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Departments of Cancer Biology, Medical Oncology, and Urology BLSB 309 Phone: 215-503-9250
To identify new therapeutic target proteins for castration-resistant and metastatic prostate cancer.
Dr. Nevalainen's research accomplishments include the development and optimization of a long-term 3D organ culture system under serum-free conditions for normal and malignant rodent and human prostate tissue. She has demonstrated that 1) prolactin (Prl) is a mitogen and survival factor for normal and malignant human and rodent prostate epithelium, 2) Prl is locally produced by normal and malignant prostate cells, 3) Stat5 is the key signaling molecule that mediates the effects of Prl in normal and malignant prostate tissue, and 4)Stat5 is a crucial survival protein for prostate cancer cells.
Dr. Nevalainen's research program focuses on identifying protein kinase signaling pathways that mediate survival of castration-resistant and metastatic prostate cancer cells, with a special focus on Stat transcription factors. Dr. Nevalainen's laboratory has shown that Stat5 is critical for the viability of human prostate cancer cells in culture and for prostate xenograft tumor growth in nude mice. Moreover, Dr. Nevalainen has shown that activation of Stat5 in primary prostate cancer predicts early disease recurrence. The current focus of Dr. Nevalainen's research program is on the identification of the molecular mechanisms by which Stat5 contributes to castration-resistant growth of prostate cancer, the individual roles of Stat5a vs. Stat5b as survival factors for prostate cancer cells, on testing whether Stat5 inhibition sensitizes prostate cancer cells for radiation, and whether acetylation of Stat5a/b contributes to transcriptional activity of Stat5 in prostate cancer cells. Recently, Dr. Nevalainen's laboratory identified small-molecule inhibitors for Stat5. Dr. Nevalainen aims to use the Jak-Stat5 pathway as a molecular target to develop novel pharmaceutical strategies for prostate cancer therapy.
1) We have established transcription factor Stat5 as a molecular target for therapy development for prostate cancer. Inhibition of Stat5a/b can be achieved by antisense oligonucleotides, RNA interference, or by development of small-molecule Stat5 inhibitors. 2) Stat5 is particularly active in high grade prostate cancer and in castration-resistant disease, which suggests that Stat5 may be specific therapeutic target for advanced prostate cancer. 3) Activation of Stat5a/b in primary prostate cancer predicts early prostate cancer recurrence. This knowledge can be used to design a prognostic assay to guide the selection of treatment for prostate cancers of intermediate Gleason scores. 4) Long-term expertise and experience in 3D-Ex vivo prostate cancer organ culture system for drug screening. 5) A new androgen-regulated and tumorigenic human prostate cancer cell line established in our lab. 6) Characterization of a small-molecule lead compound for pharmacological inhibition of Stat5a/b.
Zhiyong Liao, PhD, Research Associate, Lei Gu, MD, Research Associate, Mateusz Koptyra, Post-Doctoral Fellow, David Hoang, MD-PhD-Student Molecular Pharmacology and Strucural Biology Program) Shilpa Gupta, MD, Medical oncology Fellow, Pooja Talati, PhD-student (Molecular Pharmacology and Strucural Biology Program) Elyse Amico, MS, Research Assistant. Support: Ongoing support: 1. Principal Investigator, RO1-Grant (RCA11358A);Stat5 in Progression of Prostate Cancer, NCI. Completed Support: 1. Principal Investigator: Research Award for Prostate Cancer Research; Stat5 as a Critical Survival Factor in Prostate Cancer, American Cancer Society, Individual Allocation from an Institutional Research Grant, IRG 97-152-11. 2. Principal Investigator: Lombardi Comprehensive Cancer Center Developmental Funds, Jak - Stat5 Signaling in Prostate Cancer. 3. Principal Investigator, Investigator Initiated Grant; Lipid Modulation of Jak2-Stat5 Signal Transduction Pathway in Prostate Cancer, American Institute for Cancer Research. 4. Principal Investigator, Research Scholar Grant; Androgen-Independent Growth Signaling Pathways in Prostate Cancer, American Cancer Society. 