Castration-resistant prostate cancer

Prostate cancer is the second most common cause of cancer-related deaths in American men1. Standard of care treatment begins with local tumor ablation via radiation or prostatectomy. If locally targeted approaches fail to cause disease regression, androgen deprivation therapy is administered to block androgen stimulated prostate cancer growth signals. Most tumors initially exhibit rapid and dramatic regression following androgen deprivation therapy2. However, many patients treated with androgen deprivation therapy will have disease recurrence and develop castration-resistant prostate cancer (CRPC). It is estimated that ~15% of all prostate cancer patients develop CRPC within 5 years of follow-up3. While local, androgen sensitive prostate cancer is largely treatment sensitive, CRPC is highly metastatic, less sensitive to clinical therapeutic options, and has poor survival rates2. Although currently approved therapies can extend lifespan, metastatic CRPC is ultimately a terminal diagnosis. A schematic that models prostate cancer progression from androgen sensitive, local disease to metastatic CRPC is shown in Figure 1.

A considerable problem in treating CRPC is the prevalence of therapeutic resistance. Androgen-mediated mechanisms of resistance can include androgen receptor gene amplification, gain of function mutations, and/or splice variants such as AR-V74. At the protein level, there may be alterations in post-translational modifications to the androgen receptor, altered levels of coactivators and repressors, and androgen receptor stimulation by growth factors and intratumor androgen synthesis. Non-androgen-mediated mechanisms of androgen resistance may include aberrant FGF and TGFβ signaling, upregulated RAS/MAPK and Wnt/β-catenin signaling, and others2. To improve clinical options for CRPC, pre-clinical animal models that closely recapitulate the human disease course are an essential component of drug development.

The SRG OncoRat^®

Hera BioLabs’ SRG OncoRat^® is immunodeficient and highly permissive to human prostate cancer xenografts, both patient- and cell line-derived tumors. Developed on a Sprague-Dawley background, SRG OncoRats are Rag2/Il2rg double knockouts that lack mature B cells, T cells, and circulating NK cells5. Compared to immune-deficient mouse models, the SRG OncoRat^® provides the following advantages:

• • Allows hosting for larger tumors (up to 10x volume compared to mice)
  • Increased tumor take-rates
  • Increased tumor growth kinetics
  • Serial blood and tissue sampling for PK/PD studies

Hera BioLabs is committed to developing rodent models of cancer that mimic human disease with high fidelity. Leveraging the superior qualities of the SRG OncoRat, we used the VCaP cell line to generate a CRPC model that closely mimics the current challenges faced in clinical treatment of prostate cancer.
VCaP cells were established from a vertebral bone metastasis from a patient with CRPC, passaged in mouse xenografts, and then cultured in vitro. VCaP cells are androgen sensitive in vitro and VCaP tumors are initially androgen sensitive in vivo. Furthermore, VCaP cells express the clinically relevant AR-V7 splice variant6.
To establish a robust in vivo model of CRPC, we inoculated 10 million VCaP cells subcutaneously into the hind-flank of SRG OncoRats and monitored tumor growth. On Day 24 rats were orchiectomized and tumor growth further monitored through Day 46. As seen with androgen deprivation therapy in humans, VCaP tumors initially regressed in the SRG OncoRats. However, VCaP tumors resumed growth 14 days after castration, faithfully modeling the progression of CRPC (Figure 2). After tumor regrowth, animals were enrolled into a therapeutic efficacy study that mimics the current clinical challenges in prostate cancer treatment.

The SRG OncoRat^® is a powerful tool for in vivo oncology studies, as it can perform better than mouse xenograft models in several keyways. Our rats are extremely well-suited for hosting patient-derived xenografts (PDX) and cell-derived xenografts (CDX) for oncology studies, including drug efficacy, tumor growth kinetics, and PK/PD studies. Tumor volumes are far larger than those obtained in mice, allowing for more detailed molecular characterization of tumors as well as PDX banking.

These qualities also make the SRG OncoRat® an attractive candidate for modeling complex human diseases, such as CRPC, and offer the ideal platform for developing pharmacotherapies that could prevent or bypass CRPC, potentially leading to life-saving breakthroughs.

If your preclinical studies could use a boost, or you would like to see more data on the SRG Rat, contact Hera BioLabs for more information here.

REFERENCES

1. Siegel, D. A., O’Neil, M. E., Richards, T. B., Dowling, N. F. & Weir, H. K. Prostate Cancer Incidence and Survival, by Stage and Race/Ethnicity – United States, 2001-2017. MMWR Morb Mortal Wkly Rep 69, 1473-1480, doi:10.15585/mmwr.mm6941a1 (2020).
2. Crowley, F. et al. A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer. Res Rep Urol 13, 457-472, doi:10.2147/RRU.S264722 (2021).
3. Kirby, M., Hirst, C. & Crawford, E. D. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract 65, 1180-1192, doi:10.1111/j.1742-1241.2011.02799.x (2011).
4. Sharp, A. et al. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. J Clin Invest 129, 192-208, doi:10.1172/JCI122819 (2019).
5. 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).
6. Korenchuk, S. et al. VCaP, a cell-based model system of human prostate cancer. In Vivo 15, 163-168 (2001).