Tanya Ivanova Stoyanova. Identifying a novel glycolytic inhibitor for treatment of aggressive prostate 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 1208.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73687379","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}
引用次数: 0
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