Experimental and Molecular Therapeutics最新文献

{"title":"Abstract 1232: Using mesoporous silica nanoparticles (MSNs) for delivering the mesoionic compound MIH 2.4Bl in treating breast cancer","authors":"D. Debnath, S. Nazzal, S. Acharya, H. Souza, P. F. Filho, R. Fudała, J. Mathis","doi":"10.1158/1538-7445.AM2021-1232","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1232","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78244717","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 1434: Uncovering the mechanism of adaptive resistance to RET inhibitors in RET rearranged thyroid cancer","authors":"Renuka Raman, Jacques A Villefranc, T. Ullmann, Jessica W. Thiesmeyer, V. Anelli, C. Pauli, R. Bareja, K. Eng, P. Dorsaint, D. Wilkes, Shaham Beg, Reid Shaw, Michael Churchill, Naveen Gumpeni, T. Scognamiglio, M. Rubin, C. Grandori, J. Mosquera, Noah E. Dephoure, A. Sboner, O. Elemento, Y. Houvras","doi":"10.1158/1538-7445.AM2021-1434","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1434","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78245003","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 913: FLT3-targeting TriTACs are T cell engagers for treatment of acute myeloid leukemia","authors":"R. Austin, W. Aaron, Manasi Barath, Evan C. Callihan, Scott Gatto, Golzar Hemmati, C. Law, D. LemonBryan, J. O'rear, Purbasa Patnaik, Morgan Thompson, Lihn To, H. Wesche, Kevin Wright, Yinghua Xiao, Stephen Yu, Timothy Z. Yu","doi":"10.1158/1538-7445.AM2021-913","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-913","url":null,"abstract":"FLT3 (fms related receptor tyrosine kinase 3) is a cell surface protein expressed in hematopoietic stem and progenitor cell populations1. FLT3 RNA is overexpressed in greater than 95% of acute myeloid leukemia (AML) samples2, and FLT3 mutations are found in 25% to 35% of AML samples1. In 2020 in the United States, an estimated 19,940 new AML cases and 11,180 AML-related deaths are expected3, exemplifying that better therapies are needed to treat this disease. Given the frequency of FLT3 expression in AML and unmet medical need for patients, FLT3 represents an attractive target for T cell-redirecting immunotherapy in AML. FLT3-targeting Tri-specific T cell Activating Constructs (FLT3 TriTACs) are designed to simultaneously engage FLT3 on a target AML cell and CD3 on a T cell, resulting in T cell activation, proliferation, and lysis of the AML cell. FLT3 TriTACs are ~53 kDa molecules that consist of three binding domains: an N-terminal single domain antibody (sdAb) that binds to human FLT3, a middle sdAb that binds to human serum albumin (HSA) to extend the half-life, and a C-terminal single chain Fv (scFv) that binds to CD3e of the T cell receptor (TCR). Biophysical analyses of these molecules indicate they are stable with high monomer content. FLT3 TriTACs bind to human and cynomolgus monkey FLT3, CD3e and albumin with similar affinities. Flow cytometry analysis of T cells from various normal donors and a panel of FLT3-positive and FLT3-negative tumor cell lines confirmed binding of FLT3 TriTACs to their targets expressed on the cell surface. FLT3 TriTACs induce potent killing of FLT3-expressing AML cell lines in vitro. In co-cultures of T cells from normal human donors, target tumor cells, and HSA, these TriTACs mediated dose-dependent and FLT3-dependent cytotoxicity. Cell lines engineered to express cynomolgus FLT3 were also readily killed by T cells with FLT3 TriTACs. Preclinical evaluation of FLT3 TriTACs in vitro, in mouse tumor models, and cynomolgus monkey pharmacokinetic studies will be presented. References 1. Kazi and Ronnstrand. 2019. Physiol Rev. 99:1433-1466. 2. Data generated by the TCGA Research Network: https://www.cancer.gov/tcga. 3. Howlader et al. 2020. SEER Cancer Statistics Review, 1975-2017. Citation Format: Richard J. Austin, Wade H. Aaron, Manasi Barath, Evan Callihan, Scott Gatto, Golzar Hemmati, Che-Leung Law, Bryan D. Lemon, Jessica O9Rear, Purbasa Patnaik, Morgan Thompson, Lihn To, Holger Wesche, Kevin Wright, Yinghua Xiao, Stephen Yu, Timothy Z. Yu. FLT3-targeting TriTACs are T cell engagers for treatment of acute myeloid leukemia [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 913.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"197 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78505586","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 988: Targeting immunological and apoptotic cell death to improve therapeutic efficacy in melanoma","authors":"N. Savaraj, M. You, Ying-Ying Li, Chunjing Wu, M. Wangpaichitr, Saurez Miguel, Alfred Chicco, M. Kuo, L. Feun","doi":"10.1158/1538-7445.AM2021-988","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-988","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72624938","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 52: Mechanistic evaluation of anti-DR5 IgM antibody IGM-8444 with potent tumor cytotoxicity, without in vitro hepatotoxicity","authors":"Beatrice T. Wang, Tasnim