An estimated 1,735,350 new cancer diagnosis and 609,640 cancer related deaths are predicted to occur in the United States in 2018. To improve patient prognosis, biomarkers are needed to identify cancer in early stages. When diagnosed at an early stage, cancer is more likely to respond to treatments and patients have a higher survival rate. Consequently, there is an ever-present need to identify biomarkers that can aid in the detection of cancer. Additionally, there is a paradigm shift in the field of cancer treatment towards immunotherapy. Traditional cancer treatments include chemotherapy, radiation, and hormone therapy and are not cancer-specific, which leads to bystander effects on the patient’s normal organs that often harm the patient and create unnecessary hardship. To alleviate this, immunotherapy utilizes a patient’s own immune cells to attack and destroy cancer cells via cancer-specific biomarkers. These biomarkers are ideally on the surface of cancer cells and absent from the patient’s normal cells to avoid healthy tissue destruction. With this new therapy, there is a recent push to find surface antigens for immunotherapy techniques.
This dissertation describes the characterization of HPRT as a diagnostic and therapeutic biomarker for the detection and possible treatment of hematological and solid malignancies. We describe the general upregulation of HPRT upon malignancy and show that this elevation in protein expression is independent of stage, which indicates that it would be useful as an early stage diagnostic companion tool. We have preliminarily linked the elevation in HPRT to a mutation in one of its prime transcription factors, p53. Specific mutation in p53 called Gain of Function mutations have shown to influence salvage pathway enzyme expression, and we have shown that mutations in p53 are relevant to the elevated levels of HPRT within several cancer types. In addition, we also found that HPRT associates significantly with the membrane of several cancer cell lines as well as patient samples. We found that HPRT has insignificant expression on normal cells, which suggests it may be useful as a targetable biomarker for immunotherapy. Throughout our analysis, we also determined that HPRT might have a role in immune regulation as an elevation of the protein correlates to the decrease of several pro-inflammatory genes involved in immune activation. The knowledge gained from the data presented in this dissertation have opened up new functions for HPRT outside of simple nucleotide production and have confirmed that HPRT has a unique role in cancer that has not been previously reported.
|Advisor:||O'Neill, Kim L.|
|Commitee:||Johnson, Steven, Piccolo, Stephen R., Robison, Richard A., Weber, K. Scott|
|School:||Brigham Young University|
|School Location:||United States -- Utah|
|Source:||DAI-B 80/02(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology, Health sciences|
|Keywords:||Cancer biomarker, HPRT1 or HGPRT, Hypoxanthine guanine phosphoribosyltransferase, Salvage enzyme|
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