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The laboratory's main focus is in three different disease areas that affect many urologic patients.
Aria Olumi, MDPrincipal Investigator
Zongwei Wang, PhDInstructor
Rongbin Ge, MD, PhDSenior Investigator
Libing Hu, MDVisiting Research Scholar
Cyrus Rassoulian Undergraduate Student
Jonathan PhamGraduate Student
1. Molecular Mechanisms of Resistance to Pro-Apoptotic Agents
Tumor necrosis factor related apoptosis inducing ligand (TRAIL) delivers potent antitumor pro-apoptotic activity, and cancer cells are significantly more sensitive to TRAIL-induced apoptosis than normal cells. Therefore TRAIL is an ideal cancer therapeutic agent without significant side effects. However, some cancer cells develop resistance to TRAIL induced apoptosis. To overcome resistant cancer cells, it’s important to identify molecular pathways that differentiate between sensitive and resistant cancers. Recently, we found that the transcription factor FBXL10 has an anti−apoptotic role and mediates sensitivity to TRAIL-mediated apoptosis. We demonstrate a novel NF-kB/FBXL10/c-Fos/c-FLIP signaling pathway in TRAIL−mediated apoptosis. Our studies suggest that inhibiting FBXL10 can help overcome resistant cancer cells for pro-apoptotic therapies. Identifying molecular pathways that differentiate between TRAIL-resistant and sensitive cancer cells will improve our currently available pro-apoptotic medications and will lead to development of new and more effective pro-apoptotic agents.
2. Molecular Mechanisms of Bladder Dysfunction Associated with Type 2 Diabetes
Diabetes mellitus (DM) affects 7% of the US population. Annually, one and a half million new cases of diabetes are diagnosed. The annual estimated cost of health care related to diabetes exceeds $130 billion dollars, with $90 billion for direct medical cost and $40 billion for indirect costs such as disability, work loss and premature mortality. While DM-type 1 is thought to be secondary to autoimmune destruction of pancreatic beta cells that produce insulin, the more common type of diabetes mellitus type 2 (DM2), stems from insulin resistance. DM2 accounts for 90% of newly diagnosed cases in the US, and it is associated with a chronic hyperglycemic environment which can have deleterious complications of heart disease, stroke, hypertension, retinopathy, neuropathy, nephropathy and complications during pregnancy. From a urologic standpoint, patients present with voiding complaints, recurrent urinary tract infections and erectile dysfunction. Diabetic bladder dysfunction is a common complication and affects up to 80% of patients with diabetes, and patients present with decreased bladder sensation, increased residual urine volume, and bladder overactivity. Often, patients present with late stages of bladder dysfunction, which include inability to urinate secondary to poorly functioning decompensated bladder smooth muscle. Identifying molecular changes that are responsible for diabetic bladder dysfunction may help identify diabetic patients at risk of developing bladder dysfunction prior to presentation of the late stages of the disease. Collaborating with investigators in Children’s Hospital Boston, we identified a genetic mouse model with DM2 with conditional hepatocyte double knockout of insulin receptor substrates 1 & 2 (DKO), which mimic the diabetic bladder dysfunction in humans. DKO mice exhibited abnormal spontaneous bladder contractions, with higher amplitudes of tension to different stimulation at young ages (6, 12 weeks), while older mice demonstrated lower amplitudes – findings which are common in patients with diabetic bladder dysfunction.
To understand the molecular alterations associated with diabetic bladder dysfunction we used differential gene expression profiling, and found that the TNF superfamily inflammatory genes were up-regulated. Inhibition of the TNF pathways in in-vivo and in-vitro assays correct the bladder dysfunction that is associated with diabetic bladder cystopathy.
Our findings demonstrate that diabetic cystopathy in DKO mice is a progressive process – hyperactive bladder dysfunction in early/middle aged animals and hypoactive in older animals. Systemic inhibition of the TNF pathway in diabetic mice corrected the diabetic cystopathy without affecting serum glucose levels, suggesting that hyperglycemia alone may not be responsible for secondary complications of diabetes. Evaluating the molecular pathways that lead to diabetic cystopathy will improve our understanding of bladder dysfunction, and help devise preventive strategies for secondary complications associated with type 2 diabetes.
3. 5-alpha reductase 2 (5-AR2) is a key enzyme that is responsible of proper development of prostate tissue.
Inhibition of 5-AR2 has proven to be efficacious for management of urinary symptoms secondary benign prostatic hyperplasia (BPH). However, some patients are resistant to the therapeutic effects of 5-AR2 inhibitor for management lower urinary tract symptoms. We show that 30% of benign human prostate samples did not express the 5-AR 2 protein. Moreover, we demonstrate that the promoter region of 5-AR 2 contains a CpG island that is methylated in benign prostate epithelial cells in culture and also in 39% of benign human prostate samples. We conclude that methylation of 5-AR 2 promoter may account for low or absent expression of 5-AR 2 in human adult prostate tissues. Low or absent levels of 5-AR 2 in human prostate may have implications in long term prostatic growth rate and treatment strategies for management of BPH.
