Research Focus

Dr. William St. Clair is a physician-scientist with principal interested in advancing the efficacy of radiation therapy for the treatment of cancers. Thus, the goal of his research project is to investigate novel approaches that can enhance cancer therapeutic efficacy while protecting normal tissues against the side effects of radiation therapy. Prostate cancer is the most frequently diagnosed cancer in men and radiation therapy is used to treat early stage and inoperable, locally advanced prostate cancer. Although current radiation therapeutic strategies are very effective and successful in treating the initial cancer, treating patients who have unfavorable tumors remains a major concern. A goal of his research projects is to use mechanistic based, bench to bedside approaches to obtain novel insights into the mechanisms of prostate cancer resistant to radiation therapy. We have identified the alternative pathway of the nuclear factor kappa beta (NF-κB) as a major contributor to prostate cancer growth and progression. We have demonstrated that: 1) aggressive prostate cancers have high nuclear RelB, a member of the alternative pathway of NF-κB; 2) suppression of RelB in androgen independent-aggressive prostate cancer cells results in reduction of interleukin 8 (IL8) levels in tumor cells and reduced tumor growth in vivo; 3) overexpression of RelB in androgen responsive prostate cancer cells results in enhanced tumor growth and production of IL8 but reduced prostate specific androgen (PSA) production; and 4) suppression of RelB nuclear translocation enhances radiation sensitivity of prostate cancer. Based on these important findings, we hypothesize that RelB regulates prostate cancer response to radiation via a NF-κB switch to activate expression of IL8 and suppress expression of PSA in prostate cancer cells. This study is design to develop practical predictive measures for prostate cancer diagnostic, treatment planning and surveillance. The second goal of Dr. William St. Clair research program is to identify novel mechanisms that could lead to the development of specific measures for effective treatment of aggressive prostate cancers. A growing body of data indicates that cancer has an elevated oxidative stress level compared to normal tissue. We have recently identified Parthenolide (PN), a sesquiterpene lactone derived from the leaves of the traditional herbal medicine feverfew, as having a differential effect on the sensitivity of prostate cancer cells versus normal prostate epithelial cells to ionizing radiation. PN increase superoxide production in cancer cells via an NADPH oxidase dependent activation of the PI3K-AKT pathway, resulting in down-regulation of the FOXO3-activated antioxidants; inactives NF-κB transcriptional function; and inhibits Keap 1 dependent NRF2 activation in cancer cells but activates NRF2 function in normal cells. We are conducting a series of experiments to test this novel concept in an experimental therapeutic setting and investigate the mechanisms linking RelB levels to oxidative stress overload and invasive properties of prostate cancer.

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