Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers

Area of Science:

• Oncology
• Biochemistry
• Drug Discovery

Background:

• Current cancer therapies primarily target primary tumors, neglecting the metastatic process.
• Metastasis in prostate, breast, and ovarian cancers is linked to increased activity of mesotrypsin and kallikrein 6 (KLK6).
• Mesotrypsin and KLK6 are identified as crucial targets for anti-metastatic interventions.

Purpose of the Study:

• To develop novel therapeutic agents targeting mesotrypsin and KLK6 for advanced metastatic cancers.
• To evaluate the efficacy and properties of APPI-based mutants as anti-metastatic therapies.
• To explore the potential of these agents for cancer imaging.

Main Methods:

• Development of engineered mutants of the human amyloid β-protein precursor Kunitz protease inhibitor domain (APPI).
• Designation of APPI-3M for prostate and breast cancers, and APPI-4M for ovarian cancer.
• Preclinical testing in orthotopic models to assess tumor accumulation, therapeutic efficacy, and pharmacokinetic properties.

Main Results:

• APPI-3M and APPI-4M mutants showed significant accumulation within tumors.
• Demonstrated therapeutic efficacy in preclinical models of advanced metastatic cancers.
• Exhibited long in vivo retention times, high affinity, and favorable pharmacokinetics.

Conclusions:

• Engineered APPI mutants represent a promising novel therapy for metastatic prostate, breast, and ovarian cancers.
• These agents possess characteristics suitable for both therapeutic intervention and diagnostic imaging.
• The developed therapies have a good safety profile and are manufacturable at scale.