Research overview

A major focus of our research program is the development of molecular strategies to activate tumor suppressor pathways such as senescence and apoptosis in cancer cells through modulation of cellular redox status and DNA repair mechanisms. These protective mechanisms are typically enhanced in aggressive cancers to overcome intrinsic oncogenic stress arising from elevated levels of reactive oxygen species (ROS). Cancer cells require ROS to mediate pro-malignant signaling pathways that drive hyperproliferation, survival, metabolic adaptation and metastasis. Normal cells typically are less reliant on these redox-protective mechanisms, and thus these mechanisms protect the oxidative "Achilles heel" of cancer.   We have uncovered several such tumor-promoting mechanisms in aggressive treatment-resistant cancers and are developing clinically actionable strategies against them. 

We conducted pioneering studies on the role of the nucleotide pool-cleansing 8-oxodGTPase, MTH1, in promoting RAS-driven tumorigenesis, and are continuing to investigate how to disable this pathway in an on-target and efficacious manner. We have shown that redox-protective mechanisms are required to protect hormone-refractory (castration-resistant) prostate tumors from oxidative stress produced by inappropriate androgen receptor activation, which is a hallmark of incurable prostate cancer.  This work is now evolving from the bench to the bedside. A new focus of our research is understanding the intersection between oxidative stress, inflammation, hypoxia and metabolic dysfunction as a driver of cancer emergence and progression, with the goal of repurposing safe, metabolism-modifying drugs. We use a spectrum of experimental methodology ranging from biochemical and biophysical techniques, cell and molecular biology, experimental therapeutics, preclinical models and bedside-to-bench specimens. 

Our work has been continuously funded since 2009 by the NIH, DOD Prostate Cancer Research Program, Florida Dept of Health and other private agencies. Rai lab trainees have received NCI F31, K12, CURE supplement and multiple presentation awards.