Abstract B067: A Rag2/Il2rg double-knockout rat (SRG OncoRat) enables precision-medicine based cancer studies with cell line- and patient-derived xenografts
Authors: Noto Fallon K , Adedeji Bisoye Towobola , Moody Sam , Brenzel Chris , Crawford Jack , Narla Goutham , Evers B. Mark , Jamling Tseten Yeshi 
Published: March 2020

Abstract
Current cell line-derived cancer and PDX mouse models are hindered by low engraftment rates and slow tumor growth kinetics. Furthermore, serial passaging of patient derived tissue results in changes to the genomic landscape such that the transplanted tumor no longer reflects the primary tumor. To address these limitations, we produced an immunodeficient rat, a Sprague-Dawley Rag2/Il2rg double knockout (SRG) rat that lacked mature B cells, T cells, and circulating NK cells. We demonstrated that the SRG rat has improved tumor take rates and growth kinetics using a variety of human cell lines and PDXs. Cell lines tested include VCaP and LNCaP, which have poor or highly variable growth kinetics in commercially available immunodeficient mouse models. We have demonstrated that both of these cell lines have superior take rate and growth kinetics in the SRG rat, providing a more efficient model for drug efficacy studies. In addition, the rat can accommodate a larger tumor volume, allowing for serial fine needle aspirate biopsy for PK/PD analysis in the same animal throughout the course of the study without significantly affecting normal tumor growth. The PDXs in the SRG developed larger tumor volume, over 20,000 mm3 in the first passage, which provided an ample source of tissue for characterization and/or subsequent passage into SRG for drug efficacy studies. Larger tumor volumes enabled fewer animals to be needed for a study, allowed for faster timelines to drug efficacy data, and reduced the need for serial passaging to generate enough tissue, which limited genomic divergence from the parental tumor tissue. As proof of principle, we used next generation sequencing based genomic analysis to direct a precision medicine strategy to guide in vivo efficacy studies. Specifically, using this approach we found a novel mutation in the MET pathway in a primary patient derived sample and tested therapies that were predicted to target this mutation and compared efficacy to standard of care agents in this unique SRG rat derived PDX model. Collectively, this data suggests that this novel rat model could serve as a patient avatar to better predict outcomes to genomically-directed therapies. In addition, we tested the ability of the SRG rat to support the growth of patient-derived tissue that was cryopreserved directly from patient harvested and had not previously been xenografted into an animal model. This concept may provide a means for establishing PDX models from cryopreserved samples when animals are not immediately available for xenografting.
Citation Format: Fallon K Noto, Bisoye Towobola Adedeji, Sam Moody, Chris Brenzel, Jack Crawford, Goutham Narla, B. Mark Evers, Tseten Yeshi Jamling. A Rag2/Il2rg double-knockout rat (SRG OncoRat) enables precision-medicine based cancer studies with cell line- and patient-derived xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B067. doi:10.1158/1535-7163.TARG-19-B067