Modulation of Therapeutic Response and Pharmacokinetics of 5-FU by P53 through Repression of the Pyrimidine Catabolic Gene Dihydropyrimidine Dehydrogenase (DPYD)
Abstract
Principal Investigator: Mr. Prashanth Gokare is currently carrying out his Ph.D. degree from Penn State University at Fox Chase Cancer Center in Philadelphia under the mentorship of Dr. Wafik S. El-Deiry. He is currently pursuing his doctoral thesis on mechanism of resistance to 5-FU, a widely used chemotherapeutic drug especially in the treatment of colorectal cancer. He has extensive knowledge on 5-FU metabolism genes and its regulation. His primary contribution in the field of colorectal biology has led to identification of the control of a key drug-metabolizing gene by the tumor suppressor p53 (a cancer checkpoint gene). While pursuing his Ph.D. degree, Mr. Gokare s efforts have borne fruition and have resulted in three other publications (all submitted to peer-reviewed journals) in the field of colorectal cancer therapeutics. He was also recently invited for short talk at the American Association for Cancer Research Conference of Cancer Metabolism in June this year to present his work and was granted the scholar in training award for his contribution as young scientist. Mr. Gokare would like expand his knowledge, interest, and career in cancer therapeutics to advance science from bench to bedside. The Horizon Award will provide a right platform for his goals towards translating into an independent cancer researcher. The award will not only advance is current work, but will also provide him the opportunity to work and interact with a diverse group of clinicians and scientists so he can acquire the necessary skills and knowledge to become a successful cancer researcher. Clinical Relevance/Application of the Proposed Work: Colorectal cancer (a Fiscal Year 2015 [FY15] Peer Reviewed Cancer Research Program [PRCRP] Focus Area) is the second most leading cause of cancer-related death in the United States. A recent report from the Automated Central Tumor Registry (ACTR) of the Department of Defense highlights colorectal cancer to be the second most common cancer in terms of incidence only second to testicular and prostate cancer in men and breast and cervical cancer in women. The current mainstay of the colorectal cancer treatment for decades now is the use of the chemotherapeutic drug 5-Fluorouracil (5-FU). Patients who undergo 5-FU chemotherapy suffer from several toxic side effects and often with poor response, leading to decreased quality of life. This often arises with the inability of current methodologies to carefully assess individual response to the amount of drug administered. The proposed work explores tumor suppressor p53 and Dihydropyrimidine dehydrogenase (DPYD) (enzyme responsible for breakdown of 5-FU) as a clinical biomarker for 5-FU response and toxicity. Recent observations in the clinic and our own studies together identify p53 and DPYD as strong candidates for predictor biomarkers of response. If our study stands true, it will establish a novel interaction between p53 and DPYD whose status could directly impact the way patients are currently treated. The study can be quickly translated to the clinic where patients can be routinely monitored for p53 status (polymorphism and mutations) along with DPYD activity. Presently, few patients are monitored for certain polymorphisms in DPYD gene, which completely do not explain the variation in response to the drug. Further, the study will provide a rationale for therapeutic monitoring of 5-FU plasma levels generally achieved in 20%-30% of the patients. Previous studies from our lab have shown that pharmacokinetic monitoring of 5-FU in the plasma in colorectal patients significantly improved the disease-free survival as well as reduced toxicity in patients who were in stage II/III of the disease. In this era of precision medicine, treatment approaches based on individual characteristics will provide the greatest benefits tailored specifically to each patient. Another novel aspect of the study is that the interaction between p53 and DPYD would a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610231
Entities
People
- Prashanth Gokare
Organizations
- United States Army