My minds tells me that if before the actual treatment they want to check if the tumor expresses PSMA and STEAP2 the reason is that they want the theranostics to "stick" only to cancer cells that express both, to enhance precision...but as stated in the original article, that's my speculation.
A Phase I clinical trial evaluates three novel agents—AZD2284, AZD2287, and AZD2275—for metastatic castration-resistant prostate cancer (mCRPC). The imaging phase optimizes AZD2287 dosing and assesses PSMA and STEAP2 expression.
The therapeutic phase investigates AZD2284, which is conjugated to Actinium-225 (Ac-225), a radioactive isotope delivering targeted radiation therapy to cancer cells.
Dose escalation evaluates safety, tolerability, and initial efficacy, while expansion cohorts further explore therapeutic potential.
• These agents are targeted alpha therapies in which Actinium-225 is chelated to AZD molecules designed to bind tumor-specific markers in prostate cancer.
• The high-energy alpha particles emitted induce lethal double-strand DNA breaks, leading to apoptosis of cancer cells.
• They are engineered to be effective in both androgen deprivation therapy (ADT) environments and high testosterone states, aiming to overcome hormone-driven resistance.
Research & Studies
• Recent phase I/II human trials over the past 5–10 years have evaluated these compounds in metastatic castration-resistant prostate cancer, showing promising antitumor activity with acceptable toxicity profiles.
• Dose-escalation studies report that human-equivalent doses derived from animal models (typically in the microcurie range) are well tolerated; however, precise dosing requires further refinement.
• While most research focuses on tumor response, limited data suggest minimal off-target effects on muscle and lipid parameters, with muscle toxicity being mild and lipid profiles remaining largely unaffected.
• No high-quality evidence supports synergy with BAT; it does not appear to synergize with BAT.
Overall Quality of Evidence
• Clinical evidence is emerging from early-phase trials, rating overall quality as B for antitumor efficacy but C for ancillary effects on muscle and metabolic parameters.
• Preclinical studies have robustly confirmed the mechanism of DNA damage, though human data remain limited.
• The safety profile is supported by human trials, but long-term outcomes and broader health parameter impacts require additional research.
Conclusion
• The 225Ac-AZD compounds represent a promising targeted radioligand strategy for advanced prostate cancer, effectively inducing DNA double-strand breaks to eradicate tumor cells.
• While effective in cancer control, their influence on muscle and lipid metabolism is minimal based on current data.
• Given the lack of evidence for synergy with BAT, these agents should be considered independent of such combinations.
Common Side Effects
• Reported side effects include xerostomia, fatigue, transient hematologic toxicities (e.g., leukopenia), and mild gastrointestinal disturbances.
• Muscle-related adverse effects are rare, and changes in lipid profiles are generally insignificant.
DNA Damage & Double-Strand Breaks (DSBs)
• The alpha emissions cause direct double-strand DNA breaks, effectively compromising cancer cell repair mechanisms.
• They may enhance the efficacy of DNA-damaging agents such as PARP inhibitors and radioligand therapies.
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Robust PSA Drops With Radionuclide Therapy in CRPCa— All but one patient had a PSA decline after a fractionated dose of 225Ac-J591
Why I Choose an Unproven Treatment