GnRH Receptor Target Therapy

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The GnRH receptor can be utilized for targeted therapies such as 

- GnRH receptor-mediated chemotherapy using cytotoxic GnRH analogs

- Hormone therapy using GnRH-I and GnRH-II analogs

- GnRH receptor-mediated gene therapy

The majority of human ovarian, endometrial and breast 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 tumor cells, which is basically different of classical GnRH receptor signal transduction, known to operate in pituitary gonadotrophs.

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1.) GnRH receptor targeted chemotherapy

Funding:

• Basic Research: Deutsche Krebshilfe - Dr. Mildred Scheel Stiftung (10-1299)

• Clinicial Trials: Aeterna Zentaris Inc.

Publications:

• Westphalen S, Kotulla G, Kaiser F, Krauß W, Werning G, Elsässer HP, Nagy A, Schulz KD, Gründker C, Schally AV, Emons G (2000) Receptor mediated antiproliferative effects of the cytotoxic LHRH agonist AN-152 in human ovarian and endometrial cancer cell lines. International Journal of Oncology 17:1063-1069

• Gründker C (2000) Cytotoxic luteinizing hormone-releasing hormone conjugates and its use in gynecological cancer therapy. European Journal of Endocrinology 143:569-572

• Gründker C, Völker P, Griesinger F, Ramaswamy A, Nagy A, Schally AV, Emons G (2002) Antitumor effects of cytotoxic LHRH analog AN-152 on human endometrial and ovarian cancers xenografted into nude mice. American Journal of Obstetrics and Gynecology 187:528-537

• Günthert AR, Gründker C, Bongertz T, Nagy A, Schally AV, Emons G (2004) Induction of apoptosis by AN-152, a cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), in LHRH-R positive human breast cancer cells is independent of multi drug resistance-1 (MDR-1) system. Breast Cancer Research and Treatment 87:255-264

• Günthert AR, Gründker C, Bongertz T, Schlott T, Nagy A, Schally AV, Emons G (2004) Internalisation of cytotoxic luteinizing hormone-releasing hormone analog AN-152 induces multi drug resistance 1 (MDR-1) -independent apoptosis in human endometrial and ovarian cancer cell lines. American Journal of Obstetrics and Gynecology 191:1164-1172

• Gründker C, Günthert AR, Emons G (2006) Zielzellspezifische Chemotherapie über den GnRH-Rezeptor. Frauenarzt 47(7):590-592

• Emons G, Sindermann H, Schally AV, Gründker C (2009) LHRH receptor targeted chemotherapy using AN-152. Neuroendocrinology 90(1):15-18

• Emons G, Kaufmann M, Gorchev G, Tsekova V, Gründker C, Günthert AR, Hanker LC, Velikova M, Sindermann H, Engel J, Schally AV (2010) Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors. Gynecologic Oncology 119:457-461

• Föst C, Duwe F, Hellriegel M, Schweyer S, Emons G, Gründker C (2011) Targeted chemotherapy for triple-negative breast cancers via LHRH receptor. Oncology Reports 25:1481-1487

• Gründker C, Ernst J, Reutter M, Ghadimi BM, Emons G (2011) Effective targeted chemotherapy using AN-152 for LHRH receptor-positive pancreatic cancers. Oncology Reports 26: 629-635

• Emons G, Gorchev G, Harter P, Wimberger P, Stähle A, Hanker L, Hilpert F, Beckmann MW, Dall P, Gründker C, Sindermann H, Sehouli J (2014) Efficacy and safety of AEZS-108 (LHRH agonist linked to doxorubibin) in woman with advanced or recurrent endometrial cancer expressing LHRH receptors: a multicenter phase 2 trial (AGO GYN 5). International Journal of Gynecological Cancer 24(2):260-265

• Emons G, Gorchev G, Sehouli J, Wimberger P, Stähle A, Hanker L, Hilpert F, Sindermann H, Gründker C, Harter P (2014) Efficacy and safety of AEZS-108 (INN: Zoptarelin doxorubicin acetate) an LHRH agonist linked to doxorubibin in woman with platinum refractory or resistant ovarian cancer expressing LHRH receptors: a multicenter phase II trial of the AGO-study group (AGO GYN 5). Gynecologic Oncology 133(3):427-432

• Gründker C, Wokoun U, Hellriegel M, Emons G (2019) Inhibition of aerobis glycolysis enhances the anti-tumor efficacy of Zoptarelin Doxorubicin in triple-negative breast cancer cells. The Journal of Obstetrics and Gynaecology Research doi:10.1111/jog.13980
  

Commentary:

• Orellana C (2002) Targeted approach against ovarian and endometrial cancer. The Lancet Oncology 3:711

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2.) hormone therapy using GnRH-I and GnRH-II analogs

Funding:

• Deutsche Krebshilfe - Dr. Mildred Scheel Stiftung, approved on 08/18/2004 for 2 years

• Deutsche Krebshilfe - Dr. Mildred Scheel Stiftung, approved on 01/22/2007 for 2 years

• Deutsche Krebshilfe - Dr. Mildred Scheel Stiftung, approved on 07/24/2009 for 2 years

Publications:

• Fister S, Günthert AR, Emons G, Gründker C (2007) Gonadotropin-releasing hormone type II antagonists induce apoptotic cell death in human endometrial and ovarian cancer cells in vitro and in vivo. Cancer Research 67:1750-1756

• Fister S, Günthert AR, Aicher B, Paulini KW, Emons G, Gründker C (2009) GnRH-II antagonists induce apoptosis in endometrial, ovarian and breast cancers via activation of stress-induced MAPKs p38 and JNK and pro-apoptotic protein Bax. Cancer Research 69:6473-6481

• Gründker C, Föst C, Fister S, Nolte N, Günthert AR, Emons G (2010) GnRH-II antagonist induces apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells in vitro and in vivo. Breast Cancer Research 12(4):R49.

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Funding:

• School of Medicine, Georg-August-University of Göttingen, 2000

Publication:

• Gründker C, Huschmand Nia A, Emons G (2005) GnRH receptor-mediated gene therapy of gynecological cancers. Molecular Cancer Therapeutics 4:225-231

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