Metformin represses cancer cells via alternate pathways in N-cadherin expressing vs. N-cadherin deficient cells. Ge R, Wang Z, Wu S, Zhuo Y, Otsetov AG, Cai C, Zhong W, Wu CL, Olumi AF. Oncotarget. 2015 Oct 6;6(30):28973-87. doi: 10.18632/oncotarget.5023. PMID: 26359363
Age and Obesity Promote Methylation and Suppression of 5α-Reductase 2: Implications for Personalized Therapy of Benign Prostatic Hyperplasia. Bechis SK, Otsetov AG, Ge R, Wang Z, Vangel MG, Wu CL, Tabatabaei S, Olumi AF. J Urol. 2015 Oct;194(4):1031-7. doi: 10.1016/j.juro.2015.04.079. Epub 2015 Apr 25. PMID: 25916673
Succinate dehydrogenase B: a new prognostic biomarker in clear cell renal cell carcinoma. Cornejo KM, Lu M, Yang P, Wu S, Cai C, Zhong WD, Olumi A, Young RH, Wu CL. Hum Pathol. 2015 Jun;46(6):820-6. doi: 10.1016/j.humpath.2015.02.013. Epub 2015 Mar 11. PMID: 25827535
Activation of AKR1C1/ERβ induces apoptosis by downregulation of c-FLIP in prostate cancer cells: A prospective therapeutic opportunity. Yun H, Xie J, Olumi AF, Ghosh R, Kumar AP. Oncotarget. 2015 May 10;6(13):11600-13. PMID: 25816367
DNA methyl transferase 1 reduces expression of SRD5A2 in the aging adult prostate. Ge R, Wang Z, Bechis SK, Otsetov AG, Hua S, Wu S, Wu CL, Tabatabaei S, Olumi AF. Am J Pathol. 2015 Mar;185(3):870-82. doi: 10.1016/j.ajpath.2014.11.020. Epub 2015 Feb 17. PMID: 25700986
Clinical features of leiomyosarcoma of the urinary bladder: analysis of 183 cases. Rodríguez D, Preston MA, Barrisford GW, Olumi AF, Feldman AS. Urol Oncol. 2014 Oct;32(7):958-65. doi: 10.1016/j.urolonc.2014.01.025. Epub 2014 Jul 11. PMID: 25027684
5α-Reductase inhibitors and risk of high-grade or lethal prostate cancer. Preston MA, Wilson KM, Markt SC, Ge R, Morash C, Stampfer MJ, Loda M, Giovannucci E, Mucci LA, Olumi AF. JAMA Intern Med. 2014 Aug;174(8):1301-7. doi: 10.1001/jamainternmed.2014.1600. PMID: 24887392
Metformin use and prostate cancer risk. Preston MA, Riis AH, Ehrenstein V, Breau RH, Batista JL, Olumi AF, Mucci LA, Adami HO, Sørensen HT. Eur Urol. 2014 Dec;66(6):1012-20. doi: 10.1016/j.eururo.2014.04.027. Epub 2014 May 22. PMID: 24857538
Personalized medicine for the management of benign prostatic hyperplasia. Bechis SK, Otsetov AG, Ge R, Olumi AF. J Urol. 2014 Jul;192(1):16-23. doi: 10.1016/j.juro.2014.01.114. Epub 2014 Feb 25. Review. PMID: 24582540
Commentary on "ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients." Baena E, Shao Z, Linn DE, Glass K, Hamblen MJ, Fujiwara Y, Kim J, Nguyen M, Zhang X, Godinho FJ, Bronson RT, Mucci LA, Loda M, Yuan GC, Orkin SH, Li Z, Division of Hematology and Oncology, Boston Children's Hospital, Boston, MA, USA.: Genes Dev 2013;27(6):683-98. Olumi AF. Urol Oncol. 2014 Feb;32(2):213. doi: 10.1016/j.urolonc.2013.08.016. PMID: 24445296
Commentary on "age-related alterations in T-lymphocytes modulate key pathways in prostate tumorigenesis". De Angulo A, Faris R, Cavazos D, Jolly C, Daniel B, DeGraffenried L, Department of Nutritional Sciences, Dell Pediatric Research Institute, University of Texas, Austin, TX, USA.: Prostate 2013;73(8):855-64 [Epub 2013 Mar 26]. Olumi AF. Urol Oncol. 2014 Feb;32(2):212-3. doi: 10.1016/j.urolonc.2013.08.017. PMID: 24445295
