Molecular Oncology and Biomarkers Program
Associate Professor, Biochemistry and Molecular Biology
Georgia Cancer Center
1410 Laney Walker Blvd. CN-2141
706-723-4137 office 706-446-0193 laboratory
Mechanism of prostate cancer metastasis; novel therapeutics for bone metastatic prostate cancer
Research projects in my laboratory are aimed at understanding the biology of tumor metastasis and developing effective prevention and treatment for this lethal disease. Current specific areas are outlined below.
Role of EPLIN in prostate cancer metastasis
We have demonstrated that the epithelial protein lost in neoplasm (EPLIN) is a suppressor of epithelial-to-mesenchymal transition (EMT) and tumor metastasis. We also identified a novel mechanism by which prostate cancer (PCa) cells gain invasiveness through EGF-induced EPLIN degradation. Our ongoing studies are to address the following questions: 1) How does EPLIN act as a signaling molecule to control EMT and PCa invasiveness, stemness and therapeutic resistance? 2) What is the role of EPLIN in distant metastatic sites such as bone? Is there a reverse process of EMT that involves re-expression of EPLIN for the colonization of disseminating cancer cells? What factor(s) can induce EPLIN and promote PCa growth in bone? 3) What is the prognostic value of EPLIN signaling in predicting clinical outcomes?
Novel targeted therapy for prostate cancer bone metastasis
We have been developing small-molecule compounds for the treatment of bone metastatic PCa. One such compound, BKM1740, was shown to effectively inhibit tumor growth in bone, reduce the level of prostate-specific antigen (PSA) and improve bone structure in animal models. We further identified a mechanism of action of BKM1740 as a survivin inhibitor in bone metastatic PCa cells. We are evaluating several BKM1740 derivatives (BKM1644, BKM1972, LG1980, LG1836, GH501) with improved anti-cancer efficacy using in vitro and in vivo models of PCa bone metastasis. We are also developing micelle nanoparticles of BKM compounds to improve their in vivo bioavailability and activity. We have developed a novel high-throughput screening platform for the discovery of novel cancer drugs. We have identified LG1980 as a lead compound that selectively induces apoptosis of aggressive PCa cells and retards tumor growth in mouse models. We discovered several FDA-approved drugs that effectively inhibit chemoresistant prostate cancer. We will repurpose these drugs as novel adjunct treatments to improve standard chemotherapy in bone metastatic PCa.
Prevent and treat prostate cancer metastasis with natural compounds
We identified EPLIN as a molecular target of genistein, a major isoflavone rich in soy products. We demonstrated that genistein increased EPLIN in clinical PCa specimens. We are investigating a novel mechanism wherein genistein upregulates EPLIN through a Snail-dependent mechanism and thereby prevents/retards metastasis.
We developed a novel flavonoid formulation (ProFine®) that shows potent anti-cancer activity and significantly enhances androgen deprivation therapy and chemotherapy. We are translating ProFine® into a dietary regimen that can be readily tested in clinical settings. We hope to provide patients with a safe, efficacious and cost-effective therapy for the management of both low-risk and advanced PCa.
Chen Y, Gera L, Zhang S, Li X, Yang Y, Mamouni K, Wu AY, Liu HY, Kucuk O, Wu D. Small molecule BKM1972 inhibits human prostate cancer growth and overcomes docetaxel resistance in intraosseous models. Cancer Lett., 446: 62-72, 2019.
Yang Y, Mamouni K, Li X, Chen Y, Kavuri S, Du Y, Fu H, Kucuk O, Wu D. Repositioning dopamine D2 receptor agonist bromocriptine to enhance docetaxel chemotherapy and treat bone metastatic prostate cancer. Mol. Cancer Ther., 17: 1859-1870, 2018.
Mamouni K, Zhang S, Li X, Chen Y, Yang Y, Kim J, Bartlett MG, Coleman IM, Nelson PS, Kucuk O, Wu D. A novel flavonoid composition targets androgen receptor signaling and inhibits prostate cancer growth in preclinical models. Neoplasia, 20: 789-799, 2018.
Yu X, Ghamande S, Liu H, Xue L, Zhao S, Tan W, Zhao L, Tang S-CH, Wu D, Korkaya H, Maihle NJ, Liu H. Targeting EGFR/HER2/HER3 with a three-in-one aptamer-siRNA chimera confers superior antitumor activity in HER2 expressing breast cancer. Mol. Therapy - Nucleic Acids, 10: 317-330, 2018.
Yang Y, Li X, Mamouni K, Kucuk O, Wu D. Mifepristone has limited activity to enhance the in vivo efficacy of docetaxel and enzalutamide against bone metastatic and castration-resistant prostate cancer. Anticancer Res., 37: 6235-6243, 2017.
Hooshfar S, Linzey MR, Wu D, Gera L, Mamouni K, Li X, Chen Y, Yang Y, Olorunyolemi O, Bartlett MG. Sensitive liquid chromatography/tandem mass spectrometry method for the determination of two novel highly lipophilic anticancer drug candidates in rat plasma and tissues. Biomed Chromatogr. doi: 10.1002/bmc.4064. 2017.
Zhang S, Gera L, Mamouni K, Li X, Chen Z, Kucuk O, Wu D. Inhibition of skeletal growth of human prostate cancer by the combination of docetaxel and BKM1644, an aminobisphosphonate derivative. Oncotarget, 7:27489-27498, 2016.
Liu HY, Yu X, Liu H, Wu D, She J-X. Co-targeting EGFR and survivin with a bivalent aptamer-dual siRNA chimera effectively suppresses prostate cancer. Sci. Rep., 6:30346, 2016
Wang Y, Zhang S, Iqbal S, Chen Z, Wang X, Wang YA, Liu D, Ritenour C, Kucuk O, Wu D. (2014) Pomegranate extract inhibits the bone metastatic growth of human prostate cancer cells and enhances the in vivo efficacy of docetaxel chemotherapy. Prostate. 74:497-508.
Zhang S, Wang Y, Chen Z, Kim S, Iqbal S, Chi A, Ritenour C, Wang YA, Kucuk O, Wu D, (2013) Genistein enhances the efficacy of cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer cells. Prostate. 73:1681-9.
Wu D, (2017) Flavonoid compositions for the treatment of cancer. U.S Patent Publication. US2017/0087125 A1.
Gera L, Stewart JM, Chung LWK, Wu D, (2010) Compositions and methods for treating bone cancer. U.S Patent Publication. US2010-0144678 A1.
Chung LWK, Huang W-C, Odero-Marah V, Wu D, Hsieh C-L, Zhau HE. (2007) Methods and compositions for the utilization and targeting of osteomimicry. U.S Patent Publication. US2007/0078085 A1.
Wu D, (2017) Epithelial protein lost in neoplasm (EPLIN): Beyond a tumor suppressor. Genes & Diseases. In press.
Chung LWK, Huang W-C, Sung S-Y, Wu D, Odero-Marah V and Zhau HE. (2007) Cancer-host interactions: a paradigm shift brings new understanding and new opportunities. In Prostate Cancer: Biology, Genetics and the New Therapeutics (2nd edition) (Chung LWK, Isaacs WB and Simons JW, eds), Humana, Totowa, NJ, 73-86.