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Thomas Jefferson University - Marja Nevalainen, MD, PhD
Marja Nevalainen, MD, PhD

Cancer Biology
Kimmel Cancer Center (KCC)
Thomas Jefferson University
Jefferson Medical College
Department of Cancer Biology
Department of Medical Oncology
Department of Urology
Associate Professor
Vice Chair, Dept. of Cancer Biology
Associate Director of Education, KCC
Mailing Address
233 South 10th Street, BLSB 309A
Philadelphia, Pennsylvania 19107
United States
Contact Information
Phone: 215-503-9250
Fax: 215-503-9245
Marja.Nevalainen@jefferson.edu
Qualifications
MD
PhD
Expertise and Research Interests
Mission:
Develop effective pharmacological therapies for advanced prostate cancer.

Model systems developed:
1) Dr. Nevalainen's has developed and optimized ex vivo explant organ culture system for clinical prostate cancers.
2) Her group developed and characterized a novel prostate cancer xenograft cell line and tumor system, CWR22Pc, which models castrate-resistant growth of prostate cancer.

Ongoing Work:
Dr. Nevalainen's group provided the proof-of-principle that Stat5a/b is a therapeutic target molecule in prostate cancer and further validated the concept in numerous prostate cancer model systems. Her group showed that Stat5 promotion of PCa cell growth and viability are mediated through androgen receptor (AR)-dependent and AR-independent mechanisms and, further, Stat5 effects in prostate cancer are independent of Stat3. Her group demonstrated that Stat5 promotes prostate cancer metastases processes, and nuclear Stat5 protein levels are elevated in high-grade clinical prostate cancers. Furthermore, Dr. Nevalainen's group shoed that increased nuclear Stat5 predicted early PCa recurrence.
The current focus of Dr. Nevalainen's research program is on the identification of the molecular mechanisms underlying Stat5 promotion of castrate-resistant and metastatic growth of prostate cancer and testing whether Stat5 inhibition sensitizes prostate cancer cells for radiation. Dr. Nevalainen's laboratory identified a lead compound small-molecule inhibitor family for Stat5. This lead compound Stat5 inhibitor blocks Stat5 dimerization and phosphorylation of Stat5 in prostate cancer cells and blocks prostate cancer cell growth in vitro and in vivo. Importantly, the lead compound Stat5 inhibitor blocks BCR-Abl-driven Stat5 phosphorylation and growth of Imatinib-resistant chronic myeloid leukemia cells.

Members of the Research group:
Ayush Dagvadorj, MD, PhD, Research Instructor,
Zhiyong Liao, PhD, Research Associate,
Lei Gu, MD, Research Associate,
David Hoang, MD-PhD-Student (Molecular Pharmacology and Strucural Biology Program)
Pooja Talati, PhD-student (Molecular Pharmacology and Strucural Biology Program)
Elyse Amico, MS, Research Assistant,
Shauna Blackmon, Masters Student.

Previous Members:
Mateusz Koptyra, PhD, Post-Doctoral Fellow,
Shilpa Gupta, MD, Medical Oncology Fellow,
Feng Shen, MD,
Ana Romero-Weaver, PhD,
Viviana Vogiatzi, MD, PhD,
Junaid Abdulghani, MD,PhD,
Anita Mamtani, MD,
Shyh-Han Tan, PhD,
Hong-Zhen Li,
Moogi Dagvadorj, MD,
Jackie Lutz, MS.

Support:
Ongoing support:
1. Principal Investigator, RO1-Grant (5RO1CA113580-05) (2006-2017;
Stat5 in Progression of Prostate Cancer, NCI.

2. Principal Investigator: Sponsored Research Contract; Astra Zeneca.

3. Principal Investigator: Sponsored Research Contract; Novartis.

4. Co-PI: American Cancer Society Institutional Research Grant (IRG-114958), Thomas Jefferson University; Kimmel Cancer Center; (PI: Richard Pestell.


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, Research Scholar Grant, 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.

7. Principal Investigator: Idea Development Award; Interaction of Transcription Factor Stat5 with Androgen Receptor in Growth Promotion 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: Marja Nevalainen, MD, PhD, Kimmel Cancer Center, Thomas Jefferson University Bluemle Life Science Bldg 309A, 233 S. 10th St., 19107 Philadelphia, PA. Email: marja.nevalainen@jefferson.edu.

