Targeting Topoisomerase I in the Era of Precision Medicine

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Irinotecan and topotecan are established Topoisomerase I (TOP1) inhibitors used in cancer therapy for two decades.
• Camptothecins are crucial tools for studying DNA repair pathways involved in DNA-protein cross-links and replication stress.

Purpose of the Study:

• To review the molecular mechanisms, clinical applications, and limitations of current TOP1 inhibitors.
• To introduce novel therapeutic strategies for TOP1 inhibitors in cancer treatment.

Main Methods:

• Review of existing literature on TOP1 inhibitors.
• Introduction of novel indenoisoquinoline scaffolds (LMP400, LMP776, LMP744).
• Discussion of tumor-targeted delivery systems (liposomes, PEGylation, antibody-drug conjugates).

Main Results:

• Novel TOP1 inhibitor scaffolds and targeted delivery methods offer new therapeutic avenues.
• Tumor-specific determinants like homologous recombination defects (HRD/BRCAness) and SLFN11 expression can guide treatment selection.
• Combination therapy with DNA damage response inhibitors (PARP, ATR, CHEK1, ATM inhibitors) shows promise.

Conclusions:

• Novel TOP1 inhibitors and targeted delivery systems represent significant advancements in cancer therapy.
• Personalized medicine approaches using biomarkers (HRD, SLFN11) can optimize TOP1 inhibitor efficacy.
• Combination strategies with DNA damage response inhibitors enhance the therapeutic potential of TOP1 inhibitors.