Departments of Medicine and Pharmacology & Therapeutics
Roswell Park Cancer Institute
Grace Cancer Drug Center, GB-63
Buffalo, NY 14263
Tel: 716-845-1201
Fax: 716-845-8857

E-mail: allen.gao@roswellpark.org

Dr. Allen C. Gao joined the faculty of Roswell Park Cancer Institute (RPCI) in 2002 as an Associate Member of Departments of Medicine and Pharmacology & Therapeutics and an Associate Professor of Division of graduate School at State University of New York at Buffalo. Dr. Gao comes to RPCI from University of Pittsburgh Cancer Institute and Department of Pathology where he served as an Assistant Professor from 1998-2002.
Dr. Gao earned his doctoral degree in Medicine from West China Medical University in 1985 and Ph.D. in Molecular Biology from University of Texas, M.D. Anderson Cancer Center in 1995. He completed postdoctoral training at the Johns Hopkins Oncology Center and Department of Urology.

The mission of Dr. Gao’s laboratory is to understand molecular changes associated with the progression of prostate cancer cells, with the goals of identification of diagnostic markers and potential therapeutic targets for prostate cancer.

Current Program
· Cytokine and androgen receptor signaling in androgen-independent prostate cancer
· Mechanisms of selenium chemoprevention and therapy
· Targeting cell signaling pathways in prostate cancer
· Cancer marker detection

I. Molecular mechanisms of prostate cancer transition from androgen-dependence to androgen-independence

Most prostate cancer patients respond initially to androgen ablation and antiandrogen therapy. However, virtually all patients will relapse due to acquisition of the growth of androgen-independent tumor cells. Unfortunately, there is currently no effective treatment for men with androgen-independent prostate cancer. The molecular changes in prostate cancer cells lead to the androgen-independent growth are incompletely understood. One of my research focuses is to understand intracelluar signaling regulations in prostate cancer cells leading to androgen-independence. We have identified cytokines such as IL-6 and IL-4 as inducers of androgen-independent progression of prostate cancer cells. The roles of signaling pathways such as Stat3, Akt and NF-êB induced by IL-6 and IL-4 have been subsequently demonstrated in androgen receptor activation and progression of androgen- independent prostate cancer. Our objective is to evaluate the anti-tumor efficacy of IL-6/Stat3 targeting strategies in prostate cancer in preclinical models with the ultimate aim of designing novel therapeutic strategies for prostate cancer.

II. Mechanisms of selenium chemoprevention and therapy
Prevention trials demonstrated that selenium reduced prostate cancer incidence by 50%, establishing selenium as a promising chemopreventive agent for prostate cancer. We made several novel discoveries on molecular basis of selenium anticancer activity in prostate and breast cancer. We found that selenium downregulates androgen receptor activation in prostate cancer cells, and differentially regulates the expression of estrogen receptors in breast cancer cells. These novel findings provide molecular basis and rationale for selenium chemoprevention and therapy for prostate cancer and breast cancer. Our goal is to elucidate the importance of alteration of androgen and estrogen signaling by selenium in prostate and breast cancer chemoprevention and therapy.

III. Understanding molecular changes associated with metastasis progression of prostate cancer cells

Acquisition of metastatic ability by prostate cancer cells involves the down-regulation in the expression of a series of metastasis suppressor genes. We have identified a series of human chromosome regions that contains potential metastasis / tumor suppressor genes by microcell-mediated chromosome transfer technique. These include human chromosome 11q14-21 and chromosome 19p13.1-13.2 regions. Using positional cloning and candidate gene approaches, several metastasis suppressor genes have been identified including cell surface gene CD44. We demonstrated that metastasis suppression by the standard CD44 isoform does not require binding of prostate cancer cells to hyaluronate, a major ligand of CD44. We are currently in the process to identify the physiological ligand(s) required for the metastasis suppression by CD44. In addition, we are trying to clone the potential tumor /metastasis suppressor gene(s) located on human chromosome 11q14-21 and 19p13.1-13.2.

IV. Identification of molecular markers for prostate cancer progression

Aggressive prostatic screening of men by the most common methods such as digital rectal exam, histological grade, and serum PSA has been proposed to detect prostatic cancer at a clinical stage when it is still localized within the gland and thus still curable by local surgery. However, the major limitation of these current screening methods is that they are unable to accurately predict the prognosis of localized prostate cancer. We recently identified CD44 as a metastasis suppressor gene for prostate cancer. CD44 expression is down regulated during human prostate cancer progression and this down-regulation is correlated with higher tumor grade, aneuploidy, and distant metastasis. In addition to these results indicating that CD44 expression may be used as a potential marker for prostate cancer progression, we have found methylation of the CD44 gene is associated with CD44 down-regulation and the progression of prostate cancer. It is our hypothesis that CD44 expression as well as CD44 promoter methylation can be utilized as an indicator or will add to the ability of currently accepted clinical markers to predict prostate cancer progression. Our future plan is to extend our study on the mechanisms of CD44 downregulation in prostate cancer and evaluate whether CD44 expression as well as CD44 promoter methylation can be served as a biological marker for prostate cancer aggressiveness. In addition, we are currently evaluating the levels of IL-6 in serum as an indicator for prostate cancer progression and therapeutic response.