Licensing Opportunities:

1) United States Patent 7,306,921. Diagnostic and Monitoring Methods for Cancer. Inventors: Nevalainen, MT, Rui, H. Filed Jan 2001, issued 2007.

2) United States Patent 7,642,050. Method for predicting responsiveness of breast cancer to antiestrogen therapy. Inventors: Nevalainen, MT, Rui, H. Divisional of application filed Jan 2001, issued 2010.

3) US Provisional Patent Application, April 23, 2003. Converted to US Utility Patent Application, April 23, 2004; Office of Technology and Licensing, Georgetown University. Inventor; Marja T. Nevalainen. Methods and Compositions for the Inhibition of Stat5 in Prostate Cancer Cells. 1212/548,383. Issued, 2012.

4) US Provisional Patent Application, 2012. Office of Technology and Licensing, Thomas Jefferson University. Inventors; Marja T. Nevalainen, Vincent Njar, Zhiyong Liao, Allen Reitz, Mark E McDonnell. "Treatment of Prostate Cancer and Hematological Neoplasms", 37075-0282-P1-US, Pending (filed 8/15/2012).

5) US Provisional Patent Application, 2012. Office of Technology and Licensing, Thomas Jefferson University. Inventors; Marja T. Nevalainen, Zhiyong Liao. "Treatment of Hematological Neoplasms", 37075-0290-P1-US, Pending (filed 8/15/2012).

6) US Provisional Patent Application, 2012. Office of Technology and Licensing, Thomas Jefferson University, Georgetwon University. Inventors; Marja T. Nevalainen, Nagarajan Pattabiraman "Treatment of Prostate Cancer", 37075-0259-P3-US,Pending (filed 8/15/2012).

7) CWR22Pc cell line (androgen-regulated cell line in vitro, forms androgen-dependent tumors in nude mice when xenografted, upon androgen deprivation the tumors regress but recur as castrate-resistant tumors). Dagvadorj et al., Clinical Cancer Research 14, 2008.




