ALT Program

Targeting ALT cancers through the FANCM protein complex

The FANCM complex is crucial for Alternative Lengthening of Telomeres (ALT) as it binds to the telomeric DNA and resolves DNA damage, reducing replication stress and allowing cell proliferation. We have demonstrated that our first-in-class inhibitors target key components of the FANCM complex, leading to catastrophic DNA damage at telomeres and consequently rapid cell death specifically in ALT cancers.

Alternative Lengthening of Telomeres (ALT)

In healthy cells, telomeres progressively shorten after each cell division, limiting the number of replications. Cancer cells overcome telomere shortening and thus the replication limitations. One of these mechanisms is Alternative Lengthening of Telomeres (ALT) allowing unlimited proliferation.

ALT cancers – snapshot

ALT is an important survival mechanism in 10-15% of all cancers and is associated with poor prognosis and a lack of targeted therapies.

Each year, approximately 1 million patients die from ALT+ cancers.

ALT Companion Diagnostic (CDx)

Diagnostic development starts at early stages of our drug discovery programs.

Tessellate Bio is validating and developing a companion diagnostic (CDx) for our ALT program. The CDx determines ALT status by detecting C-Circles, which are recognized as the best biomarker for ALT+ cancers.

AACR 2024 poster

Therapeutic strategy

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LoF Program

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Publications

Lu R et al. (2019) The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT).
Nat Commun. May 28;10(1):2252.
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Silva B et al. (2019) FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops.
Nat Commun. May 28;10(1):2253.
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Henson JD et al. (2016) The C-Circle Assay for alternative-lengthening-of-telomeres activity.
Methods. Feb 1;114:74-84.
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Abbouche L, Bythell-Douglas R, Deans AJ (2024) FANCM branchpoint translocase: Master of traverse, reverse and adverse DNA repair.
DNA Rep (Amst) 2024 Aug:140:103701.
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