State: Michigan

Prostate cancer is the second leading cause of cancer-related death in American men, resulting in 29,480 fatalities last year.  Death from prostate cancer most frequently occurs following the development of resistance to first- or second-line androgen deprivation therapy (ADT).  As such, there is a critical need to discover early drivers of ADT resistance to help guide selection of patients for earlier intensification of therapy.

The majority of cancer biomarker research has focused, to date, on protein-coding genes, which are pieces of DNA that are converted to RNA and then converted to protein.  Our team instead focuses on investigating long noncoding RNAs (lncRNAs), which are pieces of DNA that are converted to RNA but are not further converted to protein.  These lncRNAs, which function as RNAs instead of proteins, represent an underexplored, but crucial, area of cancer biology.  Our team recently identified over 45,000 novel lncRNAs, and determined that several lncRNAs, including one named SChLAP1, were better indicators of disease progression than conventional protein-coding genes.

Based on our initial findings, we hypothesize that lncRNAs serve as important mediators of treatment resistance in prostate cancer.  The goals of this application are: 1) to investigate the mechanism by which our top candidate lncRNA, SChLAP1, promotes ADT resistance and 2) to determine if SChLAP1 and other lncRNAs can serve as predictive biomarkers to guide therapy selection in patients with aggressive prostate cancer, using tumor samples from a phase III clinical trial.

T-cell cancers, collectively referred to as T-cell lymphomas (TCLs), are relatively rate, difficult to classify, and poorly understood.  Skin-associated TCLs, when clinically advanced, are often aggressive and resistant to standard chemotherapy regimens.  Therefore, these lymphomas are rarely curable with existing therapies.  We believe that the biology of normal (noncancerous) human T cells provides clues that may improve our understanding of TCL classification and treatment.  For example, normal T cells maybe classified into subsets that have distinct functions and are tightly controlled by a group of regulatory proteins.  One of those proteins, called GATA-3, regulates the growth and survival of a particular T-cell subset.  Therefore, we speculated that expression of GATA-3 and other proteins in TCL may determine important aspects of TCL biology and aid in TCL classification.  We found that approximately 60% of patients with the skin-associated TCLs express GATA-3.  These findings may have significant implications for the classification and treatment of TCL, as GATA-3 regulates the expression of genes that control the biology of these TCLs.  Therefore, we aim to identify the genes that are regulated by GATA-3 in these TCLs.  We anticipate that the knowledge gained from this work will aid in the development of novel therapeutic strategies that will improve outcomes for patients afflicted with these lymphomas.