5. Principal Investigator: New Investigator Award; Stat5 a Therapeutic Target Protein for Prostate Cancer, Department of Defense Prostate Cancer Research Program. 6. Principal Investigator: Idea Development Award; Stat3 in Metastatic Progression of Prostate Cancer, Department of Defense Prostate Cancer Research Program. Training Opportunities: Training opportunities for post-doctoral fellows and students are available in our dynamic prostate cancer research laboratory. Students and fellows will receive training in a broad range of research methodologies and in writing scientific publications and grants. Studies involve in vivo and in vitro models of prostate cancer. Successful candidates must be organized and be able to work independently. Salary is dependent on experience and follows NIH-guidelines. Highly motivated candidates are encouraged to send or email an application with a brief statement of research experience and interest and CV to:
Thomas Jefferson University 309A Bluemle Life Science Building Email: marja.nevalainen@jefferson.edu. Keywords: Cancer, Prostate, Stat5, Stat3, Jak2 | ||||
| Selected Publications 46. Liao Z, Nevalainen MT. Targeting transcription factor Stat5a/b as a therapeutic strategy for prostate cancer. Am J Transl Res. 3(2):133-8, 2011. ( Abstract ) 45. Tuomas K Mirtti, Pooja Talati and Marja T Nevalainen. " Transcription Factors Stat5a/b and Stat3 in Prostate Cancer Growth and Metastases ". In: "Signalling Pathways and Molecular Mediators in Metastases", Springer, Book Chapter, In Press, 2011. 44. Gupta S, Liao Z, Nevalainen MT. "Jak2-Stat5 Pathway in Prostate Cancer". In: "The Encyclopedia of Cancer Targets". Marshall JL, Weiner L, Gelmann E, Kaufman H, Wellstein A (Editors), In Press, 2011. 43. Vogiatzi P, Nevalainen MT. "Jak2/Stat5 Signaling Axis and Novel Therapeutic Strategies in Prostate Cancer". In: "Cutting Edge Therapies for Cancer in 21st Century". Claudio PP (Ed), Bentham Science Publishers Ltd, In Press, 2011. 42. Takahiro Sato, Lynn Moretti Neilson, Amy R. Peck, Chengbao Liu, Thai H. Tran, Agnes Witkiewicz, Terry Hyslop, Marja T. Nevalainen, Guido Sauter, and Hallgeir Rui. Signal transducer and activator of transcription-3 and breast cancer prognosis. American Journal of Cancer Research, In Press, 2011. 41. Ryder A, Witkiewicz AK, Liu C, Stringer GA, Klimowicz AC, Tran TH, Yang N, Rosenberg AL, Hooke JA, Kovatich AJ, Nevalainen MT, Shriver CD, Hyslop T, Sauter G, Rimm DL, Magliocco AM, Rui H. Loss of Nuclear Localized and Tyrosine Phosphorylated Stat5 in Breast Cancer Predicts Poor Clinical Outcome and Increased Risk of Anti-Estrogen Therapy Failure. In Press, J. Clinical oncology, 2010.40. 40. Reddy A, Huang C, Liu H, DeLisi C, Nevalainen MT, Szalma S, Bhanot G. Robust Network Analysis Reveals Alteration of the Stat5a Network as a Hallmark of Prostate Cancer. In Press, Genome Informatics, 2010. 39. Dagvadorj A, Tan SH, Liao Z, Xie J, Nurmi M, Alanen K, Rui H, Mirtti T, Nevalainen MT. N-terminal truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in prostate cancer cells. Int J Biochem Cell Biol. 42(12):2037-46, 2010. ( Abstract ) 38. Gu L, Zhu XH, Visakorpi T, Alanen K, Mirtti T, Edmonston TB, Nevalainen MT. Activating mutation (V617F) in the tyrosine kinase JAK2 is absent in locally-confined or castration-resistant prostate cancer. Anal Cell Pathol (Amst). 33(2):55-9, 2010. ( Abstract ) 37. Liao Z, Shen F, Dagvadorj A, Abdulghani J, Leiby B, Tan S, Nevalainen MT. Liganded glucocoticoid receptor functionally interacts with transcription factor Stat5 in human prostate cancer cells and promotes prostate xenograft tumor growth. Submitted, Endocrinology, 2010. 36. Gu L, Vogiatzi P, Puhr M, Dagvadorj A, Lutz J, Ryder A, Addya S, Fortina P, Cooper C, Leiby B, Dasgupta A, Hyslop T, Bubendorf L, Alanen K, Mirtti T, Nevalainen MT. Stat5 promotes metastatic behavior of human prostate cancer cells in vitro and in vivo. Endocr Relat Cancer. 