Deciphering tumor resistance to radiation treatment
Radiotherapy is a major treatment modality for prostate cancer patients, however despite delivery of a high dose of radiation, up to one-third of patients will recur following treatment. Patients who develop locally recurrent disease are at significant risk of subsequently developing distant metastases, and have a poor prognosis, highlighting the importance of elucidating mediators of cancer radioresistance.
To address this important clinical problem, we generated radiation resistant cancer models and discovered that they possess an aggressive phenotype that mimics the clinical scenario. We are investigating the role of microRNA in promoting this phenotype, since they are known to possess pleotropic oncogenic effects by targeting multiple downstream gene targets. We recently demonstrated that miR-95 was enriched in radiation resistant prostate cancer cells, and its overexpression effectively recapitulated the phenotype seen in resistant cells. An essential downstream mediator of miR-95 was sphingosine-1-phosphate phosphatase 1 (SGPP1) and we were able to reverse radioresistance through the repurposing of a drug used to treat multiple sclerosis, FTY-720 (Huang et al. Cancer Res 2013).
We believe that understanding the mechanisms and consequences of relevant microRNA will identify actionable opportunities for targeting their downstream mediators to overcome radioresistance.
microRNA as biomarkers to improve prostate cancer detection and management
microRNA are detectable in patient biofluids (e.g., blood, urine, saliva), in addition to tumor, and they are inherently stable, making them excellent biomarkers. We believe that urinary microRNA are an ideal source of potential biomarkers since urine is readily obtainable and non-invasive. We believe that microRNA may also be used as predictive biomarkers to identify more aggressive forms of prostate cancer (Jeon et al, JNCI 2019; Hoey et al., J Transl Med 2019). If proven, this may allow the early identification of patients with aggressive prostate cancer so that appropriate treatment decisions can be made. The figure below (Korpela, Vesprini, Liu SK in BJC 2015) illustrates this clinical potential.
Novel approaches to minimizing treatment-related toxicity
Most cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Radiotherapy side-effects diminish patients' quality of life, yet effective biological interventions for normal tissue damage are lacking. Protecting microvascular endothelial cells from the effects of irradiation is emerging as a targeted damage-reduction strategy. We have demonstrated that administration of targeted therapies for the vasculature can protect against endothelial cell perturbations and decrease the development of acute normal tissue damage. (figure below from Korpela and Liu, Radiation Oncol 2014)
Our research program has been generously sponsored by the following agencies: