Manipulating the hypoxic tumor microenvironment to study therapy resistance
His research focused on Notch and hypoxia and their interaction in cancer development and treatment resistance. We reviewed the current knowledge of the role of Notch in breast cancer and long small long cancer and how it plays a role in development, progression and resistance to therapy. Importantly we find evidence that Notch inhibition can re-sensitise treatment resistance breast cancers providing a strong rationale for using Notch inhibitors with radiotherapy in treating breast cancer.
The main focus of the research was on the tumor microenvironment and in particular hypoxia and the role it plays. Tumours that contain areas of hypoxia are known to be more aggressive, more prone to genetic instability and mutation and are associated with more malignant tumours, immunosuppression, higher incidence of metastases, therapy resistance including to radiotherapy and chemotherapy and ultimately poorer prognosis for patients. There are a number of strategies that have been used to try and overcome or target tumour hypoxia. The reasons for their failure are numerous but a few reasons include the unforeseen activation of hypoxia activated pro-drugs in normal tissue creating normal tissue toxicity. Drugs not being able to diffuse to hypoxic regions much like oxygen, leading to insufficient concentrations to have a significant effect. And patients not being selected based on the hypoxic status of their tumours as these drugs are not expected to work in well oxygenated tumours. These failure highlight that there is a lack of insight into the biology of hypoxic niches and cells and how they respond to treatment and more knowledge is needed on their behaviour and contribution in cancer and treatment resistance.
While much is known about the cellular response to hypoxia, a lot is still unknow about the behaviour of hypoxic cells within a tumour and how they interact with the tumour microenvironment and this remains understudied. Therefore, we have created a model that allows the labelling and killing of hypoxic cells in cancer. Using this model, we find that hypoxic or post-hypoxic cells are able to divide faster. This has implications for tumor recurrence after radiotherapy, with the already more resistant hypoxic population being able to more efficiently repopulate the tumor, highlighting the importance of targeting these cells to improve patient outcome.
This model allows us to study hypoxic cells in tumours and how they behave in tumour progression, metastasis and how they respond to treatments. The ability to kill the labelled cells allows insight into how hypoxic cells contribute to treatment resistance and how effective hypoxic targeting therapies can be and how we can integrate them with other treatment strategies such as radio and chemotherapy. This model can also be used in optimising the scheduling of future hypoxia targeting treatments when combined with current treatments such as radiotherapy. Finally, this research increases our understanding of hypoxia biology and will facilitate research into future hypoxia targeting treatments, biomarkers and discovery of possible targets that can be exploited to benefit the patient.
