Experimental and Molecular Therapeutics最新文献

{"title":"Abstract 1015: mTOR inhibitor induces non-apoptotic, autophagy dependent cell death (ADCD) in TP53 mutant HNSCC","authors":"Maksudul M. Alam, Janmaris Marin Fermin, P. Spiller, Channing Dorr, Xiaohua Rong, Tara Medlin, Alok R. Khandelwal, C. Nathan","doi":"10.1158/1538-7445.AM2021-1015","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1015","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76966503","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 1050: Efficacy of AMG 176 in combination with gilteritinib in preclinical models of acute myeloid leukemia","authors":"Xiao-yun Chen, S. Caenepeel, Brian Belmontes, P. McElroy, K. Rex, T. Osgood, P. Hughes","doi":"10.1158/1538-7445.AM2021-1050","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1050","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76967051","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 1224: Discovery of novel BAF inhibitors for the treatment of transcription factor-driven cancers","authors":"Richard C. Centore, L. M. Soares, R. Vaswani, Kana Ichikawa, Zhifang Li, Hong-Yan Fan, J. Setser, D. Lahr, L. Zawadzke, Xueying Chen, Kimberly D. Barnash, Jordana Muwanguzi, N. Anthony, Gabriel J. Sandoval, K. Feldman, Ammar Adam, David Huang, Shawn E R Schiller, Kevin Wilson, J. Voigt, M. Hentemann, Millan David Simon, H. Chan, S. Bellon, C. Decicco, Lang Xu","doi":"10.1158/1538-7445.AM2021-1224","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1224","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":"78145161","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 LB111: Drug repurposing of niclosamide to regulate Wnt/beta-catenin signaling pathway through upregulating SFRP1 in colorectal cancer","authors":"M. Wu, Christy W S Tong, Vivi W Yan, K. To","doi":"10.1158/1538-7445.AM2021-LB111","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB111","url":null,"abstract":"Aim: This study investigated the inhibition of proliferation and invasiveness of colorectal cancer (CRC) by niclosamide via targeting the secreted Frizzled-related protein 1 (SFRP1) and the Wnt/beta-catenin signaling pathway. Background: CRC is the third most common cancer worldwide. Aberrant activation of various signaling pathways in CRC leads to its poor response to chemotherapy. Hyperactivation of Wnt/beta-catenin pathway is known to drive cell proliferation, invasion, and migration of CRC. Epigenetic silencing of extracellular Wnt inhibitors, such as secreted Frizzled-related proteins (SFRPs), has been shown to stabilize beta-catenin and subsequently activate the Wnt signaling pathway. Niclosamide is a clinically approved drug indicated for the treatment of tapeworm infections. We have recently reported the repurposing of niclosamide to potentiate chemotherapeutic drugs for treating CRC by STAT3 inhibition. Niclosamide was also reported to be a Wnt/beta-catenin inhibitor but the precise mechanism is not clear. Methods: The antiproliferative effect was assessed by MTT assay and colony formation assay. The mRNA level, protein expression, and methylation status of SFRP1, and sets of SFRP1 co-expressed genes in CRC were analyzed by the TCGA data portal. The mRNA expression of SFRP1 and CpG island methylator phenotype (CIMP) marker genes were measured by qRT-PCR. DNA methylation was analyzed by bisulfite genomic sequencing. Inhibition of Wnt/beta-catenin and its downstream targets were examined by Western blot analysis. Cell migration and invasion were investigated by wound healing and transwell chamber migration assay. The intracellular localization of beta-catenin was determined by immunofluorescence assay. Results: Niclosamide inhibited HCT116 cell proliferation and colony formation in a concentration-dependent manner. Compared with normal colon tissues, CRC expressed significantly lower level of SFRP1 mRNA. SFRP1 methylation was inversely correlated with its mRNA expression. The DNA-demethylating agent 5-azacytidine was shown to restore expression of SFRP1 and CIMP panel genes in HCT116 cells after 5-day treatment. However, SFRP1 mRNA level was only upregulated by 1-day niclosamide treatment, but not 3-day niclosamide treatment. The upregulation of SFRP1 by niclosamide was found not relevant to DNA demethylation according to bisulfite genomic sequencing data. Immunofluorescence and Western blotting analysis showed that the increased SFRP1 expression was accompanied by reduced expression and nuclear accumulation of beta-catenin. Moreover, a low concentration of niclosamide that has minimal effect on cell proliferation, was shown to significantly suppress migration and invasion of HCT116 cells. Conclusion: Niclosamide is a promising candidate for drug repurposing. It was shown to upregulate SFRP1 and subsequently suppress Wnt/beta-catenin signaling, thereby impairing CRC cell migration and invasion. Upregulation of SFRP1 by niclosamide was not ","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"10 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":"78317870","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 979: Bcl-2 inhibitor enhances anti-androgen therapy induced regression of castration sensitive prostate cancer","authors":"Rahim Hirani, Subhiksha Nandakumar, T. Kalidindi, Deborah Fidele, Harisha Rajanala, Ying Z. Mazzu, Yuki Yoshikawa, Lina E. Jehane, G. Lee, E. Stanchina, Adam G. Sowalsky, M. Morris, H. Schöder, N. Pillarsetty, L. Mucci, D. Danila, G. Chakraborty, P. Kantoff","doi":"10.1158/1538-7445.AM2021-979","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-979","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75151409","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 968: Focal adhesion kinase (FAK) inhibitor APG-2449 sensitizes ovarian tumors to chemotherapy via CD44 downregulation","authors":"R. Tao, Douglas D Fang, Yuanbao Li, Kaixiang Zhang, Chunhua Xu, X. Fang, Qixin Wang, Dajun Yang, Y. Zhai","doi":"10.1158/1538-7445.AM2021-968","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-968","url":null,"abstract":"Ovarian cancer is one of the deadliest malignancies in women, and up to 70% of patients with epithelial ovarian cancer have FAK overexpression, amplification, or activation. FAK plays an important role in cellular migration, growth factor signaling, cell cycle progression, cellular survival and chemoresistance. This biomarker is also significantly associated with higher tumor stage, metastasis, and shorter overall survival in patients with ovarian cancer. Inhibition of FAK is therefore emerging as a promising treatment target. APG-2449 is a clinical stage FAK/ALK/ROS1 multi-kinase inhibitor. In this study we investigated antitumor activity of APG-2449 combined with standard-of-care chemotherapeutics in ovarian cancer in the preclinical setting. In a mouse xenograft tumor model derived from ovarian cancer cell line OVCAR-3, which was resistant to platinum-based therapies, APG-2449 combined with paclitaxel, and paclitaxel plus carboplatin, synergistically enhanced antitumor activity, whereas the chemotherapeutics showed no activity. Synergistic antitumor activity was also observed in multiple patient-derived xenograft (PDX) models derived from women with chemoinsensitive ovarian cancer, which also frequently expresses high levels of FAK. By comparing gene expression profiles of PDX tumors obtained from responders and nonresponders to the combined therapy, we identified CD44 (a marker for cancer stem cells) as a potentially predictive biomarker. Western blot analysis confirmed higher protein levels of CD44 in pretreated tumors of responders. Interestingly, downregulation of CD44 levels was observed in combination-treated tumors, suggesting that these combinations reduced cancer stem cell populations in ovarian cancer. Accordingly, in ovarian cancer cells exposed to APG-2449 alone or combined with paclitaxel, numbers of cells positive for CD44 or aldehyde dehydrogenase 1 (ALDH1; another marker for cancer stem cells) decreased in a dose-dependent manner. In summary, our data suggest that FAK inhibition by APG-2449 sensitizes ovarian tumors to chemotherapeutics in preclinical tumor models of ovarian cancer. The synergistic antitumor activity was mediated by downregulation of CD44+ or ALDH1+ cancer stem cell populations. These findings encourage clinical development of APG-2449 in combination with chemotherapies for treatment of ovarian cancer. Citation Format: Ran Tao, Douglas D. Fang, Yuanbao Li, Kaixiang Zhang, Chunhua Xu, Xu Fang, Qixin Wang, Dajun Yang, Yifan Zhai. Focal adhesion kinase (FAK) inhibitor APG-2449 sensitizes ovarian tumors to chemotherapy via CD44 downregulation [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 968.","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":"75932333","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 1148: SynOV1.1: A synthetic gene circuit controlled oncolytic adenovirus demonstrating high tumor specificity, potent antitumor efficacy and high synergy with an anti-PD-L1 monoclonal antibody in preclinical hepatocellular carcinoma models","authors":"Qiang Liu, Yubing Cao, Man Zhang, Shuguang Peng, Yiqi Liu, Huiya Huang, Bin-fan Chen","doi":"10.1158/1538-7445.AM2021-1148","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1148","url":null,"abstract":"Hepatocellular carcinoma (HCC) is yet the fourth most common cause of cancer-related death although its treatment has been significantly advanced in recent years. Oncolytic viruses are among a novel class of immunotherapies that have shown promise to HCC patients with convincing abilities to selectively replicate in and kill cancer cells as well as to boost tumor immunogenicity. In order to further enhance the safety and efficacy of oncolytic viruses, SynOV1.1, a recombinant replication-competent serotype 5-based adenovirus, was constructed by deleting E1B and partial E3 genes, and incorporating a synthetic sensory switch circuit. The gene circuit was designed to enhance tumor-specific expression of E1A gene and an immune effector, human granulocyte-macrophage colony-stimulating factor (hGM-CSF) by sensing cancer-specific alpha-fetoprotein (AFP) promoter and two microRNA inputs. The specificity of SynOV1.1 to selectively kill target tumor cells and the ability to specifically express hGM-CSF in the target cells were confirmed in numerous human and mouse HCC cell lines with an IC50 approximately 3 to 35-fold less than that of normal cell lines. In vivo, intratumoral injections of SynOV1.1 in immune-deficient mice bearing human HCC cells resulted in a significant reduction of tumor volume (approximately 80%) as compared with the controls (approximately 30% for sorafenib). To further evaluate the effects of antitumor and immune stimulation, SynOV1.1m (SynOV1.1 murine surrogate) was intratumorally injected to the immune-competent mice bearing mouse HCC cells (ie., mHepa1-6), which showed SynOV1.1m induced a greater antitumor effect as well as a more robust tumor-specific immune response as compared to the controls. In addition, SynOV1.1m could significantly inhibit the growth of non-injected distal tumors after it was injected into a mHepa1-6 tumor on the other side of the mouse body, indicating that a systemic immune response was induced by SynOV1.1m. The combination of SynOV1.1m and an anti-mPD-L1 monoclonal antibody (mAb) was further explored and showed a synergistic anti-tumor effect as compared to SynOV1.1m or anti-mPD-L1 mAb alone. Preclinical safety of SynOV1.1 was examined in various toxicology species including golden hamsters, tumor-bearing mice and cynomolgus monkey, in all of which SynOV1.1 was found safe. Overall, preclinical pharmacology and toxicology data support clinical investigation of SynOV1.1 alone or in combination with atezolizumab in advanced HCC patients with positive serum AFP levels. Citation Format: Qiang Liu, Yubing Cao, Man Zhang, Shuguang Peng, Yiqi Liu, Huiya Huang, Bin Chen. SynOV1.1: A synthetic gene circuit controlled oncolytic adenovirus demonstrating high tumor specificity, potent antitumor efficacy and high synergy with an anti-PD-L1 monoclonal antibody in preclinical hepatocellular carcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"298 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76298151","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 935: Preclinical activity of seribantumab in gastrointestinal