Key publications:

• Lee SO, Nadiminty N, Wu XX, Lou W, Dong Y, Ip C, Onate SA, Gao AC. Selenium disrupts estrogen signaling by altering estrogen receptor expression and ligand binding in human breast cancer cells. Cancer Res 2005 (in press)
• Sun X, Frierson HF, Chen C, Li CL, Ran Q, Otto KB, Cantare BM, Vessella RL, Gao AC, Petros J, Miura Y, Simons JW, Dong JT. Frequent somatic mutations of the ATBF1 transcription factor in human prostate cancer. Nature Genetics, 2005 (in press)
• Tan DF, Wu XX, Hou M, Lee SO, Lou W, Wang JM, Janarthan B, Nallapareddy S, Trump DL, Gao AC. Interleukin-6 polymorphism is associated with recurrent prostate cancer. J. Urology 2005 (in press)
• Lee SO, Lou W, Qureshi KM, Mehraein-Ghomi F, Trump DL, Gao AC. RNA interference targeting Stat3 inhibits growth and induces apoptosis of human prostate cancer cells. Prostate 60:303-309, 2004
• Lee SO, Lou W, Johnson CS, Trump DL, Gao AC. Interleukin-6 protects LNCaP cells from apoptosis induced by androgen deprivation through the Stat3 pathway. Prostate 60: 178-186, 2004
• Dong Y, Lee SO, Zhang H, Marshall J, Gao AC, Ip C. Prostate specific antigen (PSA) expression is down-regulated by selenium through disruption of androgen receptor signaling. Cancer Res. 64 (1): 19-22, 2004
• Gao AC, Lou W, Dong JT, Barrett JC, Danielpour D, Isaacs JT. Defining regulatory elements in the human KAI1 (CD 82) metastasis suppressor gene. Prostate. 57(4):256-60, 2003
• Lee SO, Lou W, Hou M, Onate SA, Gao AC. Interleukin-4 enhances prostate specific antigen expression by activation of the androgen receptor and Akt pathway. Oncogene 22 (39), 7981-7988, 2003
• Lee SO, Lou W, Demiguel F, Hou M, Gao AC. Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells. Clin. Cancer Res., 9: 370-376, 2003
• Ni Z, Lou W, Dhir R, DeMiguel F, Lee SO, Grandis JR, Gao AC. Selective activation of members of the STATs family in prostate carcinomas. J. of Urology, 167: 1859-1862, 2002
• Dhir R, Ni Z, Lou W, DeMiguel F, Grandis JR, Gao AC. Stat3 activation in prostate carcinomas. The Prostate 51: 241-246, 2002
• DeMigeul F., Lou W., Lee S. O., Xiao X., Pflug B., Nelson J.B., and Gao AC. Stat3 enhances the growth of LNCaP human prostate cancer cells in intact and castrated male nude mice. The Prostate, 52: 1-7, 2002
• Ni Z.Y., Lou W., Leman E.S. and Gao AC. Inhibition of constitutively activated Stat3 signaling pathway suppresses growth of prostate cancer cells. Cancer Res. 60: 1225-1228, 2000
• Lou W., Ni Z.Y., Dyer K., Tweardy D.J., and Gao AC. Interleukin-6 induces prostate cancer cell growth accompanied by activation of Stat3 signaling pathway. The prostate, 42: 239-242, 2000
• Gao AC, Lou W., and Isaacs J.T. Enhanced GBX2 expression stimulates growth of human prostate cancer Cells via transcriptional up-regulation of the interleukin-6 gene. Clin. Cancer Res. 6: 493-497, 2000
• Lou W., Krill D., Dhir R., Becich M.J., Dong J.T., Frierson Jr. H. F., Isaacs J.T., and Gao AC. Methylation of the CD44 metastasis suppressor gene in human prostate cancer. Cancer Res. 59: 2329-2331, 1999
• Gao AC, Lou W., Ichikawa T., Denmeade S.R., Barrett J.C., Isaacs J.T. Suppression of the tumorigenicity of prostatic cancer cells by gene(s) located on human chromosome 19p13.1-13.2. The Prostate, 38: 46-54, 1999
• Gao AC, Lou W., Sleeman J.P., and Isaacs J.T. Metastasis suppression by the standard CD44 isoform does not require binding of prostate cancer cells to hyaluronate. Cancer Res., 58, 2350-2352, 1998
• Gao AC, Lou W., and Isaacs J.T. Down-regulation of homeobox gene GBX2 expression inhibits human prostate cancer clonogenic ability and tumorigenicity. Cancer Res., 58, 1391-1394, 1998
• Gao AC, Lou W., Dong J.T., and Isaacs J.T. CD44 is a metastasis suppressor gene for prostatic cancer located on human chromosome 11p13. Cancer Res., 57, 846-849, 1997
• Gleave M., Hsieh JT, Gao AC, Von Eschenbach AC, and Chung L.W.K. Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts, Cancer Res., 51, 3753-3761, 1991