First-in-Class Assets For Promising New Targets
Repare is building a pipeline of assets addressing novel targets with the potential to precisely target certain vulnerabilities of genetically defined cancers. Our lead program, PolQ, has grown from the seminal research conducted in the lab of the company co-founder Dr. Agnel Sfeir, PhD.
The PolQ gene codes for polymerase theta (Polθ) which has been shown to play an important role in repairing DNA double-strand breaks (DSBs).
DSB are primarily repaired through homologous recombination (HR) and classical non-homologous end-joining (C-NHEJ) mechanisms. A third and mechanistically distinct DSB repair pathway, termed “alternative Non-Homologous End-joining” (alt-NHEJ), is highly mutagenic and driven by the activity of Polθ. Polθ mediated alt-NHEJ is used by cells to correct DSBs, especially in the absence of HR and C-NHEJ. The use of this pathway promotes the survival of HR defective cancer cells. PolQ is over-expressed in many tumor types and associated with poor clinical outcomes in ovarian cancer and breast cancers.
Model: Polθ is required for alt-NHEJ-dependent Double Strand Break (DSB) repair
Nature 518, 254–257
Loss of PolQ has been shown to inhibit repair by alt-NHEJ and result in a concomitant increase in homology-directed repair. Importantly, depletion of Polθ has a synergistic effect on cell survival in the absence of BRCA genes. Inhibition of Polθ thus represents an exciting new therapeutic opportunity, particularly in tumors that carry mutations in homology-directed repair genes.
Repare is also progressing two additional programs based on discoveries generated through the Platform.
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