The potential of targeted alpha therapy (TAT) utilizing thorium-227 conjugates (TTCs) as a promising treatment option for prostate cancer, particularly for advanced stages of the disease, including those with bone metastases and resistance to standard therapies is significant.
Alpha particles, emitted by TTCs, possess characteristics that make them highly effective for cancer treatment. Their high linear energy transfer (LET) requires only a few hits to induce cell death, while their short penetration range minimizes damage to surrounding healthy tissues. This localized effect is particularly beneficial when addressing bone metastases, which are common in advanced prostate cancer.

Preclinical studies showed that PSMA-TTC effectively targeted and killed prostate cancer cells, leading to tumor regression in models representing different stages of prostate cancer. Even in models resistant to standard anti-androgen treatments like enzalutamide, PSMA-TTC demonstrated significant antitumor activity. This suggests its potential value in overcoming treatment resistance.
The efficacy of PSMA-TTC was also observed in a mouse model mimicking prostate cancer bone metastases, where it successfully reduced tumor growth and impacted tumor-induced bone morphology. This finding is particularly relevant given the challenges associated with treating bone metastases in prostate cancer.
Based on the promising preclinical results, a Phase I clinical trial is currently underway to evaluate PSMA-TTC in humans with metastatic castration-resistant prostate cancer (mCRPC). This trial will assess the safety, tolerability, pharmacokinetics, and antitumor activity of PSMA-TTC, both as a single agent and in combination with the androgen receptor inhibitor (ARI) darolutamide.

Furthermore, preclinical research has explored combining PSMA-TTC with other therapies to enhance its efficacy.
● Combining PSMA-TTC with a DNA-PK inhibitor, a protein involved in DNA repair, demonstrated synergistic anti-proliferative effects in prostate cancer cells, exceeding the efficacy of PSMA-TTC alone in preclinical models . This suggests a promising strategy for enhancing treatment response.
● Similarly, the combination of PSMA-TTC with the ARI darolutamide also showed synergistic tumor growth inhibition in prostate cancer models . This combination was particularly effective in models resistant to enzalutamide or hormone-independent models, indicating its potential to overcome treatment resistance.

The trial is expected to end this month, November 2024.�

Source.

Clinical trial.