Research & Development

DNA Damage Response

Many cancers have defects in the way in which cells monitor and repair damaged DNA, collectively termed DNA damage response, or DDR. These deficiencies in DDR pathways render cells more susceptible to DNA damage. Many traditional cancer treatments, such as DNA-damaging chemotherapy and radiotherapy, are based on this finding. However, such treatments are often accompanied by significant and unwanted side effects. Developing treatments which target specific DDR deficiencies to preferentially kill cancer cells, while minimizing the impact on normal cells, has potential for more selective, better tolerated therapies to improve survival in multiple cancers.

We have focused on developing treatments targeting DNA damage pathways for several years.

CDK inhibitor-based Strategies:

  • Modulate DNA repair (via HR, NHEJ pathways)
  • Decreased expression of HR DNA repair genes (BRCA1 and BRCA2)

Cyclacel's oral sapacitabine which may work best in HR-deficient tumors

Clinical Utility:

  • Single agent treatment in sensitive cancers
  • Combinations with standard of care, i.e. PARP inhibitors

We are evaluating sapacitabine in a Phase 1/2 combination study with seliciclib in patients with BRCA mutations:

  • All-oral combination of complementary mechanisms:
    sapacitabine's unique dual MoA of DNA SSBs and cell cycle arrest + CDKi modulation
  • Parts 1 & 2 durable clinical benefit (PRs & prolonged SD) in patients with BRCA +ve:
    breast, ovarian, pancreatic cancers
  • Part 3 to start: revised schedule including BRCA +ve ovarian, pancreatic cancer patients
Research & Development