Director, Center for GU Malignancies Research
Location: Cleveland Clinic Main Campus
Broadly, our group studies fundamental metabolic processes that govern prostate cancer progression. Our discoveries have revealed that cancer engages what are usually normal physiologic processes or their variants and redirects them for the purposes of tumor progression and treatment resistance. Overall, we have found that the biotransformation of steroids in peripheral tissues (e.g., prostate cancer) from inactive to active steroids (e.g., DHT), and vice versa, regulate not only broad transcriptional programs, but also and more importantly multiple clear clinical phenotypes in humans.
The first line of therapy for metastatic prostate cancer is androgen deprivation therapy, 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). Our lab investigates how CRPC cells make their own androgens, and how blocking these pathways may help treat the disease.
Education & Fellowships
Fellowship - National Cancer Institute
Bethesda, MD USA
Residency - Yale-New Haven Hospital
New Haven, CT USA
Medical Education - University of Pittsburgh School of Medicine
Pittsburgh, PA USA
Undergraduate - Virginia Polytechnic Institute and State University
Blacksburg, VA USA
Awards & Honors
Specific areas of study in the Sharifi Laboratory include:
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.
View publications for Nima Sharifi, MD
(Disclaimer: This search is powered by PubMed, a service of the U.S. National Library of Medicine. PubMed is a third-party website with no affiliation with Cleveland Clinic.)
Li, J, Berk, M, Alyamani, M., Sabharwal, N, Goins, C, Alvarado, J, Baratchian, M, Zhu, Z, Stauffer, S, Klein, E, Sharifi, N. Hexose-6-phosphosphate dehydrogenase blockade reverses prostate cancer drug resistance in xenograft models by glucocorticoid inactivation. Science Translational Medicine. 2021 May 26;13(595):eabe8226.
Gaston, B, Markozkina, N, Newcomb, DC, Sharifi, N, Zein, J. Asthma risk among individuals with androgen receptor deficiency. JAMA Pediatrics. 2021 Apr 12:e210281.
Sharifi, N. Kicking the dirt in the hunt for discoveries: pursuing a career in biomedical science. Nature Reviews Urology. 2021 Mar;18(3):129-130.
Desai, K, McManus, JM, Sharifi, N. Hormonal therapy for prostate cancer. Endocrine Reviews. 2021 May 25;42(3):354-373.
Hofmann, MR, Hussain, M, Dehm, SM, Beltran, H, Wyatt, AW, Halabi, S, Sweeney, C, Scher, HI, Ryan, CJ, Feng, FY, Attard, G, Klein, E, Miyahira, AK, Soule, HR, Sharifi, N. Prostate Cancer Foundation hormone-sensitive prostate cancer biomarker working group meeting summary. Urology. 2020 Dec 26:S0090-4295(20)31519-3.
Hearn, J, Sweeney, C, Almassi, N, Reichard, CA, Reddy, CA, Hobbs, B, Jarrard, DF, Chen, Y-H, Dreicer, R, Garcia, JA, Carducci, MA, DiPaola, RS, Sharifi, N. HSD3B1 genotype and clinical outcomes in metastatic castration-sensitive prostate cancer. JAMA Oncology. 2020 Apr 1;6(4):e196496.
Alyamani, M, Li, J, Patel, M, Taylor, S, Nakamura, F, Berk, M, Przybycin, C, Posadas, EM, Madan, RA, Gulley, JL, Rini, B, Garcia, J, Klein, E, Sharifi, N. Deep AR suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure. Annals of Oncology. 2020. Mar;31(3):369-376.
Zein, J, Gaston, B, Bazeley, P, DeBoer, MD, Igo, RP, Bleecker, ER, Meyers, D, Comhair, S, Marozkina, NV, Cotton, C, Patel, M, Alyamani, M, Xu, W, Busse, W, Calhoun, WJ, Ortega, V, Hawkins, GA, Castro, M, Chung, KF, Fahy, JV, Fitzpatrick, AM, Israel, E, Jarjour, NN, Levy, B, Mauger, D, Moore, WC, Noel, P, Peters, SP, Teague, WG, Wenzel, SE, Erzurum, SC, Sharifi, N. HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma. Proc Natl Acad Sci USA. In press.
