Experimental and Molecular Therapeutics最新文献

{"title":"Abstract 1114: Role of the FGFR1-KDM2B-EZH2 signaling axis in bone-marrow microenvironment mediated tumor survival & drug resistance in Mantle cell lymphoma","authors":"A. Sircar, S. Singh, G. Laliotis, E. Chavdoula, Amber Hart, P. Tsichlis, L. Sehgal","doi":"10.1158/1538-7445.AM2021-1114","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1114","url":null,"abstract":"Mantle Cell Lymphoma (MCL) is a rare but aggressive form of Non-Hodgkin9s lymphoma, with high rates of progression & extensive bone marrow (BM) involvement. There is a high propensity towards development of drug resistance against treatment options presently available such as ibrutinib, a Bruton9s Tyrosine Kinase (BTK) inhibitor. The BM provides a secure niche for MCL cells to thrive. Unbiased transcriptome analysis revealed Fibroblast Growth Factor Receptor-1 (FGFR1) as a major upregulated candidate in ibrutinib-resistant (IR) patients & MCL cells cultured under the influence of BM stroma. FGFR1 knockdown downregulates expression of EZH2 (a catalytic subunit of PRC2 complex involved in epigenetic regulation), which has a high expression in BM stroma cultured MCL cells & linked to poor patient survival. A putative protein linking these two is KDM2B (Lysine demethylase 2B) shown in other cancer types. We found KDM2B to be higher in BM stroma cultured MCL. However, there is no known information regarding presence/functioning of the FGFR1-KDM2B-EZH2 axis, along with if/how this axis may confer stroma-mediated proliferative or drug resistance benefits in MCL. In this study, we performed variety of proliferation, ibrutinib sensitivity & cell survival tests on MCL grown under BM stromal influence. Cytokine arrays were performed to identify specific cytokine upregulation in stromal milieu, followed by subsequent stromal knockdown & reevaluation of MCL growth kinetics. FGFR1 & KDM2B were individually knocked down (KD) in IR-MCL cells & above-mentioned assays repeated. ChIP-qPCR studies for binding to promoter of miR-101, a previously identified negative regulator of EZH2, were also performed. Our results show that ibrutinib-sensitive MCL patient derived cells have greater proliferation & decreased ibrutinib sensitivity when grown under BM stromal influence, & higher expression of FGFR1, KDM2B & EZH2. The stroma-induced growth advantage is reversed when FGFR1 inhibitor is supplemented in the stromal milieu. Cytokine array identified IL-6 as a major upregulated cytokine in BM stroma-conditioned media, with IL-6 seen to enhance FGFR1 expression & IL-6 KD in stroma reversing the MCL growth advantage. KD of FGFR1 & KDM2B individually in MCL-IR cells reduced proliferation & increased sensitivity to ibrutinib. KDM2B & EZH2 expression were lowered in FGFR1KD cells & expression of miR-101 was increased, along with decreased fold enrichment of KDM2B at the miR-101 promoter locus, indicating a decreased KDM2B-mediated repression of this negative regulator of EZH2, a possible reason for EZH2 down-regulation. These results indicate the vitality of FGFR1-KDM2B-EZH2 signaling axis in tumor progression & drug resistance, shedding light on mechanisms for BM microenvironment mediated tumor survival, paving way for identification of new druggable targets. Citation Format: Anuvrat Sircar, Satishkumar Singh, Georgios Laliotis, Evangelia Chavdoula, Amber Hart, Philip N. Tsich","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":"77022299","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 1036: Identification of Tofacitinib, Filgotinib and Ruxolitinib on experimental Sjögren's syndrome model in mice","authors":"Rui-jing Yan, Yanping Yuan, Chao Luo, Chuanzhi Yangmeng, L. Fang, Qing Lin","doi":"10.1158/1538-7445.AM2021-1036","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1036","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":"77131946","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 1458: Targeting fibroblast growth factor receptors in castration-resistant prostate cancer","authors":"Mark P. Labrecque, L. Brown, Ilsa M Coleman, Bryce Lakely, H. Nguyen, E. Corey, P. Nelson, C. Morrissey","doi":"10.1158/1538-7445.AM2021-1458","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1458","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":"82192644","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 ND01: Discovery of INCB86550: A potent, orally bioavailable small molecule inhibitor of PDL1 for the treatment of cancer","authors":"Liangxing Wu","doi":"10.1158/1538-7445.AM2021-ND01","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-ND01","url":null,"abstract":"Blocking the PD-(L)1 immune checkpoint axis with therapeutic antibodies has proven to be an effective treatment modality for multiple cancer histologies. Orally bioavailable small-molecule inhibitors of the PD-1/PD-L1 interaction have been highly anticipated as a promising alternative or complementary therapeutic to the monoclonal antibodies. This presentation will detail our discovery evolution that led to the discovery of a first-in-class small molecule PDL1 inhibitor INCB89550 which is currently in clinical trials for the treatment of cancer. The presentation will also detail our characterization of novel small molecule antagonists of the PD-(L)1 axis that function by inducing dimerization and subsequent internalization of the PD-L1 protein, effectively depleting the ligand from the cell membrane and preventing PD-1 activation on T cells. Citation Format: Liangxing Wu. Discovery of INCB86550: A potent, orally bioavailable small molecule inhibitor of PDL1 for the treatment of 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 