Group Leaders: Prof. Dr. rer. nat. Carsten Gründker and Prof. Dr. med. Günter Emons
The majority of ovarian (>80%) and endometrial (>80%) cancers express
GnRH receptors. Apart from reproductive organs (ovary, fallopian tube, uterus) that are normally
removed during surgical therapy of ovarian or endometrial cancer, other organs and hematopoetic
stem cells do not express GnRH receptors. In addition, a tumor specific signal transduction
exists in the tumor cells, which is basically different of the classical GnRH receptor signal
transduction, known to operate in the pituitary gonadotrophs. We have recently shown specific
activation of nucleus factor kappa B (NFkB) in ovarian and endometrial cancers after treatment
with GnRH. These properties of GnRH would make it an ideal candidate to induce the expression
of a therapeutic gene in GnRH-receptor positive tumors. Based on these findings we have developed
a novel gene therapy concept using the tumor specific GnRH receptor signal transduction pathway.
In this study we could demonstrate that GnRH agonist-induced activation of different reporter
genes via NFkB promotor was restricted to GnRH receptor-positive cancer cell lines. Using the
reporter gene LacZ, the concept of gene therapy via GnRH receptor dependent tumor specific
signal transduction pathway was successfully tested in nude mice bearing xenografts of human
ovarian or endometrial cancers. The GnRH receptor-positive tumors as well as the reproductive
organs exclusively showed activation of LacZ. All other organs did not show any activation
of LacZ. Using Herpes Simplex thymidine kinase as therapeutic gene, Ganciclovir as pro-drug
and GnRH agonist Triptorelin as inductor we could demonstrate specific killing of GnRH receptor-positive
cancer cells in vitro. No effects were observed on GnRH-receptor negative cells. Because of
the different GnRH receptor signal transduction no toxic effects could as well be observed
in the GnRH receptor-positive pituitary gonadotrophs. In the meantime, the Proof-Of Principle
could be demonstrated in vivo on tumor-bearing nude mice. The tumor volume of the gene therapy
given mice was significantly lower than with the control animals. Toxic side effects were not
observed.
Funding:
School of Medicine, Georg-August-University of Göttingen, 2000
Publications: