Experimental and Molecular Therapeutics最新文献_第9页

Abstract 1062: Inhibition of ovarian and endometrial cancer cell proliferation by an anti-ROR1 monoclonal antibody 摘要:抗ror1单克隆抗体对卵巢癌和子宫内膜癌细胞增殖的抑制作用

Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1062

Dongli Liu, G. Kaufmann, J. Breitmeyer, Kristie-Ann Dickson, D. Marsh, C. Ford

引用次数: 0

Abstract 1472: Novel EGFR WT sparing, HER2 selective inhibitors for the treatment of HER2 exon 20 insertion driven tumors address a clear unmet medical need 摘要:用于治疗HER2外显子20插入驱动型肿瘤的新型EGFR WT保留、HER2选择性抑制剂解决了一个明显未满足的医疗需求

Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1472

Ralph A. Neumüller, B. Wilding, D. Scharn, D. Böse, V. Santoro, D. Gerlach, P. Ettmayer, Thomas Gerstberger, Julian E. Fuchs, Matthias Treu, S. Zahn, A. Baum, P. Chetta, M. Pearson, D. McConnell, N. Kraut, Flavio Solca

引用次数: 1

Abstract 1016: A new biomarker in hematological malignancies 摘要1016:一种新的血液恶性肿瘤生物标志物

Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1016

T. Borgovan

引用次数: 0

Abstract 1229: Novel Arf1-targeting ã-dipeptides counteract triple negative breast cancer by inducing autophagic death 摘要1229:新型靶向arf1的<s:1> -二肽通过诱导自噬死亡来对抗三阴性乳腺癌

Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1229

Leilei He, A. Chavanieu, Yen Vo-Hoang, Yong Teng

引用次数: 1

Abstract 1404: Loss of adenomatous polyposis coli induces DOX resistance through upregulation of ABC transporters 摘要:大肠腺瘤性息肉病的丧失通过上调ABC转运蛋白诱导DOX抗性

Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1404

C. Stefanski, Jenifer R Prosperi, Lauren Milac

引用次数: 0

Abstract 1342: Development and preclinical evaluation of unique first-in-class small molecule inhibitors of the anti-apoptotic protein FLIP 1342:独特的抗凋亡蛋白FLIP小分子抑制剂的开发和临床前评估

Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1342

C. Higgins, J. Fox, Jamie Z. Roberts, D. Doherty, Trevor R. Perrior, R. Boffey, Tim Harrison, D. Longley

{"title":"Abstract 1342: Development and preclinical evaluation of unique first-in-class small molecule inhibitors of the anti-apoptotic protein FLIP","authors":"C. Higgins, J. Fox, Jamie Z. Roberts, D. Doherty, Trevor R. Perrior, R. Boffey, Tim Harrison, D. Longley","doi":"10.1158/1538-7445.AM2021-1342","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1342","url":null,"abstract":"In cancer, evasion of cell death is a fundamental cause of resistance to therapy, prompting the development of therapeutics that reactivate cell death pathways such as Bcl-2 family inhibitors and IAP antagonists. The apoptosis modulator Cellular FLICE-like inhibitory protein (FLIP) is a non-redundant inhibitor of caspase-8 activation and is the only human pseudo-caspase. Caspase-8 is the initiator caspase for the extrinsic apoptotic pathway and is now recognized as the molecular “switch” that controls the 3 major forms of programmed cell death: apoptosis, necroptosis and pyroptosis. As such, methods to selectively activate caspase-8 in appropriate disease contexts represent an exciting new therapeutic paradigm. FLIP is frequently overexpressed in solid and haematological cancers where it is associated with poor prognosis and chemo- and radio-resistance. Moreover, by regulating caspase-8 activity, FLIP is a key determinant of cell death induced by death ligands such as TRAIL expressed by immune effector cells. Thus, targeting FLIP9s interaction with caspase-8 represents a unique therapeutic opportunity for enhancing standard-of-care anti-cancer therapies and promoting anti-tumor immunity.We report the discovery and characterisation of small molecule first-in-class selective inhibitors capable of disrupting FLIP9s interaction with procaspase-8 in human cancer cells. These small molecule inhibitors induce caspase-8-dependent cell death as single agents and dramatically enhance apoptosis induced by recombinant TRAIL and 2nd generation multivalent TRAIL-R2 agonists in the nM concentration range. KRAS mutant non-small cell lung cancer (NSCLC) was identified as a major sensitive disease setting for FLIP inhibitors with single digit nM activity in vitro in several models and single agent in vivo efficacy. FLIP inhibitors also demonstrated in vitro efficacy in combination with KRAS G12C inhibitors in KRAS G12C mutant NSCLC and in vitro and in vivo efficacy in combination with the 3rd generation EGFR inhibitor Osimertinib in EGFR mutant NSCLC. We have also observed single agency nM efficacy in lymphoma and leukemia models and significant efficacy in combination with standard-of-care chemotherapeutics in KRAS mutant colorectal and pancreatic cancers. In summary, we have identified novel FLIP-targeted activators of caspase-8 with a unique mechanism-of-action and the potential for use in the treatment of several human cancers and leukemias either as a single agent, or in combination with standard-of-care chemotherapeutics and other clinically-relevant targeted agents. AcknowledgementsThis work was supported by a Seeding Drug Discovery award from the Wellcome Trust. Citation Format: Catherine A. Higgins, Jennifer Fox, Jamie Roberts, Declan Doherty, Trevor Perrior, Ray Boffey, Tim Harrison, Daniel B. Longley. Development and preclinical evaluation of unique first-in-class small molecule inhibitors of the anti-apoptotic protein FLIP [abstract]. In: Proceedings o","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":"79275428","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: 4

Abstract 1284: P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation 摘要1284:通过ATF4转录调控p53突变肿瘤p53通路的p53独立恢复

Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1284

X. Tian, N. Ahsan, W. El-Deiry

{"title":"Abstract 1284: P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation","authors":"X. Tian, N. Ahsan, W. El-Deiry","doi":"10.1158/1538-7445.AM2021-1284","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1284","url":null,"abstract":"A long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. A novel small-molecule, PG3-Oc, restores p53 pathway-signaling in tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates the p53-transcriptome (13.7% of public p53 target-gene dataset; 15.2% of in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53-/-). Bioinformatic analysis indicates critical p53-effectors of growth-arrest (p21), apoptosis (PUMA, DR5, Noxa), autophagy (DRAM1), and metastasis-suppression (NDRG1) are induced by PG3-Oc. ERK1/2- and CDK9-kinases are required to upregulate ATF4 by PG3-Oc which restores p53 transcriptomic-targets in cells without functional-p53. PG3-Oc represses MYC (ATF4-independent), and upregulates PUMA (ATF4-dependent) in mediating cell death. With largely nonoverlapping transcriptomes, induced-ATF4 restores p53 transcriptomic targets in drug-treated cells including functionally important mediators such as PUMA and DR5. Our results demonstrate novel p53-independent drug-induced molecular reprogramming involving ERK1/2, CDK9, and ATF4 to restore upregulation of p53 effector genes required for cell death and tumor suppression. Citation Format: Xiaobing Tian, Nagib Ahsan, Wafik S. El-Deiry. P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation [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 1284.","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":"84216702","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 1109: A novel strategy to cope with osimertinib resistance in non-small cell lung cancer by treatment with a PIM kinase inhibitor in combination with a MERTK-selective kinase inhibitor 摘要:PIM激酶抑制剂联合mertk选择性激酶抑制剂治疗非小细胞肺癌应对奥希替尼耐药的新策略

Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1109

D. Yan, Z. Tan, Xiaodong Wang, S. Frye, H. Earp, D. DeRyckere, D. Graham

{"title":"Abstract 1109: A novel strategy to cope with osimertinib resistance in non-small cell lung cancer by treatment with a PIM kinase inhibitor in combination with a MERTK-selective kinase inhibitor","authors":"D. Yan, Z. Tan, Xiaodong Wang, S. Frye, H. Earp, D. DeRyckere, D. Graham","doi":"10.1158/1538-7445.AM2021-1109","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1109","url":null,"abstract":"Osimertinib is currently the preferred treatment for EGFR-mutated non-small cell lung cancer (NSCLC) patients due to its superior therapeutic efficacy and prolonged overall survival compared to earlier generation EGFR tyrosine kinase inhibitors, but durable responses to osimertinib treatment are rare due to acquired drug resistance. Thus, there is an urgent need for novel strategies to treat osimertinib-resistant NSCLC. Recently, we found that treatment with MRX-2843, a novel MERTK-selective kinase inhibitor currently in Phase I clinical trials, resulted in dose-dependent inhibition of cell expansion and colony formation in an osimertinib-resistant (osiR) H4006 derivative cell line. An unbiased screen of 378 kinase inhibitors was carried out to identify compounds that synergized with MRX-2843 to inhibit expansion of an osiR derivative of the EGFR-mutated H4011 cell line. Treatment with 1µM PIM kinase inhibitor SGI-1776 or 100nM MRX-2843 alone reduced cell density by 5±3% and 44±7%, respectively, while treatment with MRX-2843 and SGI-1776 combined mediated an 82±0.4% decrease. Synergy was also observed in H4006 osiR and H1650 osiR derivative cell lines. Furthermore, treatment with PIM447, a structurally distinct PIM kinase inhibitor, and MRX-2843 decreased cell expansion more effectively than either agent alone. Mechanistically, treatment with a PIM kinase inhibitor in combination with MRX-2843 decreased downstream PI3K-AKT and MAPK-ERK signaling more effectively than single agents. Additionally, combined treatment with MRX-2843 and SGI-1776 prevented colony formation, while single agents had limited effect. In all, these data indicate that combining MRX-2843 and a PIM TKI may control osimertinib resistant tumor growth, providing a potential treatment strategy for osimertinib resistant EGFR-mutated NSCLC patients for whom the choices are still limited. Citation Format: Dan Yan, Zikang Tan, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, III, Deborah DeRyckere, Douglas K. Graham. A novel strategy to cope with osimertinib resistance in non-small cell lung cancer by treatment with a PIM kinase inhibitor in combination with a MERTK-selective kinase inhibitor [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 1109.","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":"84589812","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: 1

Abstract 1470: Preclinical activity of the first reversible, potent and selective inhibitor of EGFR exon 20 insertions 1470:首个可逆、有效和选择性EGFR外显子20插入抑制剂的临床前活性

Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1470

F. Siegel, S. Siegel, Keith Graham, Bethany Kaplan, K. Petersen, U. Boemer, U. Eberspaecher, D. Korr, Ursula Moenning, D. Suelzle, J. Schroeder, F. Prinz, S. Zitzmann-Kolbe, G. Karsli-Uzunbas, T. Lewis, M. Hermsen, A. Cherniack, F. Nussbaum, K. Eis, M. Meyerson, H. Greulich

引用次数: 3

Abstract 1180: A novel synthetic lethality treatment strategy for metastatic breast cancer 摘要:一种新的转移性乳腺癌合成致死性治疗策略

Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1180

Justin Zonneville, Mo Wang, Mohammed M. Alruwaili, K. Eng, T. Melendy, B. Park, R. Iyer, C. Fountzilas, Andrei V Bakin

{"title":"Abstract 1180: A novel synthetic lethality treatment strategy for metastatic breast cancer","authors":"Justin Zonneville, Mo Wang, Mohammed M. Alruwaili, K. Eng, T. Melendy, B. Park, R. Iyer, C. Fountzilas, Andrei V Bakin","doi":"10.1158/1538-7445.AM2021-1180","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1180","url":null,"abstract":"Breast carcinomas commonly carry mutations in the tumor suppressor p53, while therapeutic efforts to target mutant p53 were largely unfruitful. Here we present preclinical data supporting a novel combination therapy strategy for treatment of p53-deficient cancers. Genomic data revealed a high expression activity of Base-Excision Repair (BER) pathways in p53-deficient breast cancers. However, we found that BER-mediated repair was significantly dysregulated in p53-mutant cancer cells. Treatment with deoxyuridine analogues induced accumulation of DNA damage in p53-mutant cells and inhibitors of poly (ADP-ribose) polymerase (PARPi) greatly enhanced this response. In contrast, normal cells responded to PARPi with activation of the p53-p21 axis and cell cycle arrest. Inactivation of either p53 or p21/CDKN1A in p53 wild-type cells conferred the p53-mutant phenotype. Preclinical breast cancer studies revealed that the combination of deoxyuridine analogue with PARPi was more effective in inhibition of tumor growth and metastases than either drug alone. This work illustrates a novel combination therapy strategy that may improve survival rates and outcomes for thousands of breast cancer patients. Citation Format: Justin Zonneville, Moyi Wang, Mohammed Alruwaili, Kevin Eng, Thomas Melendy, Ben Ho Park, Renuka Iyer, Christos Fountzilas, Andrei V. Bakin. A novel synthetic lethality treatment strategy for metastatic 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 1180.","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":"85008084","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