- 1998 Magistère of Biology-Biochemistry, Ecole Normal Supérieure (Paris VI, VII and
- 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
Prostate cancer develops in the prostate
, a gland 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
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
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.
PEDF Inhibits the growth of subcutaneous tumor in vivo.
PEDF single dose prolongs the survival of tumor-bearing mice.
- Mentor of K. RAJBHANDARI, Student SABR Program (2007).
- Mentor of A. Ramirez, Undergraduate Student (2007-2008).
- Mentor of J. Marable, Student Master Biotechnology (2008-2010; Dean Award 2010).
- Mentor of J. Stevens, PGY2, Residency Program in Urology (2008-2009).
- Mentor of Jose A. Lopez, MSI, TTUHSC (Summer 2009, Laura Bush Institute Fellowship).
- Mentor of K. Rinard, PGY2, Residency Program in Urology (2009-2010).
- Mentor of James Lemert, MSIV (2009).
- Doctoral Advisory Committee member for Luis Bermudez (Master student, Department of
Cell Physiology and Molecular Biophysics).
- Mentor of Dr. Johnny Hickson, PGY2, Residency Program in Urology (2010-2011).
- Mentor of Melodie McTaggart, Student SABR Program (2011).
- Doctoral Advisory Committee member for Jood Hashem (Ph.D. graduate student, Department
of Cell Physiology and Molecular Biophysics, 2011)
- Experimental Eye Research Journal
- Oncogene Journal
- Expert Opinion on Therapeutic Targets Journal
- Pharmacological Research Journal
- Protein Journal
- Cancer control Journal
- Cell Biochemistry & Function
- Journal of Cellular Biochemistry
- BMC Cancer
- Clinical and Experimental Metastasis
- Israel Science Foundation (Israel)
- Cariplo Foundation (Italy)
- 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.
- 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
- 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
- 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
- Nelius, T. & Filleur, S.. (2010, October 8). Penis klemmt im Bratpfannen-stiel. (article in German) Medical Tribune Germany 45(40).
- 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.
- Nelius, T., & Filleur, S. (2009). Self–inflicted Penile Strangulation. Accepted in Aktuelle Urologie.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.