Auchus, RJ and Sharifi, N. Sex hormones and prostate cancer. Annual Review of Medicine. 2019 Oct 15 [Epub ahead of print]
Alyamani, M., Emamekhoo, H., Park, S., Taylor, J., Almassi, N., Upadhyay, S., Tyler, A., Berk, M.P., Hu, B., Hwang, T.H., Figg, W.D., Peer, C.J., Chien, C., Koshkin, V.S., Mendiratta, P., Grivas, P., Rini, B., Garcia, J., Auchus, R.J., Sharifi, N. HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer. J. Clinical Investigation. 2018 Aug 1;128(8):3333-3340.
Ko, H-K., Berk, M., Chung, Y-M., Willard, B., Bareja, R., Rubin, M., Sboner, A., Sharifi, N., Loss of an androgen-inactivating and isoform-specific HSD17B4 splice form enables emergence of castration-resistant prostate cancer. Cell Reports. 2018 Jan 16;22(3):809-819.
Almassi, N., Reichard, C.A., Li, J., Russell, C., Perry, J., Ryan, C., Friedlander, T., Sharifi, N. HSD3B1 and response to a non-steroidal CYP17A1 inhibitor in castration-resistant prostate cancer. JAMA Oncology. 2018 Apr 1;4(4):554-557.
Hearn, JWD., Xie, W., Nakabayashi, M., Almassi, N., Reichard, C.A., Pomerantz, M., Kantoff, P.W., Sharifi, N. HSD3B1 genotype and response to androgen deprivation therapy for biochemical recurrence after radiotherapy for localized prostate cancer. JAMA Oncology. 2018 Apr 1;4(4):558-562.
Li, J., Alyamani, M., Zhang, A., Chang, K-H., Berk, M., Li, Z., Zhu, Z., Petro, M., Magi-Galluzzi, C., Taplin, M-E., Garcia, J.A., Courtney, K., Klein, E.A., Sharifi, N. Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer. eLife. 2017 Feb 13;6 e20183 doi: 10.7554/eLife.20183
Dai, C., Heemers, H., Sharifi, N. Androgen signaling in prostate cancer. Cold Spring Harb Perspect Med. 2017 Sep 1;7(9)
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 Oct;17(10):1435-1444.
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, 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.
Postdoctoral Fellow Position Available - Molecular Mechanisms and Translational Oncology
Do you have a background in molecular, biochemical or chemical mechanisms, cancer, medicinal or analytical chemistry? Are you interested in translational medicine and taking your mechanistic findings rapidly to the bedside in a vibrant clinical research program? If so, a postdoctoral fellowship position supported by the National Institutes of Health and the Prostate Cancer Foundation is available in the laboratory of Dr. Nima Sharifi at the Cleveland Clinic.
Our laboratory focuses on mechanistic discovery to understand the metabolic and molecular mechanisms of androgen synthesis and androgen receptor gain-of-function that lead to resistance to hormonal therapy. Our work is revealing fundamental endocrine mechanisms in both normal physiology and disease, including stress, aging, and glucocorticoid resistance, that will lead to broad applications to oncology and cancer physiology.