Industrial Relevance
1) We provided and validated the proof-of-concept that transcription factor Stat5 is a therapeutic target protein in advanced prostate cancer. 2) High levels of nuclear of Stat5a/b in primary prostate cancer predict early prostate cancer recurrence and prostate cancer specific death. High expression level of nuclear Stat5 in prostate cancer predicts poor response to radical prostatectomy. 3) We have identified a small molecule lead compound family of Stat5 inhibitors. Our Stat5 inhibitors induce extensive death of prostate cancer cells in culture, inhibit prostate xenograft tumor growth in vivo and induce death of prostate cancer epithelium in clinical prostate cancers ex vivo in explant organ cultures. 4) Our Stat5 inhibitors block transcriptional activity and phosphorylation of BCR-Abl-driven Stat5 in Imatinib sensitive and Imatinib resistant chronic myeloid leukemia cells. Our Stat5 inhibitors induce extensive apoptotic death of Imatinib-resistant BCR-Abl driven leukemia cells.
Keywords
Cancer; Prostate; Stat5; Stat3; Jak2; Jak1
Languages
Finnish, Swedish, German, English
Publications
  • 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, 129:612-622, 1991.
  • 2. Väänänen HK, Valve EM, Mäkelä SI, Nevalainen MT, Härkönen PL. Hormone regulation of carbonic anhydrase II expression. In: Carbonic Anhydrase: from Biochemistry and Genetics to Physiology and Clinical Chemistry. Botre, G. Frass, B.T. Storey (Eds), Weinheim, Germany: VCH Verlagsgesellchaft, 1991, pp 345-351.
  • 3. Nevalainen MT, Härkönen PL, Valve EM, Ping W, Nurmi M, Martikainen PM. Hormone Regulation of Human Prostate in Organ Culture. Cancer Research, 53:5199-5207, 1993.
  • 4. Martikainen P, Nevalainen MT, Härkönen PL. Organ cultures of rat and human prostate, In: Techniques in reproductive biomedicine. A Method Manual. Anand Kumar (Ed), New Delhi: B.I. Churchill Livingstone, pp 666-680, 1993.
  • 5. Nevalainen MT, Valve EM, Ingleton P, Härkönen PL. Expression and Hormone Regulation of Prolactin Receptor in Rat Dorsal and Lateral Prostate. Endocrinology, 137: 3078-3088, 1996.
  • 6. Nevalainen MT, Valve EM, Ingleton PM, Martikainen PM, Nurmi M, Härkönen PL. Prolactin Receptors are Expressed and Functioning in Human Prostate. Journal of Clinical Investigation, 99:618-627, 1997.
  • 7. Nevalainen MT, Valve EM, Ahonen TJ Yagi A, Paranko J, Härkönen PL. Androgen-dependent Expression of Prolactin in Rat Prostate Epithelium In Vivo and in Organ Culture. The FASEB Journal, 11:1297-1308, 1997.
  • 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.
  • 9. Ahonen TJ, Härkönen PL, Laine J, Rui H, Martikainen PM, Nevalainen MT. Prolactin is a Survival Factor in Androgen-deprived Rat Dorsal and Lateral Prostate in Organ Culture. Endocrinology, 140:5412-5421, 1999.
  • 10. Nevalainen MT, Ahonen TJ, Yamashita H, Chandrashekar S, Bartke A, Grimley PM, Robinson GW, Hennighausen L, Rui H. Epithelial Defect in Prostates of Stat5a  deficient Mice. Laboratory Investigation, 80:993-1006, 2000.
  • 11. Uotila P, Valve EM, Martikainen PM, Nevalainen MT, Nurmi M, Härkönen PL. Increased Expression of Cyclo-oxygenase-2 and Nitric Oxide Synthase-2 in Human Prostate Cancer. Urological Research, 29:25-28, 2001.
  • 12. Valve EM, Nevalainen MT, Nurmi M, Martikainen PM, Härkönen PL. Increased Expression of FGF-8 Isoforms and FGF Receptors in Human Premalignant Prostatic Intraepithelial Neoplasia and Prostate Cancer. Laboratory Investigation, 81:815-826, 2001.
  • 13. Yamashita H, Nevalainen MT, Xu J, LeBaron MJ, Wagner KU, Erwin RA, Harmon G, Hennighausen L, Kirken RA, Rui H. Role of Serine Phosphorylation of Stat5a in Prolactin-stimulated Beta-casein Gene Expression. Molecular and Cellular Endocrinology, 183:151-163, 2001.
  • 14. Ahonen TJ, Härkönen PL, Rui H, Nevalainen MT. Prolactin Signal Transduction in the Epithelial Compartment of Rat Prostate Maintained as Long-term Organ Cultures In Vitro. Endocrinology, 143:228-238, 2002.
