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Targeting FANCM by antisense oligonucleotides in ALT-positive cancers
Galen Tieo1, Natalie Bao Ying Lim2, Kah Wai Lim2
1School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
Abstract:
Effective therapies for cancers relying on the alternative lengthening of telomeres (ALT) mechanisms are still needed. Here, using CRISPR-Cas9 strategies, we validate FANCM (Fanconi anemia complementation group M) as a crucial target for ALT-associated cancers and demonstrate its importance in both in vitro and in vivo models. We further explore the use of antisense oligonucleotides (ASOs), specifically gapmers, to target FANCM mRNA. We designed and screened several gapmers, identifying effective candidates that potently reduced FANCM expression, which led to an increased ALT activity and telomeric dysfunction, concomitant with a reduced viability of ALT-positive cancer cells. Notably, gapmer 14, one of the identified ASOs, significantly impaired the viability of ALT cells and reduced tumor growth in an ALT-positive liposarcoma xenograft model, highlighting its therapeutic potential. These findings suggest that FANCM-targeting ASOs could represent a promising effective strategy for treating ALT-positive cancers.
Insights
Targeting FANCM (Fanconi anemia complementation group M) shows promise for treating alternative lengthening of telomeres (ALT) cancers. Antisense oligonucleotides (ASOs) effectively reduced FANCM, impairing ALT cancer cell viability and tumor growth.
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.