Specific areas include:
1) Metabolic and genetic changes required for hormone therapy resistance in prostate and breast cancers
2) Discovery of entirely new mechanisms of endocrine physiology and regulation
3) Clinical validation in patients and clinical trials using innovative approaches
4) Animal models of advanced cancer for translational and therapeutic studies
5) Identifying targets for the development of new pharmacologic therapies
6) Drug discovery for new therapies
We discovered the first example of a gain-of-function in a steroid-synthesizing enzyme that enables prostate cancer resistance to hormonal therapy (Chang, et al. Cell. 2013;154:1074-84). We also recently discovered that abiraterone works by conversion to a more active steroidal metabolite (Li, et al. Nature. 2015;523:347-51), that metabolism is pharmacologically modifiable to optimize therapy (Li, et al. Nature. 2016;533:547-51) and that these events are a class effect of steroidal androgen synthesis inhibitors (Alyamani, et al. Cell Chem Biol. 2017;24:825-32) and genetic determination of metabolite generation (Alyamani, et al. J Clin Invest. 2018;128:3333-40). Most recently, we reported that blockade of hexose-6-phosphate dehydrogenase normalizes glucocorticoid metabolism and reverses enzalutamide resistance, credentialing a new pharmacologic vulnerability (Sci Transl Med 13; 2021).
This position is ideal for an individual with a strong interest in rapid translation of basic mechanistic discoveries to the bedside as this is a principal goal of the Sharifi Laboratory. For example, we have shown that our discovery of a gain-of-function in a steroid-synthesizing enzyme is a predictive biomarker of poor outcomes after hormonal therapy (Hearn, et al. Lancet Oncol. 2016;17:1435-44; JAMA Oncol. 2018;4:558-62; JAMA Oncol. 2020;6(4):e196496). We are currently evaluating this biomarker in an active clinical trial and are pursuing similar mechanisms and developing new treatment modalities based on these discoveries.
The position will provide a unique and multidisciplinary exposure to tumor metabolism, molecular oncology, drug development, and clinical trials. The ideal candidate has a PhD degree in biochemistry, chemistry or molecular biology; has the appropriate expertise in discovery of molecular, biochemical or chemical mechanisms; and is highly driven. Outstanding verbal and communication skills are required.
Interested candidates should send their CV and contact information for 3 references to: Nima Sharifi, M.D. Kendrick Family Chair for Prostate Cancer Research Department of Cancer Biology, Lerner Research Institute c/o Cassandra Talerico, PhD, firstname.lastname@example.org
The clinical trial strategy was developed through research on a gene associated with treatment-resistant prostate cancer, HSD3B1, and is in clinical trials at nine sites across the U.S.
The Prostate Cancer Foundation awarded Ashley E. Holly, PhD, MBA, with the Young Investigator Award to study clinical investigations into diet and prostate cancer.
Latest novel finding adds to list of cancers associated with the HSD3B1 gene; clinical and research teams investigating potential connections.
Dr. Nima Sharifi and a team of researchers uncovered how tumors circumvent prostate cancer therapy and identified a potential window of time after treatment when tumors may be responsive to immunotherapy.
Dr. Sharifi and collaborators identified choline, betaine and phenylacetylglutamine as nutrients and gut microbiome metabolites associated with increased risk for lethal prostate cancer, suggesting dietary interventions may help reduce disease risk.
Dr. Sharifi and a team of respiratory and prostate cancer researchers studied how a male sex hormone involved in prostate cancer may provide clues to why men are more likely to develop COVID-19 and have poorer disease-related outcomes than women.
Dr. Sharifi demonstrates that pharmacologically inhibiting the H6PD protein can reverse drug resistance in human-derived preclinical models of enzalutamide-resistant prostate cancer.
Dr. Sharifi has been selected as the 2021 recipient of the AACR Waun Ki Hong Award for Outstanding Achievement in Translational and Clinical Cancer Research for his research into the genetic underpinnings of treatment-resistant prostate cancer.
With support from a new Department of Defense grant, Drs. Sharifi and Stauffer will continue work on a promising prostate cancer drug target, which has already reached in vivo proof of concept studies.
Bringing a long-running research project to the patient bedside, Dr. Sharifi validated that men with the HSD3B1(1245C) variant more quickly develop treatment-resistant cancer and have shorter survival, suggesting genetic testing may be helpful in personalized treatment planning.