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.
Digital Object Identifier (DOI)
NCI contract HHSN261201700017C supported PDX establishment and their molecular and histological characterizations, along with their drug response studies. Hera Biolabs, Inc. provided support in the form of salaries for authors (FKN, BTA, SM, CM, JC, TYJ) and Poseida Therapeutics, Inc. provided support in the form of salaries for authors (EO, MT).
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; and Jamling, Tseten Y., "The SRG Rat, a Sprague-Dawley Rag2/Il2rg Double-Knockout Validated for Human Tumor Oncology Studies" (2020). Markey Cancer Center Faculty Publications. 154.
S1 Fig. The SRG rat contains an 8bp deletion early in its single coding exon rendering the protein out of frame. The SRG rat also carries a 16bp deletion in the first exon of the Il2rg gene to knock out its function. https://doi.org/10.1371/journal.pone.0240169.s001
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S2 Fig. Growth curve of VCaP in SCID/NCr mice. Mean weight in mg with SEM. https://doi.org/10.1371/journal.pone.0240169.s002
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S3 Fig. Growth curve of multiple patient derived lung tumors in SRG rats. Each graph depicts tumor volumes for individual animals for 6 different NSCLC patient samples (A-F). P1 is the inital implant into animals using fresh patient tissue, P2 is the first serial passage from animal to animal, P3 is the second serial passage from animal to animal. Sample 3067 (C) was implanted into SRG rats for P1 and then serially implanted into NSG mice for P2 and P3. https://doi.org/10.1371/journal.pone.0240169.s003
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S4 Fig. https://doi.org/10.1371/journal.pone.0240169.s004
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S1 Data. https://doi.org/10.1371/journal.pone.0240169.s005