A research team led by Chiu-Lien Hung at the Industrial Technology Research Institute (ITRI) successfully developed a targeted protein degradation drug named "ITRI-148" specifically designed for treating castration-resistant prostate cancer (CRPC). This innovative drug employs a protein degradation mechanism that not only inhibits androgen receptor (AR) activity to curb cancer cell growth but also directly destroys the oncogenic proteins within the cancer cells.

Prostate Cancer Challenge: High Incidence and Drug Resistance

Prostate cancer is the second most common cancer among men worldwide, and its incidence in Taiwan is steadily increasing. While hormone therapy or castration can effectively control the disease, most patients eventually relapse and progress to CRPC. At this stage, cancer cells develop resistance to treatment, severely impacting patient prognosis and quality of life. Particularly concerning is the AR-V7 variant, responsible for drug resistance in over 50% of cases. Currently, there are no effective targeted therapies for this form of resistance.

Innovative Protein Degradation Technology: Precisely Targeting Cancer Cells

Unlike traditional targeted therapies that merely inhibit AR function, ITRI-148 utilizes PROTAC (Proteolysis Targeting Chimera) technology. This approach not only inhibits AR activity but also degrades both the full-length AR protein and the AR-V7 splice variant. By binding to the target proteins rather than relying on active sites, ITRI-148 reduces the risk of developing drug resistance and broadens the range of proteins it can target. Additionally, ITRI-148 has strong tissue penetration, enabling it to reach deep into cancer cells for enhanced therapeutic effectiveness.

The advantages of ITRI-148 are further supported by the following experimental data:

• Cytotoxicity: In multiple prostate cancer cell lines, the maximum inhibitory concentration (DC50) ranged from 1 to 10 μM, demonstrating its effectiveness in suppressing cancer cell growth.
• Tumor Inhibition: In the androgen-dependent CRPC VCaP xenograft model, ITRI-148 showed a tumor growth inhibition rate of up to 147%, making it competitive with existing clinical trial drugs like ARV-110.
• Overcoming Drug Resistance: In the CWR22RV1 xenograft model, which exhibits high expression of AR and AR-V7, ITRI-148 effectively inhibited tumor growth, outperforming ARV-110.
• Safety: In a 28-day repeated-dose oral toxicity study in mice, no significant toxic reactions were observed, even at high doses, with a calculated therapeutic index (TI) of greater than 50.

Advancing Drug Development Toward Clinical Trials: A Potential Shift in Treatment Landscape

ITRI-148 has completed critical preclinical studies, including efficacy, pharmacokinetics, and initial toxicity testing. The drug's production process has also been developed for mass production. Technology transfer to manufacturers is expected to be completed by 2024, and preparations are underway to meet IND (Investigational New Drug) requirements for Phase I clinical trials.

Looking ahead, ITRI-148 holds promise as a new treatment option for CRPC patients, improving their quality of life. Furthermore, it may be expanded to treat other cancers and diseases, offering the global medical community innovative solutions.

Resource (mandarin): 去勢抗性前列腺癌新剋星！靶向藥直攻摧毀細胞致癌蛋白