Nima  Sharifi,  M.D.

Nima Sharifi, M.D.

Staff

Director, Center for GU Malignancies Research

Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195

 

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.

Specific areas of study in the Sharifi Laboratory include:

  • Genetic mutations and variations in androgen synthesis machinery. We investigate how genetic anomalies enable cancer cells to evade ADT and produce their own hormones for fuel. Our 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 (Chang, et al. Cell 2013). We have also shown that this variant alters response to treatment and could be used as a predictive biomarker when designing treatment regimens (Hearn, et al. Lancet Oncol 2016; Hearn, et al. JAMA Oncol 2018; Almassi, et al. JAMA Oncol 2018; Hearn, et al. JAMA Oncol 2020). Our laboratory is working to transition this discovery into the clinic by developing a blood test to detect the variant, and also collaborating on clinical trials to test alternative treatments for prostate cancer patients who have the inherited variant.

  • How genetics affect treatment response. Our team is interested in optimizing treatment regimens for all patient populations. Our 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. Our lab is working to confirm these results and identify an effective alternative drug for these patients (Li, et al. Nature 2015; Li, et al. Nature 2016; Alyamani, et al. J Clin Invest 2018).

  • Aberrations in glucocorticoid metabolism. We have found that prostate cancer develops aberrations in glucocorticoid metabolism that enables the development of resistance to potent AR antagonist, including enzalutamide. For example, the normal metabolic pathway that inactivates cortisol is lost, generating elevated tumor concentrations of cortisol that are required for drug resistance (Li, et al. eLife 2017). We recently identified hexose-6-phosphate dehydrogenase blockade as a strategy that can reverse aberrant metabolism and reverse drug resistance (Li, et al. Science Translational Medicine 2021). Unexpectedly, AR antagonists also perturb glucocorticoid inactivation systemically. This leads to a systemic increase and exposure to bioactive glucocorticoids in patients treated with enzalutamide and apalutamide and may be the basis for certain adverse effects that occurs with these drugs (Alyamani, et al. Annals Oncol In press).

  • Interface between glucocorticoids and androgens. Glucocorticoids have had a long-standing role in the treatment of inflammatory disease processes, including severe asthma. However, patients often have disease that is resistant to the anti-inflammatory effects of glucocorticoids. An underappreciated observation of treatment with systemic glucocorticoids is that adrenal androgens are suppressed. We have recently found that HSD3B1 genetics is associated with clinical response to glucocorticoids in severe asthma. This is probably due to suppression of adrenal androgens which are metabolized by the enzyme encoded by HSD3B1 to more powerful androgens and are processed in individual patients according to their HSD3B1 genotype (Zein, et al. PNAS In press).


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.

View Publications for Nima Sharifi, MD, on PubMed

Selected publications:

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.


11/02/2022 |  

Low-fat or lower-carb diet? Cleveland Clinic postdoc wins prestigious award to study dietary interventions for prostate cancer

The Prostate Cancer Foundation awarded Ashley E. Holly, PhD, MBA, with the Young Investigator Award to study clinical investigations into diet and prostate cancer.




09/08/2022 |  

HSD3B1 Research Shows Association Between Genotype and Endometrial Cancer

Latest novel finding adds to list of cancers associated with the HSD3B1 gene; clinical and research teams investigating potential connections.




05/18/2022 |  

Flipping the Switch on Prostate Cancer Immunotherapy

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.




10/28/2021 |  

Study Links the Gut Microbiome and Aggressive Prostate Cancer

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.




06/01/2021 |  

Investigating the Biology of Sex-Based Differences in COVID-19

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.




05/26/2021 |  

Researchers Identify New Drug Target for Treating Aggressive Prostate Cancer

Dr. Sharifi demonstrates that pharmacologically inhibiting the H6PD protein can reverse drug resistance in human-derived preclinical models of enzalutamide-resistant prostate cancer.




03/31/2021 |  

Dr. Sharifi Honored with Achievement Award for Discoveries in Cancer Research

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.




04/03/2020 |  

Seven-Year Prostate Cancer Project Reaches Drug Discovery Phase

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.




02/13/2020 |  

Link Between Genetic Variant and Poor Outcomes in Men with Advanced Prostate Cancer Validated

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.




01/13/2020 |  

Genetic Variant Related to Androgen Synthesis Linked to Treatment Resistance in Asthma

Together with a team of respiratory researchers, Dr. Sharifi found that the genetic variant HSD3B1(1245A) correlates with lung function in patients with severe asthma, specifically those taking glucocorticoids, and that this variant may serve as a biomarker of treatment response.