17(2):481-93, 2010. ( Abstract ) 35. Gu L, Dagvadorj A, Lutz J, Leiby B, Bonuccelli G, Lisanti MP, Addya S, Fortina P, Dasgupta A, Hyslop T, Bubendorf L, Nevalainen MT. Transcription factor Stat3 stimulates metastatic behavior of human prostate cancer cells in vivo, whereas Stat5b has a preferential role in the promotion of prostate cancer cell viability and tumor growth. Am J Pathol. 176(4):1959-72, 2010. ( Abstract ) 34. Liao Z, Lutz J, Nevalainen MT. Transcription factor Stat5a/b as a therapeutic target protein for prostate cancer. Int J Biochem Cell Biol. 42(2):186-92, 2010. ( Abstract ) 33. Dagvadorj A, Tan SH, Liao Z, Cavalli LR, Haddad BR, Nevalainen MT. Androgen-regulated and highly tumorigenic human prostate cancer cell line established from a transplantable primary CWR22 tumor. Clinical Cancer Research. 14(19):6062-72, 2008. ( Abstract ) 32. Tan SH, Nevalainen MT. Signal transducer and activator of transcription 5A/B in prostate and breast cancers. Endocrine Related Cancer. 15(2):367-90, 2008. ( Abstract ) 31. Abdulghani J, Gu L, Dagvadorj A, Lutz J, Leiby B, Bonuccelli G, Lisanti MP, Zellweger T, Alanen K, Mirtti T, Visakorpi T, Bubendorf L, Nevalainen MT. Stat3 promotes metastatic progression of prostate cancer. American Journal of Pathology. 172(6):1717-28, 2008. ( Abstract ) 30. Dagvadorj A, Kirken RA, Leiby B, Karras J, Nevalainen MT. Transcription factor signal transducer and activator of transcription 5 promotes growth of human prostate cancer cells in vivo. Clinical Cancer Research. 14(5):1317-24, 2008. ( Abstract ) 29. Tan SH, Dagvadorj A, Shen F, Gu L, Liao Z, Abdulghani J, Zhang Y, Gelmann EP, Zellweger T, Culig Z, Visakorpi T, Bubendorf L, Kirken RA, Karras J, Nevalainen MT. Transcription factor Stat5 synergizes with androgen receptor in prostate cancer cells. Cancer Research. 68(1):236-48, 2008. ( Abstract ) 28. Powell M, Lisanti MP, Nevalainen MT, Wang C, Pestell RG. Androgen receptor epigenetic modification and acetylation regulate prostate cellular growth. In: Pestell RG and Nevalainen MT (Eds.) Prostate Cancer: Signaling Networks, Genetics and New Treatment Strategies. New York: Humana Press; 2008. p. 147 – 162. 27. Pestell RG and Nevalainen MT.(Eds.) Prostate Cancer: Signaling Networks, Genetics and New Treatment Strategies. New York: Humana Press; 2008. 26. Nevalainen MT., Culig Z. Transcription factors Stat5 and Stat3: Key survival factors for prostate cancer cells.In: Pestell RG and Nevalainen MT (Eds.) Prostate Cancer: Signaling Networks, Genetics and New Treatment Strategies. New York: Humana Press; 2008. p. 257 – 290. 25. Popov VM, Wang C, Shirley LA, Rosenberg A, Li S, Nevalainen MT, Fu M, Pestell RG.The functional significance of nuclear receptor acetylation. Steroids. 72:221-230, 2007. 24. Dagvadorj A, Collins S, Jomain JB, Abdulghani J, Karras J, Zellweger T, Li H, Nurmi M, Alanen K, Mirtti T, Visakorpi T, Bubendorf L, Goffin V, Nevalainen MT. Autocrine prolactin promotes prostate cancer cell growth via Janus kinase-2-signal transducer and activator of transcription-5a/b signaling pathway. Endocrinology. 148(7):3089-101, 2007. ( Abstract ) 23. LeBaron MJ, Ahonen TJ, Nevalainen MT, Rui H. In vivo response-based identification of direct hormone target cell populations using high-density tissue arrays. Endocrinology. 148(3):989-1008, 2007. ( Abstract ) 22. Li H, Zhang Y, Glass A, Zellweger T, Gehan E, Bubendorf L, Gelmann EP, Nevalainen MT. Activation of signal transducer and activator of transcription-5 in prostate cancer predicts early recurrence. Clinical Cancer Research. 11(16):5863-8, 2005. ( Abstract ) 21. Sultan AS, Xie J, LeBaron MJ, Ealley EL, Nevalainen MT, Rui H. Stat5 promotes homotypic adhesion and inhibits invasive characteristics of human breast cancer cells. oncogene. 24(5):746-60, 2005. ( Abstract ) 20. Li H, Ahonen TJ, Alanen K, Xie J, LeBaron MJ, Pretlow TG, Ealley EL, Zhang Y, Nurmi M, Singh B, Martikainen PM, Nevalainen MT. Activation of signal transducer and activator of transcription 5 in human prostate cancer is associated with high histological grade. Cancer Research. 64(14):4774-82, 2004. ( Abstract ) 19. Nevalainen MT, Xie J, Torhorst J, Bubendorf L, Haas P, Kononen J, Sauter G, Rui H. Signal transducer and activator of transcription-5 activation and breast cancer prognosis. Journal of Clinical Oncology. 