Combinatorial androgen receptor targeted therapy for prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Prostate cancer progression involves a shift in androgen receptor (AR) signaling from paracrine to autocrine dependence.
• AR gains novel functions in cancer, activating unique genomic and non-genomic pathways for cell proliferation and survival.
• AR signaling persists even after androgen ablation due to further molecular changes and co-factor interactions.

Purpose of the Study:

• To highlight the need for combinatorial androgen receptor targeted therapy (CART) to overcome treatment failure in prostate cancer.
• To propose a strategy for developing CART by combining agents targeting different points of the AR signaling cascade.
• To identify key therapeutic targets within the AR signaling pathway for combination therapy.

Main Methods:

• Review of AR signaling alterations in prostatic carcinogenesis and progression.
• Conceptual framework for developing combinatorial therapy by combining novel agents with androgen ablation.
• Identification of potential therapeutic agents including 5alpha-reductase inhibitors, AR protein downregulators (e.g., geldanamycin analogs), AR antagonists ('bulky' steroids), and MEK inhibitors.

Main Results:

• AR signaling undergoes malignant conversion, promoting prostate cancer cell proliferation and survival.
• AR signaling pathways remain active in advanced prostate cancer, contributing to resistance to androgen ablation.
• Combination therapy targeting multiple AR pathway components is proposed as a strategy to enhance treatment efficacy.

Conclusions:

• A combinatorial androgen receptor targeted therapy (CART) approach is essential to combat treatment-resistant prostate cancer.
• Combining androgen ablation with agents targeting AR signaling (e.g., 5alpha-reductase inhibitors, AR protein downregulators, AR antagonists, MEK inhibitors) holds promise.
• Further research is needed to define optimal combinations and dosing for maximal therapeutic effect in prostate cancer patients.