ND01.","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":"81370972","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 1038: PMD-026, a first in class oral RSK inhibitor, demonstrates synergy when combined with standard of care in breast cancer tumor models","authors":"Aarthi Jayanthan, My-my Huynh, Jangsoon Lee, G. Los, Lambert Yue, M. Pambid, N. Ueno, S. Dunn","doi":"10.1158/1538-7445.AM2021-1038","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1038","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":"81475249","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 990: Differential immunoregulatory effects of decitabine on lipid metabolism in doxurobicinversustamoxifen treated breast cancer cells","authors":"M. Fouad, M. Sayed-Ahmed","doi":"10.1158/1538-7445.AM2021-990","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-990","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":"78866415","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 1468: NUV-655 (NVL-655) is a selective, brain-penetrant ALK inhibitor with antitumor activity against the lorlatinib-resistant G1202R/L1196M compound mutation","authors":"H. Pelish, A. Tangpeerachaikul, N. Kohl, J. Porter, M. Shair, J. Horan","doi":"10.1158/1538-7445.AM2021-1468","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1468","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":"76025107","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 1453: Antibiotic treatment targeting gram negative bacteria prevents neratinib-induced diarrhea in rats","authors":"K. Secombe, Imogen A. Ball, Anthony D. Wignall, Emma H Bateman, I. Diala, A. Lalani, J. Bowen","doi":"10.1158/1538-7445.AM2021-1453","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1453","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":"87466379","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 985: BI 905711 selectively induces apoptosis and anti-tumor response in TRAILR2/CDH17- expressing pancreatic cancer models","authors":"Jingchao Han, Annette A. Machado, Mikhila Mahendra, J. Daniele, C. Bristow, Justin K. Huang, A. Carugo, Robert A. Mullinax, B. Bivona, Ningping Feng, Poojabahen Gandhi, N. Schweifer, P. Chetta, J. M. García-Martínez, F. Hilberg, C. Vellano, T. Heffernan, J. Marszalek","doi":"10.1158/1538-7445.AM2021-985","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-985","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":"86834432","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 1401: MYC mediates retinoic acid resistance by suppressing cellular retinoic acid-binding protein (CRABP2) transcription in HER2-enriched breast cancers","authors":"Won-Shik Choi, Rong-Zong Liu, R. Godbout","doi":"10.1158/1538-7445.AM2021-1401","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1401","url":null,"abstract":"Introduction: HER2-positive (HER2+) breast cancers express high levels of the growth-promoting HER2 protein. The development of a targeted drug, trastuzumab, has greatly improved clinical outcome for HER2+ patients. However, intrinsic and acquired resistance to trastuzumab are common. Clearly, additional therapeutic interventions are required for the clinical management of HER2-enriched breast cancers. Retinoic acid (RA) is a vital signaling molecule that regulates multiple biological processes, including cell proliferation, differentiation, and death. RA has been successfully used in the treatment of acute promyelocytic leukemia. RA also holds promise for the treatment of solid cancers like breast cancer. RA action is mediated through transcription factor RARα and the RA binding protein CRABP2, which deliver RA to RARα in the nucleus. The HER2 gene (ERBB2) is frequently co-amplified with the gene encoding RARα, a key determinant of RA sensitivity. It seems surprising, therefore, that HER2+ breast cancers are refractory to RA treatment. MYC is an oncogene that inhibits RARα activity in leukemia cells. Importantly, MYC is preferentially amplified and overexpressed in HER2+ breast cancers. My research aims to elucidate the mechanism underlying RA resistance in HER2+ breast cancers, with a special focus on the role of MYC. Hypothesis: MYC attenuates RA action by inhibiting the CRABP2-RARα pathway. Results: RNA levels of MYC are negatively correlated with CRABP2 RNA levels. Depletion of MYC upregulates CRABP2 at both the RNA and protein levels. Furthermore, we found that MYC binds to the CRABP2 promoter region suggesting that MYC may directly suppress CRABP2 gene transcription activity. Our results show that ectopic expression of MYC inhibits, whereas depletion of MYC activates RAR activity. Consistently, ectopic expression of MYC increases RA resistance, whereas depletion of MYC sensitizes cells to RA treatment. When CRABP2 is depleted along with MYC-knockdown, cell proliferation is rescued, suggesting that MYC mediates RA resistance, at least partially through downregulation of CRABP2. We also found that RA treatment enhances trastuzumab responsiveness in HER2+ breast cancer cells. Significance: This study sheds light on the role and mechanism of MYC in governing RA resistance in HER2+ breast cancer cells. Our results support the use of RA and trastuzumab for the treatment of subsets of patients with HER2+/low MYC breast cancers. Citation Format: Won-Shik Choi, Rong-Zong Liu, Roseline Godbout. MYC mediates retinoic acid resistance by suppressing cellular retinoic acid-binding protein (CRABP2) transcription in HER2-enriched breast cancers [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 1401.","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":"88884962","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}