Urology Research

Education

• 1998   Magistère of Biology-Biochemistry, Ecole Normal Supérieure (Paris VI, VII and XIII).
• 2002   Ph.D. Thesis - Specialty Molecular and Cellular Biology (P.M. Curie University-Paris-France)

Inhibiting modalities of the Pigment Epithelium-Derived Factor (PEDF) in prostate cancer growth.

Prostate cancer develops in the male reproductive system. It is the most common malignancy in American men and the second leading cause of cancer-related deaths in men. While many prostate cancers are slowly growing and curable, more advanced (metastatic) prostate cancers are highly aggressive and virtually incurable. New therapeutic alternatives are therefore urgently needed. Anti-angiogenic strategies, affecting the blood vessels and blood supply, have already shown great promise in the treatment of other cancers. For example, in metastatic kidney cancer, it now represents the first line treatment. Angiogenesis, the growth of new capillary blood vessels in the body, is a natural process important for healing and reproduction. The body controls angiogenesis by producing a precise balance of growth and inhibitory factors in healthy tissues. When this balance is disturbed, the result is either too much or too little angiogenesis. Abnormal excessive blood vessel growth is now recognized as a “common denominator” underlying many deadly and debilitating conditions, including cancers. In our laboratory, we have demonstrated that the Pigment Epithelium-Derived Factor (PEDF) is a natural and extremely potent factor that blocks angiogenesis in the prostate.

PEDF is present in the healthy prostate gland. In contrast, PEDF disappears in prostate cancer, leading subsequently to increased angiogenesis and chaotic proliferation/growth of tumor cells. This leads to prostate cancer progression and localized tumors dissemination to distant sites (process also called metastases formation). Our main goal is to validate PEDF as a new therapeutic alternative to block prostate cancer progression. To achieve this, we have established prostate cancer cell lines which express or do not express PEDF. The resulting cells were then injected into the hindquarters of immuno-compromised mice (subcutaneous model) and tumor growth was followed over time. Our results showed that all animals injected with cancer cells formed tumors; however, tumors that grew in the presence of PEDF were ~ 70% smaller compared to tumors in which PEDF was not present (Figure 1). We identified at least four molecular mechanisms involved in PEDF growth inhibitory effects; i.e.: i) stimulation of death of endothelial cells in the tumor compartment, leading to reduced tumoral angiogenesis and delayed tumor growth; (ii) decrease proliferation/growth of prostate cancer cells; (iii) induction of tumor cells differentiation towards a less malignant phenotype; and (iv) stimulation of an effective host inflammatory immune response. These results emphasize the significance of PEDF as a potential new therapeutic option in prostate cancer patients.

In the near future, we will focus our research on two different goals. First, we will validate PEDF anti-tumor properties in novel experimental prostate cancer mouse models. The model that we chose is called an orthotopic model. In this model, tumor cells are inoculated/injected into the prostate glands of mice simulating the natural course of this malignancy. After injection, animals develop prostatic tumors that will, over time, metastasize to distant sites such as bones, a common and therapeutically challenging site of disease in patients with advanced prostate cancer. In this model, we have already demonstrated that the pretreatment of tumor cells with a single dose of purified PEDF prolonged the survival of the mice compared to control/non-treated group (Figure 2). To increase the survival effect that we previously observed, this model will now be further used with prostate cancer cell lines that endogenously express or do not express PEDF (cell lines used in Figure 1).

Second, we will work on establishing a delivery system that will allow us to deliver specifically and with a high efficiency PEDF to the tumors. This research will allow us to achieve a decisive step towards clinical application of PEDF-based strategy for treating prostate cancer patients.

This therapeutic tool/approach is new and innovative because it will develop preclinical data that may support further development of the natural PEDF factor for treating prostate cancer. At the study completion, we expect that we will have elucidated the mechanisms by which PEDF blocks prostate tumor progression and metastases formation. The data from this study can potentially lead to the development of improved therapeutic approaches for prostate cancer. We are well prepared to pursue this study because of our previous published research on prostate cancer and PEDF, our strong collaborations and our institution commitment to develop novel strategies to treat cancer.

• Experimental Eye Research Journal
• Oncogene Journal
• Expert Opinion on Therapeutic Targets Journal
• Pharmacological Research Journal
• Neoplasia
• Protein Journal
• Cancer control Journal
• Cell Biochemistry & Function
• Journal of Cellular Biochemistry
• BMC Cancer
• BioFactors
• Clinical and Experimental Metastasis

• Israel Science Foundation (Israel)
• Cariplo Foundation (Italy)

1. Marable-Hirsch, J.,Johnson, C., Nelius, T., de Riese, W., Kennedy, R., & Filleur, S. (2010). PEDF inhibits IL8 production in prostate cancer cells through PEDF receptor/Phospholipase A2 receptor and regulation of NFκB and PPARγ. Accepted for publication in Cytokine.
2. Nelson, J., Rinard, K., Haynes, A., Filleur, S., & Nelius, T. (2011). Extraluminal Colonic carcinoma invading into Kidney — Case Report and Review of the Literature. Accepted in ISRN Urology
3. Nelius, T., Rinard, K., & Filleur, S. (2010). Oral/Metronomic Cyclophosphamide-based Chemotherapy as Option for Patients with Castration-Refractory Prostate Cancer — Review of the Literature. Accepted in Cancer Treatment Reviews
4. Nelius, T. & Filleur, S. (2010, September 16). National Prostate Cancer Month, 2010 by Texas Tech Physicians web-based publication: http://ko-kr.connect.facebook.com/note.php?note_id=152642804756724
5. Nelius, T. & Filleur, S.. (2010, October 8). Penis klemmt im Bratpfannen-stiel. (article in German) Medical Tribune Germany 45(40).
6. Filleur, S., Hirsch, J., Wille, A., Schön, M., Sell, C., Shearer, M., Nelius, T. & Wieland, I. (2009). INTS6/DICE1 inhibits the growth of human androgen-independent prostate cancer cells by altering cell cycle profile and Wnt signaling. Cancer Cell International, 9, 28-36.
7. Nelius, T., & Filleur, S. (2009). Self–inflicted Penile Strangulation. Accepted in Aktuelle Urologie.
8. Nelius, T., & Filleur, S. (2009). PSA Surge/Flare–up in Patients with Castration–Refractory Prostate Cancer during the Initial Phase of Chemotherapy — Review of the Literature. Prostate, 41(1), 64-66.
9. Nelius, T., Stevens, J., Samathanam, C., Filleur, S. (2009). Leiomyosarcoma of the urinary bladder presenting as life threatening gross hematuria. Medical Oncology, 27(2), 562-567.
10. Nelius, T., Klatte, T., de Riese, W., Haynes, A., & Filleur, S.(2009). Clinical outcome of patients with Docetaxel–resistant hormone–refractory prostate cancer treated with second–line cyclophosphamide–based metronomic therapy. Medical Oncology, 27(2), 363-367.
11. Filleur, S., Nelius, T., de Riese, W., & Kennedy, R.C. (2009) Characterization of PEDF: A multi-functional serpin family protein. Journal of Cellular Biochemistry, 106(5), 769-776.
12. Smith, N.D., Schulze-Hoepfner, F.T., Veliceasa, D., Filleur, S., Huang, L., Huang, X., Volpert, O.V. (2008). PEDF and IL-6 control prostate neuroendocrine differentiation via feed forward mechanism. The Journal of Urology, 179, 2427-2434.
13. Nelius, T., Filleur, S., Yemeyanov, A., Budunova, I., Shroff, E., Mirochnik, Y., Veliceasa, D., & Volpert, O.V. (2007, September 1). The pro–apoptotic and anti–angiogenic effects of androgen in the vivo model of prostate cancer. Int J Cancer, 121(5), 999-1008.
14. Nelius, T., Klatte, T., de Riese, W., Filleur, S. (2007). Impact of PSA flare-up in patients with hormone-refractory prostate cancer undergoing chemotherapy. Int Urol Nephrol, 40(1), 97-104.
15. Klatte, T., Böhm, M., Nelius, T., Filleur, S., Allhoff, E.P. (2007, July). Evaluation of perioperative peripheral and renal venous levels of pro–angiogenic and anti–angiogenic factors and their relevance in patients with renal cell carcinoma. BJU Int, 100(1), 209-214.
16. Nelius, T., Klatte, T., Yap, R., Kalinski, T., Röpke, A., Filleur, S., & Allhoff, E.P. (2006). Randomized study of docetaxel and dexamethasone with low or high dose estramustine for patients with advanced hormone–refractory prostate cancer. BJU Int, 98(3), 580-585.
