Abstract B170: Novel immunodeficient rat models offer a unique platform for drug efficacy studies in human tumor xenografts

Abstract

Abstract Immunodeficient mouse models seek to recapitulate the clinical features of advanced human cancers. However, drug efficacy testing and downstream analysis such as pharmacokinetic (PK) /pharmacodynamic (PD)-based studies are limited because of variability in tumor growth and kinetics, limited tumor growth potential, requiring the enrollment of larger numbers of mice in each treatment group to achieve required cohort sizes. Considering the distinctive advantages of rats in terms of their larger size, and ease of sampling at different time points for drug efficacy and clinical testing, we have developed unique immunodeficient rat models: the Rag2 knockout SDRTM rat (absence of mature B and T cells) and the Rag2/Il2rg double knockout SRGTM rat (absence of mature B and T cells, and lower NK cells) on a Sprague- Dawley background. Our group has previously demonstrated higher engraftment, better tumor kinetics, and increased tumor volume of xenografts in these rat models compared to available immunodeficient mouse strains for various cancer xenograft models. The purpose of the present study is to demonstrate the feasibility of drug efficacy studies using targeted molecular agents directed against cancer-associated drivers in our newly developed SDR and SRG rat models. We tested the efficacies of a combination treatment of an AKT inhibitor (MK2206) and MEK inhibitor (AZD6244), and a small-molecule activator of PP2A (SMAP) (DT-061) in a SDR rat xenograft model of human KRAS-mutant non-small cell lung cancer. 1 x 106 H358 cells were transplanted subcutaneously on the left hind flank in SDR rats. When tumor size reached 100-150 mm3, the rats were randomized to either control or treatment groups. The treatment groups received either a combination of AZD6244 with MK2206, or DT-061, and the vehicle-only control received n, n-dimethylacetamide + Solutol®/Kolliphor® HS 15, twice daily for 30 days by oral gavage. Both the kinase-inhibitors combination and SMAP treatment inhibited the growth of lung tumor xenograft in the SDR rats as shown by decreased mean tumor volume and fold changes in tumor volume compared to the control group. The combination treatment dose was just as effective at half the dose reported in previous mouse studies, demonstrating that lower dosing is sufficient for efficacy testing in rats. Importantly, no mortality, behavioral abnormalities, or changes in body weight were observed during the study, indicating a favorable tolerability profile in this model. We have also demonstrated that a human prostate cancer cell line VCaP, which has very poor engraftment and growth profiles in existing mouse models, grows well in our SRG rats. The SRG rat is now being used to study the chemotherapeutic efficacy of the benchmark androgen receptor inhibitor enzalutamide, in this VCaP tumor xenograft model. In addition, weekly blood sampling to measure PSA levels in the serum is being performed in the VCaP tumor xenograft efficacy study to demonstrate the flexibility of frequent sampling in the rat model to evaluate correlations between tumor growth and serum PSA levels. Citation Format: Kamesh Ravi, Fallon Noto, Christopher McClain, Angela Arey, Goutham Narla, Jack Crawford, Tseten Yeshi. Novel immunodeficient rat models offer a unique platform for drug efficacy studies in human tumor xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B170.