Commentary on "integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer." Weischenfeldt J, Simon R, Feuerbach L, Schlangen K, Weichenhan D, Minner S, Wuttig D, Warnatz HJ, Stehr H, Rausch T, Jäger N, Gu L, Bogatyrova O, Stütz AM, Claus R, Eils J, Eils R, Gerhäuser C, Huang PH, Hutter B, Kabbe R, Lawerenz C, Radomski S, Bartholomae CC, Fälth M, Gade S, Schmidt M, Amschler N, Haß T, Galal R, Gjoni J, Kuner R, Baer C, Masser S, von Kalle C, Zichner T, Benes V, Raeder B, Mader M, Amstislavskiy V, Avci M, Lehrach H, Parkhomchuk D, Sultan M, Burkhardt L, Graefen M, Huland H, Kluth M, Krohn A, Sirma H, Stumm L, Steurer S, Grupp K, Sültmann H, Sauter G, Plass C, Brors B, Yaspo ML, Korbel JO, Schlomm T, Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.: Cancer Cell 2013;23(2):159-70. Olumi AF. Urol Oncol. 2014 Feb;32(2):212. doi: 10.1016/j.urolonc.2013.08.018. PMID: 24445294
Commentary on "identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array." Eeles RA et. al. Olumi AF. Urol Oncol. 2014 Feb;32(2):211. doi: 10.1016/j.urolonc.2013.08.019. PMID: 24445293
Commentary on "the E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity." Qi J, Tripathi M, Mishra R, Sahgal N, Fazli L, Ettinger S, Placzek WJ, Claps G, Chung LW, Bowtell D, Gleave M, Bhowmick N, Ronai ZA, Signal Transduction Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.: Cancer Cell 2013;23(6):332-46. Olumi AF. Urol Oncol. 2014 Feb;32(2):210-1. doi: 10.1016/j.urolonc.2013.08.020. PMID: 24445292
Commentary on "randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and Ki67 labeling in prostate cancer patients." Wagner D, Trudel D, Van der Kwast T, Nonn L, Giangreco AA, Li D, Dias A, Cardoza M, Laszlo S, Hersey K, Klotz L, Finelli A, Fleshner N, Vieth R, Department of Nutritional Sciences, University of Toronto, Ontario, Canada.: J Clin Endocrinol Metab 2013;98(4):1498-507 [Epub 2013 Mar 5]. Olumi AF. Urol Oncol. 2014 Feb;32(2):210. doi: 10.1016/j.urolonc.2013.08.021. PMID: 24445291
Medical oncology consultation and minimization of overtreatment in men with low-risk prostate cancer. Aizer AA, Paly JJ, Michaelson MD, Rao SK, Nguyen PL, Kaplan ID, Niemierko A, Olumi AF, Efstathiou JA. J Oncol Pract. 2014 Mar;10(2):107-12. doi: 10.1200/JOP.2013.000902. Epub 2014 Jan 7. PMID: 24399853
Prognostic significance of indeterminate lung nodules in renal cell carcinoma. Xu R, Horick N, McGovern FJ, Dahl DM, Feldman AS, Blute ML, Olumi AF, Michaelson MD. Urol Oncol. 2014 Apr;32(3):355-61. doi: 10.1016/j.urolonc.2013.09.001. Epub 2014 Jan 4. PMID: 24397994
Inhibition of PP2A activity confers a TRAIL-sensitive phenotype during malignant transformation. Yang H, Chen X, Wang X, Li Y, Chen S, Qian X, Wang R, Chen L, Han W, Ruan A, Du Q, Olumi AF, Zhang X. Mol Cancer Res. 2014 Feb;12(2):217-27. doi: 10.1158/1541-7786.MCR-13-0441. Epub 2013 Dec 2. PMID: 24296757
Primary spermatic cord tumors: disease characteristics, prognostic factors, and treatment outcomes. Rodríguez D, Barrisford GW, Sanchez A, Preston MA, Kreydin EI, Olumi AF. Urol Oncol. 2014 Jan;32(1):52.e19-25. doi: 10.1016/j.urolonc.2013.08.009. Epub 2013 Nov 13. PMID: 24239475
Models of care and NCCN guideline adherence in very-low-risk prostate cancer. Aizer AA, Paly JJ, Zietman AL, Nguyen PL, Beard CJ, Rao SK, Kaplan ID, Niemierko A, Hirsch MS, Wu CL, Olumi AF, Michaelson MD, D'Amico AV, Efstathiou JA. J Natl Compr Canc Netw. 2013 Nov;11(11):1364-72.
Aria F. Olumi, MD
Yawkey Building 7E
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