Kothambawala, Kevin C. Hart, Xingjie Chen, M. Desbois, Susan E. Calhoun, P. Yakkundi, Rodnie Rosete, Yuan Cao, Katie Cha, T. Matthew, Ling Wang, P. Hinton, M. Leabman, G. Hernandez, M. Kotturi, E. Humke, A. Sinclair, B. Keyt","doi":"10.1158/1538-7445.AM2021-52","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-52","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":"72649657","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 1339: Investigations into rational combination approaches with ivosidenib in a mutant IDH1 acute myeloid leukemia patient-derived xenograft model","authors":"Christine C. Hudson, R. Narayanaswamy, Sébastien Ronseaux, C. Bowden, Brandon Nicolay","doi":"10.1158/1538-7445.AM2021-1339","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1339","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77441948","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 958: Effective targeting of pancreatic ductal adenocarcinoma metastases with an integrin αvβ6-targeting peptide-drug conjugate","authors":"Elizabeth R. Murray, N. Brown, P. Howard, Luke A Masterson, F. Zammarchi, Patrick Van Berkel, J. Marshall","doi":"10.1158/1538-7445.AM2021-958","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-958","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) exhibits an extremely poor prognosis, with 5 year-survival rates 80% of human PDAC tumors including their paired metastases but is not significantly expressed by healthy pancreas tissue. Thus, αvβ6 represents a promising therapeutic target. We previously developed the αvβ6-specific peptide-drug conjugate (PDC) SG3299, composed of the DNA-binding pyrrolobenzodiazepine (PBD)-based compound tesirine conjugated to the αvβ6-targeting peptide A20FMDV2. Relative to the non-targeting PDC SG3511, SG3299 showed anti-tumor efficacy against αvβ6-positive human PDAC xenografts in immunodeficient mouse models. The present study aimed to evaluate the efficacy of αvβ6-targeted therapy on primary tumors and metastases in an immunocompetent murine model of PDAC. We have previously reported that KPC (Kras-G12D P53-R172H Pdx1-Cre) transgenic mouse PDAC tumors do not express αvβ6, so we ectopically expressed murine integrin-β6 in the TB32043 KPC-derived PDAC cell line, creating the αvβ6-expressing line TB32043mb6S2. When injected orthotopically into immunocompetent C57BL/6 mice, TB32043mb6S2 cells produced primary pancreatic tumors with αvβ6-positive metastases to the liver, peritoneum, and lung. Mice injected orthotopically with TB32043mb6S2 cells exhibited increased primary tumor desmoplasia, increased incidence of peritoneal metastases (100% vs 20%, p Citation Format: Elizabeth R. Murray, Nicholas F. Brown, Philip Howard, Luke Masterson, Francesca Zammarchi, Patrick H. van Berkel, John F. Marshall. Effective targeting of pancreatic ductal adenocarcinoma metastases with an integrin αvβ6-targeting peptide-drug conjugate [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 958.","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":"77549055","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 LB118: Mechanisms underlying synergistic activity in MYD88MTDLBCL of KT-413, a targeted degrader of IRAK4 and IMiD substrate","authors":"C. Klaus, S. Rusin, K. Sharma, S. Bhaduri, M. Weiss, A. Mcdonald, M. Mayo, D. Walker, Rahul Karnik","doi":"10.1158/1538-7445.AM2021-LB118","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB118","url":null,"abstract":"Relapsed/refractory DLBCL remains an incurable disease, and single-agent therapies typically show low response rates and/or transient clinical responses. Oncogenic MYD88 mutations occur in ~25% of DLBCL and drive constitutive NFkB activation, promoting proliferation and survival. Despite its role in tumor biology, targeting MYD88MT by inhibiting or degrading IRAK4 alone, a key component of the MYD88 complex, does not drive significant antitumor activity in preclinical models. One potential reason is the frequent redundant NFkB pathway activation by co-mutations, highlighting the need for combination therapies to effectively target the NFkB pathway in DLBCL. To address this challenge, we have developed IRAKIMiDs, heterobifunctional degraders that simultaneously degrade both IRAK4 and IMiD substrates, as a rational therapeutic combination in a single molecule. IRAKIMiDs show increased antitumor activity in vitro and in vivo in MYD88MT cells as compared to IMiD or IRAK4-targeting alone, highlighting suggesting their potential as single agents in R/R DLBCL.Our lead IRAKIMiD, KT-413, is a potent degrader of IRAK4 (DC50 6nM) and IMiD substrates (Ikaros/Aiolos DC50 2nM), inducing rapid and potent cell killing in vitro and complete and sustained tumor regressions in vivo in MYD88MT models of DLBCL. This activity is superior to the IMiD CC-220, which has similar activity against IMiD substrates (Ikaros/Aiolos DC50 1 nM), supporting the synergistic role of IRAK4 degradation in the context of IMiD biology. We show here that the