Nima Sharifi, M.D.

Staff
Director, Center for GU Malignancies Research

Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
Location:NB4-79
sharifn@ccf.org
Phone: (216) 445-9750
Fax: (216) 445-6269


Journal of Clinical Investigation Author’s Take


The first line of therapy for metastatic prostate cancer is androgen deprivation therapy (ADT), which suppresses testicular androgens that fuel cancer cells to grow and spread, including gonadal testosterone and intratumoral concentrations of the most potent androgen, dihydrotestosterone (DHT). While ADT is successful early on, cancer cells eventually become resistant and learn to make their own DHT (termed castration-resistant prostate cancer; CRPC). Dr. Sharifi’s lab investigates how CRPC cells make their own androgens, and how blocking these pathways may help treat the disease.

Specific areas of study in the Sharifi Laboratory include:

  • Genetic mutations and variations in androgen synthesis machinery. The Sharifi laboratory investigates how genetic anomalies enable cancer cells to evade ADT and produce their own hormones for fuel. The team discovered that a variation in the HSD3B1 gene—called HSD3B1 (1245C)—encodes an enzyme that is effectively hyperactive and plays an important role in this process. Dr. Sharifi has shown that this variant alters response to treatment and could be used as a predictive biomarker when designing treatment regimens. The lab is working to transition this discovery into the clinic by developing a blood test to detect the variant, and also collaborating on a clinical trial to test alternative treatments for prostate cancer patients who have the inherited variant.
  • How genetics affect treatment response. Dr. Sharifi’s team is interested in optimizing treatment regimens for all patient populations. His team found that patients with the HSD3B1 (1245C) variant metabolize abiraterone (a commonly prescribed prostate cancer drug) differently than men without the variant. They produce higher levels of a metabolite that shares a similar molecular structure with androgens, thereby “tricking” androgen receptors into turning on pro-cancer pathways. The lab is working to confirm these results and identify an effective alternative drug for these patients.


Description: Endocrine Axis and Hormonal Interventiuons in Prostate Cancer

 

Specific goals of this laboratory are:
1) Elucidation of metabolic and molecular mechanisms of prostate cancer resistance to hormonal therapies.
A) We have discovered the first mutation and genetic variant in a steroidogenic enzyme that is responsible for increasing dihydrotestosterone (DHT) synthesis from extragonadal (non-testicular) precursor steroids.  This mutation in 3βHSD1 occurs in tumors from patients with CRPC (Chang, K-H, et al. Cell. 2013; 15:1074-85).  This missense is also encoded by a very common (20-35% allele frequency) germline variant in the gene HSD3B1.  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 found that the same HSD3B1 genetic variant is a biomarker for treatment response in patients.  The HSD3B1 germline variant that encodes for the more active enzyme and drives higher levels of extra-testicular androgen synthesis confers worse outcomes after ADT in patients with advanced prostate cancer.  It also confers a tumor vulnerability to blocking extragonadal androgens.

2) Exploiting new mechanisms of existing drugs to improve treatment.

Surprisingly, the same HSD3B1 germline variant regulates metabolism of abiraterone (a steroidal drug) to multiple metabolites that we discovered.  Some of these metabolites have more potent anti-tumor activity, while others appear to stimulate androgenic pathways.

3) We are also investigating how these mechanisms of steroid metabolism drive other aspects of normal physiology and pathophysiologic processes not previously appreciated.
•         Stay tuned!

Individuals interested in this work and the possibility of joining the laboratory may inquire by contacting Dr. Sharifi.

Mohammad  Alyamani   Ph.D.
Mohammad Alyamani Ph.D.
Postdoctoral Fellow
Location:NB4-79
Phone:(216) 445-9751
alyamam@ccf.org
Mehdi  Baratchian  Ph.D.
Mehdi Baratchian Ph.D.
Postdoctoral Fellow
Location:NB4-25
Phone:(216) 445-9752
baratcm@ccf.org
Michael P. Berk  M.S.
Michael P. Berk M.S.
Lead Research Technologist
Location:NB4-90
Phone:(216) 445-9752
berkm@ccf.org
Kelsey  Bohn  Ph.D.
Kelsey Bohn Ph.D.
Postdoctoral Fellow
Location:NB4-15
Phone:(216) 445-9752
bohnk@ccf.org
Yoon-Mi  Chung  M.S.
Yoon-Mi Chung M.S.
Lead Research Technologist
Location:NB4-137
Phone:(216) 445-9751
chungy2@ccf.org
Di  Cui  MD, PhD
Di Cui MD, PhD
Research Scholar
Location:NB4-137
Phone:(216) 445-9751
cuid@ccf.org
Yijing  Dai  Ph.D.
Yijing Dai Ph.D.
Postdoctoral Fellow
Location:NB4-15
Phone:(216) 445-9752
daiy2@ccf.org
Aimalie  Hardaway  Ph.D.
Aimalie Hardaway Ph.D.
Postdoctoral Fellow
Location:NB4-15
Phone:(216) 445-9752
hardawa@ccf.org
Erik  Hedrick  Ph.D.
Erik Hedrick Ph.D.
Postdoctoral Fellow
Location:NB4-137
Phone:(216) 445-9751
hedrice@ccf.org
Hyun-Kyung   Ko  Ph.D.
Hyun-Kyung Ko Ph.D.
Postdoctoral Fellow
Location:NB4-137
Phone:(216) 445-9751
koh@ccf.org
Xiuxiu  Li  Ph.D.
Xiuxiu Li Ph.D.
Postdoctoral Fellow
Location:NB4-137
Phone:(216) 445-9751
lix7@ccf.org
Jianneng  Li  Ph.D.
Jianneng Li Ph.D.
Postdoctoral Fellow
Location:NB4-137
Phone:(216) 445-9751
lij7@ccf.org
Jeffrey  McManus  Ph.D.
Jeffrey McManus Ph.D.
Postdoctoral Fellow
Location:NB4-137
Phone:(216) 445-9752
mcmanuj@ccf.org
Mona  Patel  M.S.
Mona Patel M.S.
Senior Research Technologist
Location:NB4-137
Phone:(216) 445-9751
patelm2@ccf.org
Liang  Qin  Ph.D.
Liang Qin Ph.D.
Postdoctoral Fellow
Location:NB4-25
Phone:(216) 445-9752
qinl@ccf.org
Naveen  Sabhaswal  B.S.
Naveen Sabhaswal B.S.
CCLCM Medical Student
Location:NB4-137
Phone:(216) 445-9751
sabharn@ccf.org
Susan  Taylor  B.S.N.
Susan Taylor B.S.N.
Research Coordinator
Location:NB4-137
Phone:(216) 445-9751
taylors7@ccf.org
Lewis  Thomas  M.D.
Lewis Thomas M.D.
Clinical Fellow
Location:NB4-15
Phone:(216) 445-9752
thomasl5@ccf.org
Haijing  Zhang  M.D.
Haijing Zhang M.D.
Resident
Location:NB4-15
Phone:(216) 445-7220
zhangh3@ccf.org
Ziqi  Zhu  Ph.D.
Ziqi Zhu Ph.D.
Postdoctoral Fellow
Location:NB4-137
Phone:(216) 445-9751
zhuz@ccf.org

Current publications

Hearn JW, AbuAli G, Reichard CA, Reddy CA, Magi-Galluzzi C, Chang KH, Carlson R, Rangel L, Reagan K, Davis BJ, Karnes RJ, Kohli M, Tindall D, Klein EA, Sharifi N. HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol. 2016 Aug 26.  [Epub ahead of print]

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 May 25;533(7604):547-51.

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.