In order to progress beyond a certain size, tumours need to develop their own blood supply for nutrients and oxygen. Although tumours are able to create their own blood supply this process is not perfect and so tumours have regions which do not receive enough oxygen. Hypoxia is the term used to describe any situation where there is insufficient oxygen. Most solid tumours have regions of hypoxia, which is significant because many studies have shown that the more hypoxic a tumour is, the worse the patient does (Figure 1).
Importantly, this is independent of the therapy type the patient receives. Hypoxic tumours are resistant to both chemotherapy and radiotherapy as well as being more likely to spread and are therefore the most aggressive and hardest to treat. To improve the effectiveness of cancer therapy it is vital that we target the hypoxic part of tumours. Our group has three approaches to this problem:
- We are investigating the biological response to hypoxia and in particular a pathway known as the DNA damage response. This pathway is active in hypoxic conditions despite a lack of detectable hypoxia-induced DNA damage. There are many drugs to target this pathway and it is possible that they will prove particularly useful in killing hypoxic cells when combined with standard therapies such as radiation.
- We are developing novel drugs which only work in the absence of oxygen and so can be used to target the hypoxic areas of tumours. This approach allows us to use potentially toxic drugs as the normal cells in the body are unaffected.
- Finally, it is vital that novel inhibitors/drugs are tested in conditions which mimic those found in tumours. Therefore, we test drugs in conditions which more closely resemble those found in tumours, including low oxygen, to determine if they are likely to be effective.
- Preclinical testing of an Atr inhibitor demonstrates improved response to standard therapies for esophageal cancer. Leszczynska KB. et al, (2016), Radiother Oncol, 121, 232 - 238
- Design, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugs. O'Connor LJ. et al, (2016), Nat Protoc, 11, 781 - 794
- Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT. Leszczynska KB. et al, (2015), J Clin Invest, 125, 2385 - 2398
- Replication Stress and Chromatin Context Link ATM Activation to a Role in DNA Replication. Olcina MM. et al, (2013), Molecular Cell
- CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and Aurora A. Cazares-Körner C. et al, (2013), ACS Chem Biol, 8, 1451 - 1459