Targeting DNA Topoisomerase I for the Treatment of Cancer: Past, Present and Future

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Topoisomerase I (TOP1) is an enzyme essential for managing DNA topology in human cells.
• Despite its ubiquitous presence, TOP1 is a validated target for anticancer therapies, with several FDA-approved drugs and ongoing research.
• Understanding TOP1 biology is key to developing effective cancer treatments.

Purpose of the Study:

• To review the current landscape of TOP1-directed cancer therapies.
• To discuss the cellular consequences of stabilizing TOP1-DNA complexes.
• To explore resistance mechanisms and strategies to overcome them.
• To introduce novel therapeutic approaches targeting TOP1.

Main Methods:

• Review of existing literature on TOP1 biology and anticancer agents.
• Analysis of cellular effects of TOP1 inhibitors.
• Examination of resistance mechanisms and potential countermeasures.
• Description of novel drug delivery systems like nanoparticles and antibody-drug conjugates.

Main Results:

• Six FDA-approved antineoplastic treatments target TOP1.
• Stabilizing TOP1-DNA covalent complexes leads to DNA damage and cell death.
• Resistance to TOP1 inhibitors can occur through various cellular mechanisms.
• New generations of targeted therapies, including nanoparticles and antibody-drug conjugates, show promise for high drug concentration at tumor sites.

Conclusions:

• TOP1 remains a significant target for cancer therapy development.
• Novel strategies involving targeted delivery systems and combination therapies (with DNA damage response inhibitors, epigenetic modifiers, or immune modulators) can enhance treatment efficacy.
• These advanced TOP1-directed agents hold promise for improving outcomes in various solid tumors.