Targeting FANCM by antisense oligonucleotides in ALT-positive cancers.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Alternative lengthening of telomeres (ALT) is a mechanism used by some cancers to maintain telomere length, contributing to their progression and resistance to therapy.
• Developing targeted therapies for ALT-positive cancers remains a critical unmet need in oncology.

Purpose of the Study:

• To validate FANCM (Fanconi anemia complementation group M) as a therapeutic target for ALT-positive cancers.
• To investigate the efficacy of antisense oligonucleotides (ASOs) targeting FANCM mRNA as a potential treatment strategy.

Main Methods:

• CRISPR-Cas9 strategies were employed to validate FANCM as a target in both in vitro and in vivo models.
• Antisense oligonucleotides (ASOs), specifically gapmers, were designed and screened to target FANCM mRNA.
• The effects of FANCM inhibition on ALT activity, telomeric dysfunction, and cancer cell viability were assessed.
• A liposarcoma xenograft model was used to evaluate the in vivo therapeutic potential of a lead ASO candidate.

Main Results:

• FANCM was confirmed as a crucial target for ALT-associated cancers.
• Effective gapmers were identified that potently reduced FANCM expression.
• Reduced FANCM expression led to increased ALT activity, telomeric dysfunction, and decreased viability in ALT-positive cancer cells.
• Gapmer 14 significantly impaired ALT cell viability and reduced tumor growth in an in vivo xenograft model.

Conclusions:

• FANCM is a validated and important therapeutic target for ALT-positive cancers.
• FANCM-targeting ASOs, particularly gapmer 14, demonstrate significant potential as an effective therapeutic strategy for treating ALT-positive cancers.
• This approach offers a promising new avenue for developing novel cancer therapies.