Our 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), which blocks the release of gonadal testosterone and suppresses intratumoral concentrations of the most potent androgen, dihydrotestosterone (DHT). However, metastatic disease eventually becomes resistant to ADT. Prostate cancer that progresses in the face of ADT is termed castration-resistant prostate cancer (CRPC) and is frequently driven by tumors acquiring the capability of making their own DHT. We study how this process occurs. Our most important discoveries include identification of the first mutation in the androgen synthesis machinery that is responsible for increasing DHT synthesis in CRPC, demonstration that DHT synthesis in patients with CRPC follows a pathway that circumvents testosterone, and the identification of abiraterone metabolites that impinge upon the androgen axis and regulate treatment response. We are currently applying these findings to the study of CRPC as it occurs in patients.
I am a medical oncologist and physician-scientist with a sole clinical and scientific focus on prostate cancer. Androgens are a driving force in prostate cancer disease progression. As such, for seven decades the upfront treatment of advanced prostate cancer has been depriving tumors of this driving force (androgens). Unfortunately, treatment resistance almost always occurs in metastatic prostate cancer, through tumors making their own androgens. We study how these tumors make their own androgens with a view toward blocking these pathways with the development of new treatment modalities. Our hope is that these discoveries will eventually be brought to the clinic for the benefit of men with prostate cancer. We work closely with our colleagues at Cleveland Clinic and other collaborators from around the world to make this happen.
Li, Z., Alyamani, M., Li, J., Upadhyay, S., Balk, S.P., Taplin, M-E., Auchus, R.J., Sharifi, N. Redirecting abiraterone metabolism to biochemically fine tune prostate cancer anti-androgen therapy. Nature. 2016 In press.
Li, Z., Bishop, A., Alyamani, M., Garcia, J.A., Dreicer, R., Bunch, D., Liu, J., Upadhyay, S.K., Auchus, R.J., Sharifi, N. Conversion of abiraterone to D4A drives antitumor activity in prostate cancer. Nature. 2015 Jul 16;523:347-51.
Goodwin, J.F., Kothari, V., Drake, J.M., Zhao, S., Dylgjieri, E., Dean, J.L., Schiewer, M.J., McNair, C., Magee, M.S., Den, R.B., Zhu, Z., Graham, N.A., Vashisht, A.A., Wohlschlegel, J.A., Graeber, T.G., Davicioni, E., Sharifi, N., Witte, O.N., Feng, F.Y., Knudsen, K.E. DNA-PK mediated transcriptional regulation drives tumor progression and metastasis. Cancer Cell. 2015 Jul 13;28(1):97-113.
Sharifi, N. Steroid receptors aplenty in prostate cancer. N Engl J Med. 2014 Mar 6;370(10):970-1.
Chang, K-H., Li, R., Kuri, B., Lotan, Y., Roehrborn, C.G., Liu, J., Vessella, R., Nelson, P., Kapur, P., Guo, X., Mirzaei, H., Auchus, R.J., Sharifi, N. A gain-of-function mutation in DHT synthesis in CRPC. Cell. 2013 154(5):1074-84.
Chang, K-H and Sharifi, N. Prostate cancer – from steroid transformations to clinical translation. Nature Reviews Urology. 2012 Dec;9(12):721-4.
Li, R, Evaul, K, Sharma, KK, Chang, K-H, Yoshimoto, J, Liu, J, Auchus, RJ, Sharifi, N. Abiraterone inhibits 3β-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in CRPC. Clin Cancer Res. 2012 Jul 1;18(13):3571-9.
Chang, K-H, Papari-Zareei, Watumull, L, Zhao, YD, Auchus, RJ, Sharifi N. Dihydrotestosterone synthesis bypasses testosterone to drive CRPC. Proc Natl Acad Sci USA. 2011 Aug 16;108(33):13728-33.
I am a medical oncologist and physician-scientist with a sole clinical and scientific focus on prostate cancer. This includes clinical treatment, clinical trials, investigation of resistance to hormonal therapies and the identification of new targets for the development of better treatments. In addition to my laboratory research program in the Department of Cancer Biology, I hold appointments in the Glickman Urological and Kidney Institute and the Department of Solid Tumor Oncology of the Taussig Cancer Institute. My goal, simply stated, is to advance the state of the art for the management and treatment of men with prostate cancer. My belief is that this is best done by making fundamental discoveries using interdisciplinary clinical and scientific approaches in a collaborative environment with colleagues who have the same ultimate goals.
Our 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 of CRPC.
Specific goals of this laboratory are:
A) We have recently discovered the first mutation in a steroidogenic enzyme that is responsible for increasing dihydrotestosterone (DHT) synthesis from precursor steroids. This mutation in 3βHSD1 occurs in tumors from patients with CRPC and in a preclinical model of resistance to abiraterone (Chang, K-H, et al.Cell. 2013; 15:1074-85), suggesting that tumors that harbor this mutation may be susceptible to treatment with pharmacologic inhibitors of 3βHSD1 and that detection of this mutation may serve as a companion biomarker. This work was cited in a "Research Watch" in Cancer Discovery and a "Research Highlight" in Nature Reviews Urology. See figure below from this manuscript for a graphical summary.
B) We discovered that CRPC is unexpectedly driven by DHT 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 Cancer Foundation (see figure below).
We have shown that abiraterone, which is a newly approved drug for the treatment of CRPC, blocks the enzyme 3β-hydroxysteroid dehydrogenase, along with its known target. This work devises a new clinical strategy to improve initial treatment response to abiraterone or to reverse therapy resistance (Li, R, Evaul, K, Sharma, KK, Chang, KH, Yoshimoto, J, Liu, J, Auchus, RJ and Sharifi, N. Clin Cancer Res. 2012;18(13):3571-9).
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.
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 figure below is a molecular model of an experimental compound bound to AR that we have described (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.