||Nima Sharifi, M.D.
||Internal Medicine - Hematology-Oncology
||Simmons Comprehensive Cancer Center
||Nima Sharifi, M.D.
This laboratory is focused on steroid metabolism and androgen receptor (AR) function as it relates
to prostate cancer. The first line of therapy for metastatic prostate cancer is androgen deprivation
therapy (ADT), often with gonadotropin-releasing hormone agonists (GnRH-A), which block the release
of gonadal testosterone (see figure below). Almost all prostate cancers express AR and require AR
for survival, growth and disease progression, which is why the majority of patients initially
respond well to ADT. However, metastatic disease eventually becomes resistant to ADT. Prostate
cancer that progresses in the face of ADT is termed castration-resistant prostate cancer (CRPC).
Several laboratories have shown that AR is somehow reactivated by a gain-of-function in CRPC and
is often driven by these tumors making their own androgens. Therefore, compounds that block the
synthesis of androgens or antagonize AR with novel mechanisms should be useful for the treatment
Specific goals of this laboratory are:
1) Elucidation of mechanisms of androgen receptor gain-of-function in prostate cancer that is resistant to ADT.
We have recently discovered that CRPC is unexpectedly driven by dihydrotestosterone
synthesis from adrenal precursors in a pathway that circumvents testosterone, instead requiring
5α-androstanedione, a previously underappreciated intermediate metabolite. This metabolic pathway
occurs commonly in all CRPC models and patient tumors tested (Chang, K-H, Li, R, Papari-Zareei, M,
Watumull, L., Zhao, YD, Auchus, RJ and Sharifi, N.
Proc Natl Acad Sci USA.
2011 Aug 16;108(33)13728-33). This work was cited as a "must read" by the
Faculty of 1000, was featured as a Research Highlight
in Nature Reviews Urology.
2011 Sept 8;8(9):470 and is cited as one of the Top Scientific Achievements for 2010-2011 by the Prostate
2) Devising novel methods of inhibiting androgen receptor transcription.
We have shown that blocking the enzyme 3β-hydroxysteroid dehydrogenase will block
the androgen-response from adrenal precursors and resultant CRPC growth. This work validates this
enzyme as a potential pharmacologic target for the treatment of CRPC (Evaul, K, Li, R, Papari-Zareei,
M, Auchus, RJ, and Sharifi, N.
Endocrinology. 2010. 151(8):3514-20).
We have also been involved in the identification of genetic mechanisms that may
help predict response or resistance to hormonal therapy. Specifically, these mechanisms are related
to germline single nucleotide polymorphisms (SNPs) in steroid transmembrane transporters that
predispose certain patients to acquiring castration-resistant disease more quickly than others.
The following publications refer to this work:
Sharifi, N., Hamada, A., Sissung, T., Danesi, R., Venzon, D., Gulley, J., Dahut,
W.L., and Figg, W.D. A polymorphism in a transporter of testosterone is a determinant of androgen
independence in prostate cancer. BJU Int. 2008;102(5):617-21.
Sharifi, N., Dahut, W.L. and Figg, W.D. The genetics of castration-resistant
prostate cancer: What can the germline tell us? Clin Cancer Res. 2008;14(15):4691-31.
Hamada, A., Sissung, T., Price, D.K., Danesi, R., Chau, C.H., Sharifi, N., Venzon,
D., Maeda, K., Nagao, K., Sparreboom, A., Mitsuya, H., Dahut, W.L., and Figg, W.D. A polymorphism
in SLCO1B3 affects testosterone transport and is a determinant of clinical outcome in patients
with prostate cancer. Clin Cancer Res. 2008;14:3312-8.
Yang M, Xie W, Mostaghel E, Sun T, Pomerantz M, Freedman M, Ross R, Regan M,
Sharifi N, Figg WD, Balk S, Brown M,. Oh WK, Lee GSM, Kantoff PW. SLCO2B1 and SLCO1B3 are
pharmacogenomic determinants of resistance to androgen deprivation therapy for prostate cancer.
J. Clin Oncol. 2011. Jun;29(18):2565-73.
The ultimate goal of our program is to develop more effective treatments for
prostate cancer. Toward this end, we will build on our prior collaborations and work with medicinal
chemists in devising novel compounds that block pathways that lead to AR function and tumor
progression. The following publications refer to work on the synthesis and characterization of
new compounds specifically designed for the treatment of prostate cancer:
Sharifi, N., Qi, J., Bane, S., Sharma, S., Li, R., Robey, R., Figg, W.D.,
Farrar, W.L., Kingston, D.G. Survivin is not induced by novel taxanes. Mol Pharm. 2010
Sharifi, N., Hamel, E., Lill, M., Prabhakar, R., Kane, C.T., Hossain, M.T.,
Jones, A., Dalton, J., and Farrar, W.L. A Bifunctional Colchicinoid that Binds to the
Androgen Receptor. Molecular Cancer Therapeutics. 2007;6:2328-37.
The figure below is a molecular model of one of these compounds bound to
AR (Sharifi, et al. Mol Cancer Ther. 2007).
Individuals interested in this work and the possibility of joining the laboratory
may inquire by contacting Dr. Sharifi.
(Molecular model of CCN bound to the androgen receptor)