22(11):2053-60, 2004. ( Abstract ) 18. Ahonen TJ, Xie J, LeBaron MJ, Zhu J, Nurmi M, Alanen K, Rui H, Nevalainen MT. Inhibition of transcription factor Stat5 induces cell death of human prostate cancer cells. Journal of Biological Chemistry. 278(29):27287-92, 2003. ( Abstract ) 17. Rui H, Nevalainen MT.Prolactin.In: Thomson A and Lotze MT (Eds.) Cytokine Handbook, 4th Edition.London: Academic Press; 2003. p. 113-146. 16. Nevalainen MT, Xie J, Bubendorf L, Wagner KU, Rui H. Basal activation of transcription factor signal transducer and activator of transcription (Stat5) in nonpregnant mouse and human breast epithelium. Molecular Endocrinology. 16(5):1108-24, 2002. ( Abstract ) 15. Xie J, LeBaron MJ, Nevalainen MT, Rui H. Role of tyrosine kinase Jak2 in prolactin-induced differentiation and growth of mammary epithelial cells. Journal of Biological Chemistry. 277(16):14020-30, 2002. ( Abstract ) 14. Ahonen TJ, Härkönen PL, Rui H, Nevalainen MT. PRL signal transduction in the epithelial compartment of rat prostate maintained as long-term organ cultures in vitro. Endocrinology. 143(1):228-38, 2002. ( Abstract ) 13. Yamashita H, Nevalainen MT, Xu J, LeBaron MJ, Wagner KU, Erwin RA, Harmon JM, Hennighausen L, Kirken RA, Rui H. Role of serine phosphorylation of Stat5a in prolactin-stimulated beta-casein gene expression. Molecular and Cellular Endocrinology. 183(1-2):151-63, 2001. ( Abstract ) 12. Valve EM, Nevalainen MT, Nurmi MJ, Laato MK, Martikainen PM, Härkönen PL. Increased expression of FGF-8 isoforms and FGF receptors in human premalignant prostatic intraepithelial neoplasia lesions and prostate cancer. Laboratory Investigation. 81(6):815-26, 2001. ( Abstract ) 11. Uotila P, Valve E, Martikainen P, Nevalainen MT, Nurmi M, Harkonen P.Increased expression of cyclo-oxygenase-2 and nitric oxide synthase-2 in human prostate cancer. Urological Research. 29:25-28, 2001. 10. Nevalainen MT, Ahonen TJ, Yamashita H, Chandrashekar V, Bartke A, Grimley PM, Robinson GW, Hennighausen L, Rui H. Epithelial defect in prostates of Stat5a-null mice. Laboratory Investigation. 80(7):993-1006, 2000. ( Abstract ) 9. Ahonen TJ, Härkönen PL, Laine J, Rui H, Martikainen PM, Nevalainen MT. Prolactin is a survival factor for androgen-deprived rat dorsal and lateral prostate epithelium in organ culture. Endocrinology. 140(11):5412-21, 1999. ( Abstract ) 8. Kallajoki M, Alanen KA, Nevalainen MT, Nurmi M, Nevalainen TJ.Expression of group II phospholipase A2 in male reproductive organs and male genital tumors. Prostate. 35:263-272, 1998. 7. Nevalainen MT, Valve EM, Ahonen T, Yagi A, Paranko J, Härkönen PL. Androgen-dependent expression of prolactin in rat prostate epithelium in vivo and in organ culture. The FASEB Journal. 11(14):1297-307, 1997. ( Abstract ) 6. Nevalainen MT, Valve EM, Ingleton PM, Nurmi M, Martikainen PM, Härkönen PL. Prolactin and prolactin receptors are expressed and functioning in human prostate. Journal of Clinical Investigation. 99(4):618-27, 1997. ( Abstract ) 5. Nevalainen MT, Valve EM, Ingleton PM, Härkönen PL. Expression and hormone regulation of prolactin receptors in rat dorsal and lateral prostate. Endocrinology. 137(7):3078-88, 1996. ( Abstract ) 4. Nevalainen MT, Härkönen PL, Valve EM, Ping W, Nurmi M, Martikainen PM. Hormone regulation of human prostate in organ culture. Cancer Research. 53(21):5199-207, 1993. ( Abstract ) 3. Martikainen P, Nevalainen MT, Härkönen PL.Organ cultures of rat and human prostate. In: Kumar A (Ed.) Techniques in reproductive biomedicine. A method manual. New Dehli: B.I. Churchill Livingstone, 1993. p. 666-680. 2. Väänänen HK, Valve EM, Mäkelä, SI, Nevalainen MT, Härkönen PL. Hormone regulation of carbonic anhydrase II expression.In: Botre, Frass G, Storey BT (Eds.) Carbonic anhydrase: from biochemistry and genetics to physiology and clinical chemistry. Weinheim, Germany: VCH Verlagsgesellchaft, 1991. p. 345-351. 1. Nevalainen MT, Valve EM, Mäkelä SI, Bläuer M, Tuohimaa PJ, Härkönen PL. Estrogen and prolactin regulation of rat dorsal and lateral prostate in organ culture. Endocrinology. 129(2):612-22, 1991. ( Abstract ) | ||||
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