Research studies have demonstrated that nutrients, including genistein, an isoflavones, could induce apoptosis, suppress the formation and growth of prostate cancer (CaP). As these isoflavones are structurally and funcrtionally similar to estrogen, they are considered phytoestrogens. We recently demonstrated that androgens and estrogens repressed the FOXO1 activity in prostate cancer cells, a process that is independent of the PKB/AKT-mediated FOXO1 phosphorylation. The repression is AR and ERa-dependent, respectively, and mediated through the formation of receptor-FOXOl protein complex. Our preliminary data thus demonstrates that FOXO1 as a novel target for genistein in CaP cells. In two recently completed phase II trials, we observed significant increases in plasma isoflavones with treatment (40,60, 80 mgs) without producing toxicity. Significant increases in serum total estradiol and lower percentage of prostate cancer cells expressing Ki-67, post treatment were observed in the 40 mgs treatment arm. Based on these studies, we hypothesize that 40 mgs purified isoflavones administered to men in the presurgical period (from biopsy to prostatectomy) for a 4-6 week period will significantly increase plasma isoflavone levels and serum estradiol resulting in decrease in markers of prostate cancer progression as indicated by changes in validated CaP progression markers, compared with men receiving a placebo, without producing toxicity. We propose that the primary pathway by which isoflavones will suppress prostate tumorigenesis is mediated by the ERfS, which can be suppressed by ERa in prostate cancer cells such that ERB is decreased. In addition, genistein will inhibit androgen signaling through FOXO1 by down regulating AR expression, resulting in apoptosis and leading to the suppression of prostate carcinogenesis. Based on this observation of mechanism of action, we hypothesize that the effectiveness of isoflavones to modulate prostate carcinogenesis will be significantly higher in AA men compared to Caucasian men. To test this hypothesis, our specific aims will be to randomize and treat 130 AA men and 130 Caucasian men (n=260;65/arm) diagnosed with clinically localized CaP to receive purified isoflavones at a dose of 40 mgs per day or placebo in the presurgical period for 4-6weeks and evaluate compliance, symptoms, toxicity, and markers of disease progression and treatment-related decrease in expression of the androgen receptor and increased expression of FOXO1 and its target genes in prostate cancer patients and whether the changes in the AR-FOXO axis is more profound in African American patients as compared to Caucasian men.
Our study is the first phase II clinical trial to examine and compare the effect and safety of isoflavones on prostate cancer progression in African American and Caucasian men, with a greater relevance to AA men. If the safety and the effectiveness of isoflavones on modulation of prostate cancer progression are demonstrated in the proposed trial, this agent can be developed into a drug for the prevention of CaP in high-risk populations and specifically target AA men with a family history of CaP.
|Mogos, Mulubrhan F; Salemi, Jason L; Sultan, Dawood H et al. (2015) Trends in Cervical Cancer Among Delivery-Related Discharges and its Impact on Maternal-Infant Birth Outcomes (United States, 1998-2009). Open Nurs J 9:42-50|
|Sultan, Dawood H; Rivers, Brian M; Osongo, Ben O et al. (2014) Affecting African American men's prostate cancer screening decision-making through a mobile tablet-mediated intervention. J Health Care Poor Underserved 25:1262-77|
|Rivers, Brian M; Bernhardt, Jay M; Fleisher, Linda et al. (2014) Opportunities and challenges of using technology to address health disparities. Future Oncol 10:519-22|
|Wilson, Danyell S; Dapic, Virna; Sultan, Dawood H et al. (2013) Establishing the infrastructure to conduct comparative effectiveness research toward the elimination of disparities: a community-based participatory research framework. Health Promot Pract 14:893-900|
|Gwede, Clement K; Ashley, Atalie A; McGinnis, Kara et al. (2013) Designing a community-based lay health advisor training curriculum to address cancer health disparities. Health Promot Pract 14:415-24|
|Mogos, Mulubrhan F; Rahman, Shams; Salihu, Hamisu M et al. (2013) Association between reproductive cancer and fetal outcomes: a systematic review. Int J Gynecol Cancer 23:1171-7|
|Mogos, Mulubrhan F; Salihu, Hamisu M; Aliyu, Muktar H et al. (2013) Association between reproductive cancer and fetal outcomes: a population-based study. Int J Gynecol Cancer 23:218-26|
|Pidala, J; Craig, B M; Lee, S J et al. (2013) Practice variation in physician referral for allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 48:63-7|
|Green, B Lee; Rivers, Desiree A; Kumar, Nagi et al. (2013) Establishing the infrastructure to comprehensively address cancer disparities: a model for transdisciplinary approaches. J Health Care Poor Underserved 24:1614-23|
|Salihu, Hamisu M; Salinas, Abraham; Mogos, Mulubrhan (2013) The missing link in preconceptional care: the role of comparative effectiveness research. Matern Child Health J 17:776-82|
Showing the most recent 10 out of 24 publications