Elizabeth R. Murray, N. Brown, P. Howard, Luke A Masterson, F. Zammarchi, Patrick Van Berkel, J. Marshall
{"title":"958:整合素αvβ6靶向肽-药物偶联物有效靶向胰腺导管腺癌转移","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":null,"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":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"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. 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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. 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引用次数: 1
摘要
胰腺导管腺癌(PDAC)预后极差,人类PDAC肿瘤包括其配对转移瘤的5年生存率为80%,但在健康胰腺组织中未显着表达。因此,αvβ6是一个很有前景的治疗靶点。我们之前开发了αvβ6特异性肽-药物偶联物(PDC) SG3299,由结合dna的吡咯苯二氮卓(PBD)为基础的化合物tesirine偶联到αvβ6靶向肽A20FMDV2组成。相对于非靶向PDC SG3511, SG3299在免疫缺陷小鼠模型中对αvβ6阳性的人PDAC异种移植物具有抗肿瘤作用。本研究旨在评价αvβ6靶向治疗小鼠PDAC的原发肿瘤和转移瘤的疗效。我们之前报道过KPC (Kras-G12D P53-R172H Pdx1-Cre)转基因小鼠PDAC肿瘤不表达αvβ6,因此我们在TB32043 KPC衍生的PDAC细胞系中异位表达小鼠整合素-β6,构建了表达αvβ6的细胞系TB32043mb6S2。将TB32043mb6S2细胞原位注射到免疫功能正常的C57BL/6小鼠体内,产生原发性胰腺肿瘤,并伴有αvβ6阳性转移至肝脏、腹膜和肺部。原位注射TB32043mb6S2细胞的小鼠显示原发性肿瘤结缔组织增生增加,腹膜转移发生率增加(100% vs 20%), p引用格式:Elizabeth R. Murray, Nicholas F. Brown, Philip Howard, Luke Masterson, Francesca Zammarchi, Patrick H. van Berkel, John F. Marshall。整合素αvβ6靶向肽-药物偶联物有效靶向胰腺导管腺癌转移瘤[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要第958期。
Abstract 958: Effective targeting of pancreatic ductal adenocarcinoma metastases with an integrin αvβ6-targeting peptide-drug conjugate
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.