combined activity of these 2 mechanisms drives a synergistic effect on NFkB and IRF4 signaling with greater downstream effect on NFkB and type 1 interferon (IFN) signaling and cell cycle gene expression than either mechanism alone. In THP1 cells engineered with NFkB and IRF4 reporters, KT-413 but not CC-220 inhibits TLR-stimulated NFkB and IRF4 transcription, supporting a role for IRAK4 but not IMiDs in MYD88-driven survival and proliferation signals. IMiDs have previously been shown to modulate type1 IFN signaling through downregulation of IRF4. We propose that simultaneous targeting of both NFkB and type 1 IFN signaling with KT-413 drives synergistic cell killing in MYD88MT cells. In MYD88MT OCI-Ly10 cells, KT-413 leads to greater IRF4 downregulation, increased type 1 IFN signaling, and preferential downregulation of NFkB pathway and cell cycle transcripts when compared to CC-220. These data support the hypothesis that the synergistic activity of targeting IRAK4 and IMiD substrates by KT-413 in MYD88MT DLBCL is a result of dual targeting of NFkB and IRF4/Type1 IFN through degradation of both IRAK4 and IMiD substrates,driving significantly greater cell killing as compared to either mechanism alone, supporting the potential for the first single agent targeted therapy in MYD88MT DLBCL. KT-413 is on track for initiation of a Phase 1 trial in B cell lymphoma in 2H 2021. Citation Format: Christine R. Klaus, Scott F. Rusin, Kirti Sharma, ","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"154 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77729654","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 1293: A novel protide purine antimetabolite combines with the prodrug glutamine antagonist JHU395 in preclinical models of Ras-driven sarcomas","authors":"K. Lemberg, J. M. H. Aguilar, J. Alt, M. Krečmerová, P. Majer, R. Rais, B. Slusher","doi":"10.1158/1538-7445.AM2021-1293","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1293","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80037758","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 1461: PHI-101, a potent and novel inhibitor of CHK2 in ovarian and breast cancer cells","authors":"J. Han, Kyu‐Tae Kim, Jeejin Im, Sojung Park, M. Choi, Inki Kim, Ky-Youb Nam, Jeong-Hyeok Yoon","doi":"10.1158/1538-7445.AM2021-1461","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1461","url":null,"abstract":"Purpose: Development of the potent and selective checkpoint kinase 2 (CHK2) inhibitor to overcome limiting clinical utility of poly(ADP-ribose) polymerase 1 (PARP1) inhibitors. Experimental Procedure: Preclinical evaluation of PHI-101 for cellular and molecular potency in ovarian and breast cancer cell lines and patient derived primary cells; it includes biochemical binding assay, cellular assays, animal efficacy studies, combination study, signaling pathway effect examination, and cell cycle analysis. Summary: CHK2 is a serine/threonine kinase and a cell cycle checkpoint regulator involved in the ATM-mediated DNA repair upon replication blocks and DNA damage. It has been proposed that Chk2 functions as a barrier to tumorigenesis by maintaining genomic stability, and this DNA damage induction is thought to prevent or delay genetic instability and tumorigenesis. The inhibition of CHK2 is a promising approach to achieve synthetic lethality of cancer cells when combined with PARP1 inhibitors. Solid cancer indications of PHI-101 was identified by the Chemiverse Network module which is an AI and Big data-based in-house drug discovery platform. Biochemical kinase assays for PHI-101 showed stronger affinity to CHK2 over CHK1 more than 5-fold. PHI-101 treatment of ovarian and breast cancer cells for 72 hrs elicit a synergistic lethal response in combination with PARP1 inhibitor Olaparib regardless of functional BRCA and P53 in the cells. PHI-101 also potentiates a countermeasure to dose-limiting toxicity triggered by genotoxic agents such as cisplatin and topotecan. The present results from in vivo and in vitro preclinical testing do demonstrate that PHI-101 is a highly potent inhibitor of CHK2 and may exert mono- and combinational therapeutic activity in ovarian and breast cancer model. Conclusion: The preclinical evaluation of PHI-101, a novel CHK2 inhibitor, showed clear evidence of anticancer activity for refractory ovarian and breast cancer cells and improved efficacy in both in vitro and in vivo models. Consequently, PHI-101 is currently under investigation in Phase 1 clinical trials for relapsed or refractory ovarian cancer patients. Citation Format: June H-J Han, Kyu-Tae Kim, Jeejin Im, Sojung Park, Min Kyung Choi, Inki Kim, Ky-Youb Nam, JeongHyeok Yoon. PHI-101, a potent and novel inhibitor of CHK2 in ovarian and breast cancer cells [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 1461.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"230 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80237120","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}