The overall age-adjusted mortality rate for prostate cancer has not decreased markedly since 1930. Although the good news is the proportion of men with prostate cancer surviving up to 5 years has increased from 67 to 93% over the last 20 years, attributed to increasing early detection (American Cancer Society Statistics). However, the 5 year survival rate for advanced prostate cancer is 33% and new therapies are desperately needed for this stage of the disease. Androgen Deprivation Therapy (ADT) for advanced prostate cancer involves reduction of androgen by either surgical or chemical castration, leading to tumor shrinkage, PSA lowering and pain reduction. Tumor regrowth and subsequent mortality in the presence of these lowered androgen levels is a serious problem.
The re-growth of ADT-resistant prostate cancer may be
caused by several mechanisms. Two of the mechanisms most relevant
to our projects are up regulation of Androgen Receptor (AR) regulated pathways,
enabling a growth response in lowered androgen levels (1,2). Secondly
the up regulation of MAPK-mediated growth factor pathways can lead to enhanced
growth in the milieux of reduced androgen (3-5). Both AR and growth
factor pathways can pass through the Ras protein to activate the MAPK enzyme
(6) a major contributor to cell growth. MAPK activation is associated
with advanced prostate cancer. Weber and colleagues (7) found that
about 60% of high Gleason score tumors had very high activated MAPK and
80% of tumors with low Gleason score had very low MAPK activity in a study
of 82 tumor samples. Price and colleagues (5) compared localized
prostate cancer to autopsied normal prostate tissue and found a significant
and consistent increase in MAPK activity in In a study of 22 prostate cancer
samples, Blackledge and colleagues (3) reviewed the early clinical
trial literature for novel therapies of advanced prostate cancer.
They found that inhibition of growth factor pathways, expected to inhibit
MAPK activity, induce positive responses in patients with advanced prostate
cancer.
Our Projects
1) The mechanisms of resistance to ADT.
We use models of cells that have developed resistance to ADT. We are examining signaling pathways in these cells to determine why the cells are growing in conditions that normally would suppress growth.
2) Development of therapies for advanced prostate cancer.
Based on published observations (above) that advanced
prostate cancers have upregulated signal transduction pathways, we and
others have proposed that inhibition of these pathways might be effective
prostate cancer therapies. We are conducting pre-clinical trials
of novel agents to determine their effectiveness against cellular models
of advanced prostate cancer. Our ultimate aim is to get effective
drugs into the clinic.
REFERENCE FOR THIS PAGE
(1) Jenster, G. Ligand-independent activation of the androgen
receptor in prostate cancer by growth factors and cytokines, J Pathol.
191: 227-8., 2000.
(2) Montgomery, J. S., Price, D. K., and Figg, W. D.
The androgen receptor gene and its influence on the development and progression
of prostate cancer, J Pathol. 195: 138-46., 2001.
(3) Barton, J., Blackledge, G., and Wakeling, A. Growth
factors and their receptors: new targets for prostate cancer therapy, Urology.
58: 114-22., 2001.
(4) Gioeli, D., Mandell, J. W., Petroni, G. R., Frierson,
H. F., Jr., and Weber, M. J. Activation of mitogen-activated protein kinase
associated with prostate cancer progression, Cancer Res. 59: 279-84., 1999.
(5) Price, D. T., Rocca, G. D., Guo, C., Ballo, M. S.,
Schwinn, D. A., and Luttrell, L. M. Activation of extracellular signal-regulated
kinase in human prostate cancer, J Urol. 162: 1537-42., 1999.
(6) Migliaccio, A., Castoria, G., Di Domenico, M., de
Falco, A., Bilancio, A., Lombardi, M., Barone, M. V., Ametrano, D., Zannini,
M. S., Abbondanza, C., and Auricchio, F. Steroid-induced androgen receptor-oestradiol
receptor beta-Src complex triggers prostate cancer cell proliferation,
Embo J. 19: 5406-17., 2000.
(7) Gioeli, D., Mandell, J. W., Petroni, G. R., Frierson,
H. F., Jr., and Weber, M. J. Activation of mitogen-activated protein kinase
associated with prostate cancer progression, Cancer Res. 59: 279-84., 1999.