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 demonstrated that select miRNA such as miR-95, miR-106a, and miR-191 are enriched in radiation resistant prostate cancer cells, and their overexpression effectively recapitulated the phenotype seen in resistant cells. 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.
Leveraging patient immune response in recurrent and aggressive prostate cancer
Once prostate cancer metastasizes to distant sites, it is considered incurable. Hormone therapy is the standard treatment for metastatic PCa; a subset of these men may have a further survival benefit from RT. However, there is currently a lack of biomarkers for early prediction of patient response post RT. We recently published our findings in which RT response in high-risk PCa patients displayed a distinct circulating immune cell signature that may have potential as an early predictive biomarker (Wang et al., Radiother Oncol. 2020). To further investigate this, we are measuring the activation of immune cells in patients who have spread of their cancer beyond the prostate, before and after radiation treatment. This will allow us to determine if high dose radiation to the prostate activates the immune system and reduces the rate of cancer progression. This work allows exploration of biomarkers for early prediction of response to radiation treatment using immune system activation.
Patient-derived cell lines for personalized therapy prediction
The treatment of metastatic prostate cancer has undergone a transformation with several large randomized clinical trials demonstrating a survival benefit with the addition of newer androgen axis targeting agents (ARATs), chemotherapy and radiotherapy. A major clinical limitation is our inability to accurately predict disease response in the context of an individual patient due to the lack of predictive biomarkers. This is further hindered by the lack of research models that represent the clinical heterogeneity of metastatic prostate cancer, including ethnic diversity, which impedes ongoing research. We have begun to successfully grow prostate cancer cells isolated from prostate core biopsies in our lab, and determine their sensitivity to clinically approved treatments. We believe that this approach will provide clinically-actionable information to guide therapy prediction while facilitating in depth studies about the underlying biology of advanced prostate cancer.
Our research program has been generously sponsored by the following agencies: