On January 18, 2022 Hera BioLabs’ reported that SRG OncoRat is immunodeficient and highly permissive to human prostate cancer xenografts, both patient- and cell line-derived tumors (Press release, Hera BioLabs, JAN 18, 2022, View Source [SID1234605535]). Developed on a Sprague-Dawley background, SRG OncoRats are Rag2/Il2rg double knockouts that lack mature B cells, T cells, and circulating NK cells. Compared to immune-deficient mouse models, the SRG OncoRat provides the following advantages:
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Increased tumor take-rates (>90% for MDVR-VCaP cells)
Drug efficacy can be combined with toxicity and metabolism endpoints
Easier surgical procedures including orthotopic tumor implantation
Serial blood and tissue sampling including tumor biopsies for biomarker analysis
Leveraging the superior qualities of the SRG rat (OncoRat), Hera BioLabs has generated a robust platform for evaluating the efficacy of both androgen-dependent and -independent AR blockers. We have generated an enzalutamide (MDV3100)-resistant VCaP prostate cancer cell line (MDVR-VCaP) by passaging VCaP cells under enzalutamide selection. VCaP cells are particularly useful for interrogating AR signaling pathways because they mimic amplification of the AR gene that is commonly seen in men4. Like the parental cell line, MDVR-VCaP cells display robust tumor formation when inoculated into our SRG OncoRat.
Recently published work conducted by Hera highlights the utility of evaluating enzalutamide and castration resistant VCaP xenografts5. In this study, we started by inoculating SRG OncoRats subcutaneously with VCaP or MDVR-VCaP. When tumors reached the size of 1,000-3,000 mm3, rats were castrated and the tumors allowed to progress as CRPC. After a period of tumor regression and re-growth to 2000 mm3, rats were randomized to receive vehicle, enzalutamide, or UT-34 (a selective AR degrader). Figure 1 (adapted from 5) shows percent change in tumor volume for VCaP and MDVR-VCaP tumors following treatment. In SRG rats carrying VCaP tumors, the UT-34 caused significantly more tumor regression than enzalutamide. In rats carrying MDVR-VCaP tumors, enzalutamide did not cause a significant reduction in tumor volume, but UT-34 was highly efficacious and reduced tumors to unmeasurable volumes.
Does your compound circumvent the heartbreaking difficulties of treating castration-resistant or enzalutamide-resistant prostate cancer? Do you need to assess your compound’s efficacy while de-risking your preclinical pipeline? If so, connect with Hera to learn more about how we can assist you.
REFERENCES
Schalken, J. & Fitzpatrick, J. M. Enzalutamide: targeting the androgen signalling pathway in metastatic castration-resistant prostate cancer. BJU Int 117, 215-225, doi:10.1111/bju.13123 (2016).
Vander Ark, A., Cao, J. & Li, X. Mechanisms and Approaches for Overcoming Enzalutamide Resistance in Prostate Cancer. Front Oncol 8, 180, doi:10.3389/fonc.2018.00180 (2018).
Noto, F. K. et al. The SRG rat, a Sprague-Dawley Rag2/Il2rg double-knockout validated for human tumor oncology studies. PLoS One 15, e0240169, doi:10.1371/journal.pone.0240169 (2020).
Greene, S. B. et al. Chromosomal Instability Estimation Based on Next Generation Sequencing and Single Cell Genome Wide Copy Number Variation Analysis. PLoS One 11, e0165089, doi:10.1371/journal.pone.0165089 (2016).
Ponnusamy, S. et al. Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer. Cancer Res 77, 6282-6298, doi:10.1158/0008-5472.CAN-17-0976 (2017).