Arun Seth

Biography

Our laboratory characterizes breast and prostate cancer biomarkers that have diagnostic and therapeutic applications. Functional testing of these biomarkers is done to understand molecular mechanisms of human tumorigenesis. New molecular therapies arising from our mechanistic understanding of cancer development are tested in a clinically relevant patient-derived tumor xenografted mouse model.           Our laboratory characterizes breast and prostate cancer biomarkers that have diagnostic and therapeutic applications. Functional testing of these biomarkers is done to understand molecular mechanisms of human tumorigenesis. New molecular therapies arising from our mechanistic understanding of cancer development are tested in a clinically relevant patient-derived tumor xenografted mouse model.          

Research Interest

CANCER BIOMARKERS Molecular investigation of variations in the incidence of cancer in diverse regions and populations bearing unique genetic mutations has made it clear that different cancers have separate and distinct mutations that underlie clinical similarities. Our laboratory can rapidly screen samples for somatically acquired mutations found in human cancers that have known biological functions. Panels of known mutations with strong clinical significance are used to classify patient tumors for individualized prediction of outcome and treatment decisions. Family histories and DNA/RNA samples from affected and unaffected families are essential to linking specific genetic changes to clinical disease. We apply these cancer gene panels for Canadian breast and thyroid cancer patients, as well as tumor samples from collaborators around the world. PROSTATE CANCER BIOMARKERS microRNA (miRNA) markers are increasingly important as independent prognostic markers for prostate cancer progression or recurrence after surgical treatment. We are searching for miRNAs that distinguish between patients with lethal or indolent disease in order to improve how patients are selected for treatment. Some miRNAs are already known to be associated with aggressive forms of prostate cancer that develop and progress to metastasis. When those microRNAs are detected at an early stage in prostate cancer they become a screening tool for early stage prostate cancer. We used whole genome analysis of microRNA expression in tumors from patient groups with lymph node metastasis or recurrence after radical prostatectomy. Early results have yielded a novel panel of five miRNAs that is predictive of which patients will develop recurrent prostate cancer after surgical treatment. With functional testing we found that ectopic expression of two of those miRNAs in prostate cancer cell lines enhanced motility and invasiveness, suggesting direct involvement in metastatic progression. Effects of overexpressing those miRNAs on tumor development are being investigated in our NOD/SCID mouse xenograft model of human prostate cancer.  Extension of this analysis to biopsy samples is underway, providing a less invasive option for monitoring of prostate cancer in patients. PROSTATE CANCER THERAPY A second avenue of investigation is testing ETS gene translocations as biomarkers of prostate cancer and potential therapeutic targets. In some prostate cancers, we have identified that part of the TMPRSS2 gene that is normally activated by androgen is translocated upstream of a cancer related ERG gene. Thus the resulting TMPRSS2:ERG fusion gene becomes abnormally active in response to androgen, but only in prostate cancer not in benign tissue. It is therefore a potential marker of malignancy. Our future research is designed to test whether screening for this gene in patient blood and tumor samples could predict progression and metastasis of prostate cancer that will be of great utility in aiding clinical management for cancer patients. We have been investigating the status of TMPRSS2:ERG fusion and associated target genes, whose expression is dysregulated in many prostate cancers. We characterized an ERG specific antibody and used it to show, perhaps for the first time, that ERG protein is in fact expressed from the ERG fusion mRNA. This is a key clinical testing breakthrough demonstrating that immunohistochemistry can be used to detect ERG overexpression in archived tumor samples. miRNAs are effective regulators of gene expression that have a significant role in the pathogenesis of prostate and various other cancers. A high prevalence of aberrant miRNA expression in prostate cancer suggests they can be used as biomarkers and next generation of molecular anticancer therapeutics. Characterizing mechanisms by which miRNAs control the translation of androgen induced ERG overexpression is currently done in our lab. We have already identified several miRNAs that interact with the 3′UTR of the ERG mRNA, likely affecting its expression in prostate tumors. Candidate miRNAs that reduce ERG expression are being tested in our mouse model of human prostate cancer in order to regress or eliminate xenografted tumors. BREAST CANCER THERAPY One of our goals is to develop new therapeutics for treatment and cure of molecularly defined subsets of breast cancer. A current focus of that work is on recombinant IGFBP7 protein as candidate for preclinical testing. A member of the insulin-like growth factor binding protein family, we have studied IGFBP7 in breast cancer for many years, finding it to be expressed at high levels in benign breast tumors, and that patients with high levels of IGFBP7 in their tumors have a better prognosis.