  • 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, 277:14020-14030, 2002.
  • 16. Nevalainen MT, Xie J, Bubendorf L, Wagner KU, Rui H. Basal Activation of Transcription Factor Stat5 in Nonpregnant Mouse and Human Breast Epithelium. Molecular Endocrinology, 16:1108-1124, 2002.
  • 17. Ahonen TJ, Xie J, LeBaron MJ, Zhu J, Nurmi M, Alanen KA, Rui H, Nevalainen MT. Inhibition of Transcription Factor Stat5 Induces Cell Death of Human Prostate Cancer Cells. Journal of Biological Chemistry, 278:27287-27292, 2003.
  • 18. Rui H, Nevalainen MT. Prolactin. In: Cytokine Handbook, 4th Edition, Angus Thomson and Michael T Lotze (Eds), London, UK: Academic Press, Elsevier Science Ltd, pp 113-146, 2003.
  • 19. Nevalainen MT, Xie J, Torhorst J, Bubendorf L, Haas P, Kononen H, Sauter G, Rui H. Transcription Factor Stat5 Activation and Breast Cancer Prognosis. Journal of Clinical Oncology, 22(11):2053-2060, 2004.
  • 20. Li HZ, Ahonen TJ, Alanen KA, Xie J, LeBaron MJ, Pretlow TG, Ealley EE, Zhang J, Nurmi M, Singh B, Martikainen P, Nevalainen, MT Activation of Signal Transducer and Activator of Transcription 5 (Stat5) in Human Prostate Cancer is Associated with High Histological Grade. Cancer Research, 64:4774-4782, 2004.
  • 21. Sultan AS, Xie J, LeBaron MJ, Ealley EE, Nevalainen MT, Rui H. Transcription Factor Stat5 Stimulates Homotypic Adhesion and Inhibits Invasive Characteristics of Human Breast Cancer Cells. Oncogene, 24(5):746-760, 2005.
  • 22. Li HZ, Zhang Y, Glass A, Zellweger T, Gehan E, Bubendorf L, Gelmann EP, Nevalainen MT. Activation of Signal Transducer and Activator of Transcription-5 (Stat5) in Prostate Cancer Predicts Early Recurrence. Clinical Cancer Research, 11:5863-5868, 2005.
  • 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, 148:989-1008, 2007.
  • 24. Dagvadorj A, Collins S, Jomain, J, Abdulghani J, Karras J, Zellweger T, Li HZ, Alanen KA, Mirtti TK, Visakorpi T, Bubendorf L, Goffin V, Nevalainen MT. Autocrine Prolactin Promotes Prostate Cancer Cell Growth via Jak2-Stat5 Signaling Pathway. Endocrinology, 148:3089-3101, 2007.
  • 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.
  • 26. Culig Z, Pestell RG, Nevalainen MT. Transcription Factors Stat5 and Stat3: Key Survival Factors for Prostate Cancer Cells. In: Prostate Cancer: Signaling Networks, Genetics and New Treatment Strategies. Nevalainen MT and Pestell RG (Eds), New York: Humana Press (Springer Verlag), 2008.
  • 27. Powell M, Lisanti MP, Nevalainen MT, Wang C, Pestell RG. Androgen Receptor Epigenetic Modification and Acetylation Regulate Prostate Cellular Growth. In: Prostate Cancer: Signaling Networks, Genetics and New Treatment Strategies. Nevalainen MT and Pestell RG (Eds), New York: Humana Press, (Springer Verlag), 2008.
  • 28. Book on: Prostate Cancer: Signaling Networks, Genetics and New Treatment Strategies, Pestell R, Nevalainen MT, (eds), Humana Press, (Springer Verlag), 2008.
  • 29. Tan SH, Nevalainen MT. Transcription Factor Stat5 in Breast and Prostate Cancer. Endocrine Related Cancer, 15:367-390, 2008.
  • 30. 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, 68:1-13, 2008. Featured in Washington Post.
  • 31. Dagvadorj, A, Kirken, RA, Karras, J, Nevalainen, MT. Transcription Factor Stat5 Promotes Growth of Human Prostate Cancer Cells In Vivo. Clinical Cancer Research, 14:1317-1324, 2008. Featured article. Also featured in OncoLink and CDMRP (Congressionally Directed Medical Research Programs) Research Highlights.
  • 32. Abdulghani J, Gu L, Dagvadorj A, Lutz J, Leiby B, Bonucelli G, Lisanti MP, Zellweger T, Alanen K, Mirtti TK, Visakorpi T, Bubendorf L, Nevalainen MT. Transcription Factor Stat3 Promotes Metastatic Behavior of Prostate Cancer. American Journal Pathology, 172:1717-1728, 2008. Featured in Uro.Today and ScienceNews.com.
  • 33. Dagvadorj A, Tan SH Cavalli L, Haddad B, Nevalainen MT. Androgen-Dependent and Highly Tumorigenic Human Prostate Cancer Cell Line Established from a Transplantable Primary CWR22 Tumor. Clinical Cancer Research, 14:6062-6072, 2008. Featured in UroToday.com, Nov. 12, 2008.
