Priyamvada Rai, Ph.D.
Assistant Professor of Medicine
Description of Research
Dr. Rai's major research interests center around the effect of reactive oxygen species (ROS) levels and oxidative DNA damage on tumor suppressor pathways. Many tumors are characterized by high levels of oxidative stress due to elevated metabolic activity, impaired mitochondrial function and ROS production through hyperactivation of oncogenic signaling. A number of chemotherapeutics have been developed to exploit this situation by selectively killing cancer cells via enhancement of existing oxidative stress and DNA damage. However, some aggressive types of cancers are resistant to such treatments and in many cases, chemoresistance has been linked to elevated levels of certain cellular antioxidants. There is a strong likelihood that many such redox-protective proteins, being structurally small and well-defined, may serve as potential drug targets for therapuetics that can selectively destroy transformed but not normal cells. Additionally, a causal role for this class of proteins in protecting against specific stress responses can also render them valuable prognostic or diagnostic markers, allowing for individualized treatment regimens.
Accordingly, Dr. Rai is interested in studying the mechanisms by which cancer cells combat oxidative stress and utilize redox and DNA repair pathways to evade tumor suppressor responses. A major focus of her studies is to develope molecular strategies to reactivate or enhance tumor suppressor pathways such as senescence and apoptosis in cancer cells, through modulation of cellular redox status and DNA repair mechanisms.
Dr. Rai is currently focusing on studying the pro-tumorigenic conributions of two functionally distinct redox-protective proteins, thioredoxin (TRX), a thiol protein, and human MutT Homolog (MTH1), the major mammalian 8-oxoGTPase. TRX is found at elevated levels in advanced prostate cancer whereas MTH1 expression is enhanced in ocogenic RAS-sustaining tumors. In order to assess their role in facilitating tumor progression and chemoresistance, Dr. Rai has developed gain-of-function/loss-of-function systems for use in cell and xenograft models. Her research encompasses a critically understudied area, namely the segregation of pleiotropic functions of ROS at a molecular level so their effect on tumor versus normal cells can be studied under specific contexts. The eventual goal of her research is to move the experimental findings from her laboratory towards optimizing existing treatment regimens and/or identifying therapeutic targets that can be utilized by oncologists to successfully treat cancer patients. To this end, Dr. Rai is developing collaborations with UM/SCCC pathologists in order to validate her findings in human tissue samples.
Dr. Rai believes there are many areas of synergy between her research interests and those of current SCCC members, which should facilitate several collaborative projects. Her research on the role of MTH1 in promoting tumor growth and progression in nonsmall cell lung carcinoma (NSCLC) is being done in collaboration with Dr. Wayne Balkan (Medicine), Dr. David Robbins (Thoracic Oncology/Surgery) and Dr. Dao Nguyen (Pathology). Dr. Rai's study on the role of TRX in promoting outgrowth of ADT-resistant prostate cancer cells is being done in collaboration with Dr. Carlos Perez-Stable (Medicine) and Dr. Merce Jorda (Pathology).
Highlights
- Developed cell-physiologic models to isolate the role of oxidative DNA damage from pleiotropic oxidant effects in tumor suppressor pathway activation and induction of cellular senescence.
- Showed that oxidative DNA damage to the nucleotide pool is a critical pathway for oncogenic Ras-mediated DNA double-strand breaks and oncogene-induced senescence.
- Demostrated novel contributions from a senescent microenvironment in promoting outgrowth of androgen-refractory prostate cancer cell subpopulations; developed an innovative method for generating androgen-refractory cell subpopulations.
Selected Cancer-Related Publications
Programs
Collaborating in the Multidisciplinary Research Program(s):