Prostate cancer remains one of the leading causes of cancer-related death among men, with metastatic disease posing the greatest clinical challenge. While localized cancer can often be treated successfully, bone metastases and therapy resistance are common in advanced cases.
Recent research presented in a Taconic Biosciences webinar by Dr. Stephen Kregel, PhD, Assistant Professor, Loyola University Chicago, showcases how humanized immune system (HIS) mouse models transform our ability to study treatment resistance, immune interactions, and metastatic progression in a clinically relevant context.
Why Use Humanized Models for Prostate Cancer Research?
Conventional mouse models can struggle to address the complexities of prostate cancer:
- Anatomical differences: Mouse and human prostates differ significantly in structure and histology.
- Lack of bone metastasis: Most models don’t replicate the strong bone tropism seen in human prostate cancer.
- Different AR dynamics: Many mouse models quickly lose androgen receptor (AR) expression, limiting their value in testing AR-targeted therapies.
These limitations drive the need for human tumor xenografts in humanized mice for prostate cancer research, where tumors maintain AR dependence and exhibit human-like metastatic patterns.
Humanized Models: huNOG and huNOG-EXL
Taconic’s huNOG and huNOG-EXL models address these gaps:
- huNOG: T cell–dominant immune profile, ideal for modeling immune activation and immunotherapy response.
- huNOG-EXL: Myeloid cell–rich profile, closely resembling immune-cold tumors common in prostate cancer patients.
Both models enable testing of androgen receptor antagonists such as enzalutamide, as well as newer treatment strategies.
Enzalutamide’s Dual Role in Metastasis
Kregel’s research revealed a striking difference in treatment outcomes:
- In humanized mice, enzalutamide blocked metastatic growth in bone, brain, and other sites.
- In immunocompromised mice, the drug sometimes increased metastatic spread.
These results point to an immune-mediated mechanism in which AR antagonism enhances T cell infiltration and activation, potentially suppressing metastatic outgrowth.
Hot and Cold Immune Environments
By using both huNOG and huNOG-EXL models, researchers can simulate two distinct tumor-immune interactions:
- Hot Tumors: T cell–rich, responsive to AR antagonism, reduced metastasis.
- Cold Tumors: Dominated by myeloid-derived suppressor cells, resistant to enzalutamide, and persistent metastasis.
This dual-model approach helps identify strategies to convert cold tumors into hot ones, potentially improving checkpoint inhibitor efficacy.
Combining AR Antagonists with Immunotherapy
In experiments with VCaP cells, combining enzalutamide and pembrolizumab in huNOG mice led to complete tumor regression. The synergy was absent in immunocompromised controls, highlighting the importance of immune context in combination therapy success.
Expanding Research Possibilities
These humanized models can be adopted to study:
Key Takeaways
