A neutralizing anti-fibroblast growth factor (FGF) 8 monoclonal antibody shows anti-tumor activity against FGF8b-expressing LNCaP xenografts in androgen-dependent and -independent conditions.

Abstract

BACKGROUND:

Fibroblast growth factor 8-isoform b (FGF8b) has been detected in human clinical sex-organ related cancers including hormone-refractory prostate cancer. There are, however, few relevant experimental models. A murine monoclonal anti-FGF8 antibody, KM1334, has been shown to neutralize FGF8b and inhibit the growth of androgen-dependent mouse mammary SC-3 cells in vitro and in vivo. In the present study, we evaluated the anti-tumor activity of KM1334 against androgen-dependent and -independent progression of FGF8b-expressing human prostate cancer xenografts.

METHODS:

FGF8b cDNA was transfected into androgen-dependent human prostate cancer cell line LNCaP, and its xenograft tumors were established subcutaneously in SCID mice with or without castration. KM1334 at the dose of 400 microg/head was injected twice weekly.

RESULTS:

FGF8b-expressing LNCaP cells secreted FGF8b, showed enhanced level of Erk1/2 phosphorylation, and showed more potent growth properties than mock-expressing cells in vitro and in vivo. KM1334 reduced these properties in vitro, inhibited tumorigenecity in vivo (T/C=0.33), and showed anti-tumor activity against established tumors (T/C=0.47) of FGF8b-expressing cells. FGF8b-expressing LNCaP tumors were androgen-dependent. However, they recurred as androgen-independent FGF8b positive tumors after castration. KM1334 also inhibited the growth of established FGF8b-expressing tumors in the androgen-independent states (T/C=0.47).

CONCLUSIONS:

These results indicate that humanized monoclonal antibodies, conserving the paratope of KM1334, are a promising candidate for therapy of FGF8b-expressing clinical prostate cancers. Follow-up studies using xenograft models with clinical FGF8b-expressing tumors are required to validate these early findings.

• Authors: Kumiko Maruyama-Takahashi, Naoki Shimada, Teruyoshi Imada, Yoshimi Maekawa-Tokuda, Toshihiko Ishii, Jun Ouchi, Hideaki Kusaka, Hiromasa Miyaji, Shiro Akinaga, Akira Tanaka, Kenya Shitara
• Journal: The Prostate (Prostate) Vol. 68 Issue 6 Pg. 640-50 (May 01 2008) ISSN: 0270-4137 [Print] United States
• PMID: 18213631 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Fgf8 protein, mouse
• Fibroblast Growth Factor 8
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinase 6

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Antineoplastic Agents (immunology, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Immunologic
• Female
• Fibroblast Growth Factor 8 (genetics, immunology, metabolism)
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred ICR
• Mice, SCID
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Mitogen-Activated Protein Kinase 6 (metabolism)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Transfection
• Xenograft Model Antitumor Assays