The SRG rat, a Sprague-Dawley Rag2/Il2rg double-knockout validated for human tumor oncology studies

• Published in: PloS one Vol. 15; no. 10; p. e0240169
• Main Authors: Noto, Fallon K, Sangodkar, Jaya, Adedeji, Bisoye Towobola, Moody, Sam, McClain, Christopher B, Tong, Ming, Ostertag, Eric, Crawford, Jack, Gao, Xiaohua, Hurst, Lauren, O'Connor, Caitlin M, Hanson, Erika N, Izadmehr, Sudeh, Tohmé, Rita, Narla, Jyothsna, LeSueur, Kristin, Bhattacharya, Kajari, Rupani, Amit, Tayeh, Marwan K, Innis, Jeffrey W, Galsky, Matthew D, Evers, B Mark, DiFeo, Analisa, Narla, Goutham, Jamling, Tseten Y
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.10.2020; Public Library of Science (PLoS)
• Subjects: Animal models; Animal research models; Animals; Biology and life sciences; Biotechnology; Cancer; Cancer research; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Colorectal cancer; Drug therapy; Gene Deletion; Genes; Growth kinetics; Hematology; Humans; Immunodeficiency; Interleukin Receptor Common gamma Subunit - genetics; Kinetics; Laboratory animals; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lymphocytes; Lymphocytes B; Lymphocytes T; Medicine; Medicine and Health Sciences; Methods; Mice; Model testing; Neoplasms, Experimental - genetics; Neoplasms, Experimental - pathology; Non-small cell lung carcinoma; Oncology; Pediatrics; Pharmacokinetics; Prostate cancer; RAG2 protein; Rats; Rats, Sprague-Dawley; Research and Analysis Methods; Rodents; Tissues; Toxicology; Tumor cell lines; Tumors; Xenograft Model Antitumor Assays - methods; Xenograft Model Antitumor Assays - standards; United States; New York; United States > US; Ohio; Lexington Kentucky; California; Ann Arbor Michigan; Michigan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0240169

We have created the immunodeficient SRG rat, a Sprague-Dawley Rag2/Il2rg double knockout that lacks mature B cells, T cells, and circulating NK cells. This model has been tested and validated for use in oncology (SRG OncoRat®). The SRG rat demonstrates efficient tumor take rates and growth kinetics with different human cancer cell lines and PDXs. Although multiple immunodeficient rodent strains are available, some important human cancer cell lines exhibit poor tumor growth and high variability in those models. The VCaP prostate cancer model is one such cell line that engrafts unreliably and grows irregularly in existing models but displays over 90% engraftment rate in the SRG rat with uniform growth kinetics. Since rats can support much larger tumors than mice, the SRG rat is an attractive host for PDX establishment. Surgically resected NSCLC tissue from nine patients were implanted in SRG rats, seven of which engrafted and grew for an overall success rate of 78%. These developed into a large tumor volume, over 20,000 mm3 in the first passage, which would provide an ample source of tissue for characterization and/or subsequent passage into NSG mice for drug efficacy studies. Molecular characterization and histological analyses were performed for three PDX lines and showed high concordance between passages 1, 2 and 3 (P1, P2, P3), and the original patient sample. Our data suggest the SRG OncoRat is a valuable tool for establishing PDX banks and thus serves as an alternative to current PDX mouse models hindered by low engraftment rates, slow tumor growth kinetics, and multiple passages to develop adequate tissue banks.