  • 34. Gu, L*, Vogiatzi PV*, Puhr M, Dagvadorj A, Lutz J, Ryder A, Addya S, Fortina P, Cooper C, Leiby C, Dasgupta A, Hyslop T, Bubendorf L, Mirtti TK, Nevalainen MT. Stat5 Promotes Metastatic Behavior of Human Prostate Cancer Cells In Vitro and In Vivo. Endocrine-Related Cancer, 18:481-493, 2010. * Equal contribution.
  • 35. Gu L, Dagvadorj A, Lutz J, Leiby B, Bonucelli G, Lisanti M, Addya S, Fortina P, Dasgupta A, Hyslop T, Rhimm J, Bubendorf L, Nevalainen MT. Transcription Factor Stat3 Stimulates Metastatic Behavior of Human Prostate Cancer Cells In Vivo While Stat5 Has a Preferential Role in the Promotion of Prostate Cancer Cell Viability and Tumor Growth. American Journal of Pathology, 176:195, 2010. Featured in Uro.Today.
  • 36. 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. Genome Informatics, 24:139-153, 2010.
  • 37. Gu L, Zhu XH, Visakorpi T, Alanen K, Mirtti T, Bocker Edmonston T, Nevalainen MT.
  • Activating Mutation (V617F) in the Tyrosine Kinase Jak2 is Absent in Locally-confined or Castration-Resistant Prostate Cancer. Analytical Cellular Pathology; Cellular Oncology, 33:55-59, 2010.
  • 38. Dagvadorj A*, Tan S*, Xie J, Nurmi M, Alanen K, Rui H, Mirtti T, Nevalainen MT. N-Terminal truncation of Stat5a/b circumvents PIAS3-mediated inhibition of Stat5 in prostate cancer cells. Int. J. Biochem. Cell Biology, 12:2037-2046, 2010. * Equivalent first authors.
  • 39. Liao Z, Lutz J, Nevalainen MT. Transcription Factor Stat5a/b as a Therapeutic Target Protein for Prostate Cancer. International Journal of Biochemistry and Cell Biology, 42:186-192, 2010.
  • 40. Liao Z and Nevalainen MT. Targeting transcription factor Stat5a/b as a therapeutic strategy for prostate cancer. Am. J. Translational Research, 3:133-138, 2011.
  • 41. Koptyra M, Gupta S, Talati P, Nevalainen MT: Transcription Factor Stat5a/b in Prostate Cancer. In: Int. J. Biochemistry and Cell Biology, Molecules in Focus, 43:1417-1421, 2011.
  • 42. Sato T, Neilson LM, Peck AR, Liu C, Tran TH, Witkiewicz A, Hyslop T, Nevalainen MT, Sauter G, and Rui H. Signal transducer and activator of transcription-3 and breast cancer prognosis. American Journal of Cancer Research, 1:347-355, 2011.
  • 43. Peck AR, Witkiewicz AK, Liu C, Stringer GA, Klimowicz AC, Pequignot E, Freydin B, 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. J Clin Oncol, 18, 2448-53, 2011. Subject of Editorial: Tweardy D, Chang JC. Stat5: from breast development to cancer prognosis, prediction, and progression. J Clin Oncol. 29, 2443-4, 2011.
  • 44. Gupta S, 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, 2012, In Press.
  • 45. 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 (Eds). Springer Verlag, 2012, In Press.
  • 46. Mirtti TK, Talati P, and Nevalainen MT: Trascription Factors Stat5a/b and Stat3 in Prostate Cancer Growth and Metastases. In: Signalling Pathways and Molecular Mediators in Metastases. Fatatis A (Ed), Springer, Book Chapter, p 245-260, 2012.
  • 47. Goffin G, Hoang DT, Bogorad RL, Nevalainen MT: The Role of Prolactin in the Prostate Gland: A Female Player in a Male Game. Nature Reviews in Urology, 4:597-607, 2011.
  • 48. Leiby B, Mirtti, TK, Abdulghani A, Altonen E, Pavela M, Mamtani A, Alanen K, Granfors EL, Josefsson A, Stattin P, Bergh A, Nevalainen MT. Increased Nuclear Stat5a/b Expression in Prostate Cancer Predicts both Early Recurrence and Prostate Cancer-Specific Death. Human Pathology, In Press, 2012.
  • 49. Stankiewicz TR, Loucks FA, Schroeder WK, Nevalainen MT, Tyler KL, Aktories K, Bouchard RJ, Linseman DA. Signal transducer and activator of transcription-5 mediates neuronal apoptosis induced by the inhibition of Rac GTPase activity. J Biol. Chem., In Press, 2012.

Individual Expertise profile of Marja Nevalainen, MD, PhD, Copyright © Marja Nevalainen, MD, PhD.
Last Updated by Marja Nevalainen, MD, PhD : Tuesday, October 23, 2012 10:50:49 AM



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