cancers withNRG1fusions","authors":"I. Odintsov, A. Lui, P. Bloom, M. Vojnic, S. Leland, M. Ladanyi, R. Somwar","doi":"10.1158/1538-7445.AM2021-935","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-935","url":null,"abstract":"Background. Oncogenic rearrangements of the neuregulin 1 gene (NRG1) consist of a 59 partner fused to a 39 NRG1 sequence that retains the EGF-like domain, and are found in 0.2% of solid tumors including lung, breast and gastrointestinal (GI) cancers. Carcinomas of GI origin, including pancreatic and cholangiocarcinoma, represent around 20% of solid tumors harboring NRG1 fusions and there is no approved therapy for this group of cancers. The chimeric NRG1 oncoproteins bind to HER3/ERBB3 leading to trans-activation of other ERBB family members and trigger a signaling cascade that culminates in oncogenesis. Although targeting HER3 represents a rational therapeutic strategy for cancers harboring NRG1 fusions, this has remained relatively unexplored for NRG1 fusion-positive GI malignancies. In this study we investigated the efficacy of the anti-HER3 monoclonal antibody seribantumab in preclinical models of NRG1-driven GI cancers. Methods. We developed models of isogenic pancreatic cancer cells with NRG1 fusions by lentiviral-mediated cDNA expression of ATP1B1-NRG1 and SLC3A2-NRG1 fusions in immortalized pancreatic ductal cells (H6c7). Seribantumab efficacy was evaluated in isogenic cell lines and in patient-derived xenograft (PDX) models of pancreatic adenocarcinoma (CTG-0943, APP-NRG1 fusion) and intrahepatic cholangiocarcinoma (CH-07-0068, RBPMS-NRG1 fusion). Western blotting analysis was used to evaluate protein phosphorylation. Expression of NRG1 fusions was confirmed by RT-PCR and NGS. Results. Expression of NRG1 fusions in H6c7 cells resulted in enhanced phosphorylation of HER3 and AKT and increased sensitivity to afatinib, as compared to empty vector control cells (H6c7-EV). Treatment of H6c7-SLC3A2-NRG1 cells with seribantumab resulted in a dose-dependent inhibition of HER3 and AKT phosphorylation. Seribantumab treatment of H6c7-ATP1B1-NRG1 and H6c7-SLC3A2-NRG1 cells resulted in dose-dependent inhibition of cell growth with IC50 values of 0.05 and 0.2 µM, respectively. In contrast, growth of H6c7-EV cells was much less sensitive to seribantumab (IC50 > 1µM). Tumor growth inhibition was observed after administration of seribantumab to PDX mouse models of pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma. While seribantumab (5 mg and 10 mg per dose, BIW) was equally effective to the clinical equivalent dose of afatinib (5 mg/kg QD) in the cholangiocarcinoma PDX model, the two doses of seribantumab were more effective than afatinib in the pancreatic cancer PDX model, causing tumor shrinkage of up to 55% (23-77% range). There was no shrinkage of afatinib-treated pancreatic PDX tumors. Our results here suggest that seribantumab is effective at reducing tumor growth in preclinical models of gastrointestinal cancers with NRG1 fusions. These data support the use of seribantumab to treat GI and other cancers with NRG1 fusions in the ongoing phase 2 CRESTONE study (NCT#04383210). Citation Format: Igor Odintsov, Allan J. Lui, Paul R. Bloom, M","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74721840","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 1071: Studying the ability of retinoids to inhibit growth of CRC cells based on their retinoid pathway genotype","authors":"Victoria O. Hunsu, C. Facey, Lynn M. Opdenaker, B. Boman","doi":"10.1158/1538-7445.AM2021-1071","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1071","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":"74220007","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 912: CLDN6 and CLDN9 dual targeting antibody drug conjugates for the treatment of ovarian and endometrial cancers","authors":"Du Liang, Hongyan Zhang, L. Jin, Yali Chen, Tingting Wan, L. Xu","doi":"10.1158/1538-7445.AM2021-912","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-912","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74220494","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}