17. Nelius, T., Reiher, F., Lindenmeir, T., Kalinski T, Rau, O., Filleur, S., & Allhoff, E.P. (2006). Idiopathic Retroperitoneal Fibrosis (Ormond’s Disease) — A Case Report. Aktuel Urol 2006, 37, 284-288.
18. Nelius, T., de Riese, W., Reiher, F., Filleur, S., & Allhoff, E.P. (2006). Laser Therapy in the Treatment of Urological Diseases. In “Photonic Therapeutics and Diagnostics II”. Proc. SPIE, 6078, 342-351.
19. Nelius, T., Reiher, F., Lindenmeir, T., Klatte, T., Rau, O., Burandt, J., Filleur, S., & Allhoff, E.P. (2005, October 10). Characterization of Prognostic Factors and Efficacy in a Phase–II Study with Docetaxel and Estramustine for Advanced Hormone–refractory Prostate Cancer. Onkologie, 28, 573-578.
20. Filleur, S., Volz, K., Nelius, T., Zaichuk, T.A., Huang, H., Mirochnik, Y., Aymerich, M.S., Becerra, S.P., Yap, R., Veliceasa, D., Shroff, H.E., & Volpert, O.V. (2005). Two functional epitopes of PEDF block angiogenesis and induce differentiation in prostate cancer. Cancer Research, 65(12), 5144-5152.
21. Fontana, A., Filleur, S. (Co–first authors), Frappart. L., Bruno-Bossio, G., Boissier, S., Guglielmi, J., Cabon, F., & Clezardin, P. (2005). How Human Breast Tumors Override The Antiangiogenic Effect of Stromal Thrombospondin–1 In Vivo. Int J Cancer, 116(5), 686-691.
22. Quesada, A.J., Nelius, T., Yap, R., Zaichuk, T.A., Alfranca, A., Filleur, S., Volpert, O.V., & Redondo, J.M. (2005). In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment. Cell Death Differ, 12(6), 649-658.
23. Nelius, T., de Riese, W., Reiher, F., Lindenmeir, T., Filleur, S., & Allhoff, E.P. (2005). Laparoscopic (Endoscopic) Radical Prostatectomy: Techniques and Results. In “Lasers in Surgery: Advanced Characterization, Therapeutics, and Systems ”. Proc. SPIE, 5686, 375-382.
24. Colombel, M., Filleur, S. (Co–first authors), Fournier, P., Merle, C., Guglielmi, J., Courtin, A., Degeorges, A., Serre, C.M., Bouvier, R., Clézardin, P., & Cabon, F. (2005). Androgens Repress the Expression of the Angiogenesis Inhibitor Thrombospondin–1 in the Normal and Neoplastic Prostate. Cancer Research, 65(1), 300-308.
25. Zaichuk, T.A., Shroff, E.H., Emmanuel, R., Filleur, S., Nelius, T., Volpert, O.V. (2004). Nuclear factor of activated T cells balances angiogenesis activation and inhibition. J Exp Med, 199(11), 1513-1522.
26. Nelius, T., de Riese, W., & Filleur, S. (2004). Photodynamic Therapy a promising Alternative in Oncology. In “Lasers in Surgery: Advanced Characterization, Therapeutics, and Systems XIV”. Proc. SPIE, 5312, 234-242.
27. Filleur, S., Courtin, A., Ait–Si–Ali, S., Guglielmi, J., Merle, C., Harel–Bellan, A., Clézardin, P., & Cabon, F. (2003). SiRNA–mediated inhibition of vascular endothelial growth factor severely limits tumor resistance to antiangiogenic thrombospondin–1 and slows tumor vascularization and growth. Cancer Research, 63(14), 3919-3922.
28. Fournier, P., Boissier, S., Filleur, S., Guglielmi, J., Cabon, F., Colombel, M., & Clézardin, P. (2002). Bisphosphonates inhibit angiogenesis in vitro and testosterone–stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Research, 62(22), 6538-6544.
29. Filleur, S., Volpert, O.V., Degeorges, A., Voland, C., Reiher, F., Clézardin, P., Bouck, N., & Cabon, F. (2001). In vivo mechanisms by which tumors producing thrombospondin 1 bypass its inhibitory effects. Genes and Development, 15, 1373-1382.
30. Ait–Si–Ali, S., Polesskaya, A., Filleur, S., Ferreira, R., Duquet, A., Robin, P., Vervish, A., Trouche, D., Cabon, F., Harel–Bellan, A. (2000). CBP/p300 histone acetyl&nsdash;transferase activity is important for the G1/S transition. Oncogene 19(20), 2430-2437.
31. Dejong, V., Degeorges, A., Filleur, S., Ait–Si–Ali, S., Mettouchi, A., Bornstein, P., Binétruy, B., & Cabon, F. (1999). The wilms’ tumor gene product represses the transcription of thrombospondin 1 in response to overexpression of c–Jun. Oncogene, 18(20), 3143-3151.