Radiation is one of the primary modalities for the treatment of localized cancer and a number of factors can influence the response of tumours and surrounding normal tissues to such treatment. These factors, which can be specific to the individual tumour or normal tissue and to their environment, can vary from patient to patient. One part of the research in my laboratory focuses on understanding how these factors control tumour and normal tissue response to radiation treatment in individual patients.Our current work involves:
- Examination of hypoxia in human tumours with a focus on cancer of the cervix and soft tissue sarcomaIn these studies we are collaborating with the clinical groups at the Princess Margaret Hospital in examining methods to measure hypoxia in tumours in relation to their value as predictors of treatment outcome.
- Studies of the cellular radiosensitivity of normal human fibroblasts from skin in vivoThese studies are focusing on the use of assays of fibroblast response to irradiation as a possible local dosimeter following accidental exposure to irradiation.
- Examination of the sensitivity of lung tissue to different volumes of irradiationThese studies in rat and mouse lungs are investigating mechanisms associated with the response of the lung to radiation damage (believed to be associated with the induction of a localized but prolonged inflammatory response), which can result in deleterious effects both inside and outside the radiation field.
The second major focus of our research is the spread of cancer from its initial site of growth to other locations in the body (metastasis), which is a major factor influencing the likelihood of successful treatment. The formation of metastasis by tumour cells is thought to be dependent on the expression of specific phenotypes by individual tumour cells. Our research is examining metastatic phenotypes that are expressed only transiently and that may be induced by exposure of tumour cells to conditions, such as hypoxia, which occur in the tumour microenvironment. Recent clinical results have suggested that tumours that contain substantial hypoxic regions may be more likely to form metastases. We have found in animal model systems that exposure to hypoxia, both in vitro and in vivo, can cause transient increases in the metastatic potential of tumour cells and that exposure to transient hypoxic episodes may be particularly important for this increased metastatic potential. We are examining the effect of hypoxic exposure in modifying the expression of genes likely to be associated with the cancer stem cell phenotype, metastasis and tumour progression. Recent studies by our clinical collaborators have identified elevated levels of interstitial fluid pressure, a characteristic of many tumours, as another factor that may affect metastasis. We are developing animal models to investigate the mechanisms responsible for this effect.
The predictive value of nadir neutrophil count during treatment of cervical cancer: Interactions with tumor hypoxia and interstitial fluid pressure (IFP).
Clin Transl Radiat Oncol. 2017 Oct;6:15-20
Targeting the CXCL12/CXCR4 Pathway and Myeloid Cells to Improve Radiation Treatment of Locally Advanced Cervical Cancer.
Int J Cancer. 2018 Feb 08;:
Metabolic targeting of HIF-dependent glycolysis reduces lactate, increases oxygen consumption and enhances response to high-dose single-fraction radiotherapy in hypoxic solid tumors.
BMC Cancer. 2017 Jun 15;17(1):418
Radiat Res. 2017 May 30;:
Cancer initiating-cells are enriched in the CA9 positive fraction of primary cervix cancer xenografts.
Oncotarget. 2016 Nov 25;:
Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts.
Br J Cancer. 2016 Nov 22;:
Plerixafor Improves Primary Tumor Response and Reduces Metastases in Cervical Cancer Treated with Radio-Chemotherapy.
Clin Cancer Res. 2016 Oct 3;:
Br J Radiol. 2016 Aug 2;:20160474
Recent Results Cancer Res. 2016;198:25-44
Neoplasia. 2016 Jun;18(6):347-55
Emeritus Scientist, Princess Margaret Cancer Centre
Professor, Department of Radiation Oncology, University of Toronto
Professor, Department of Medical Biophysics, University of Toronto