AEZS-108: A targeted cytotoxic analog of LHRH for the treatment of cancers positive for LHRH receptors

Joerg Engel, Guenter Emons, Jacek Pinski, Andrew V Schally

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Introduction: Receptors for the luteinizing hormone-releasing hormone [LHRH, also known as gonadotropin-releasing hormone (GnRH)] can be regarded as an ideal target for a personalized medicine approach in cancer therapy. LHRH receptors are expressed in about 80% of human endometrial and ovarian cancers, 86% of prostate cancer, and about 50% of breast cancers including triple-negative breast cancer, as well as bladder, colorectal, and pancreatic cancers, sarcomas, lymphomas, melanomas, and renal cell carcinomas. Apart from the pituitary and reproductive organs, other organs and hematopoietic stem cells express LHRH receptors. Thus, a targeted cytotoxic LHRH analog such as AEZS-108 (formerly known as AN-152), in which doxorubin is linked to the LHRH agonist [D-Lys 6]LHRH, appears to be a suitable drug for targeted chemotherapy of cancers expressing receptors for LHRH, which would be more efficacious and less toxic than standard systemic chemotherapy. Areas covered: This review discusses the development of AEZS-108, its targeting mechanism, preclinical studies, and clinical trials in patients with endometrial, ovarian, prostatic, and bladder cancers. We emphasize its development as a personalized medicine approach. The studies reviewed demonstrate the effects of the cytotoxic LHRH analog, AEZS-108, mediated by LHRH receptors, in in vivo models of LHRH-receptor-positive human endometrial, ovarian, breast, prostatic, colorectal, pancreatic, and bladder cancers xenografted into nude mice. Intravenous administration of AEZS 108 inhibits the growth of LHRH-receptor-positive tumors better than equimolar doses of the cytotoxic agent doxorubicin and is far less toxic. AEZS 108 has no antitumor activity in cancers negative to LHRH receptor. This strongly supports the concept of targeting cytotoxic chemotherapy to tumor cells expressing LHRH receptors. Early clinical trials have demonstrated the efficacy of AEZS-108. A Phase I trial assessed the maximum tolerated dose and pharmacokinetics and pharmacodynamics of AEZS-108 given once every 3 weeks in patients with gynecological cancers. Two Phase II studies in heavily pretreated ovarian and recurrent endometrial cancers showed good clinical activity after a maximum of six courses of AEZS-108 as a single agent. Ongoing clinical studies with AEZS-108 in men with castration-resistant prostate cancer and patients with chemotherapy refractory bladder cancer had shown early signs of clinical efficacy. Side effects are moderate and easily manageable. In particular, no pituitary or cardiac toxicity is observed. Expert opinion: AEZS-108 is a cytotoxic analog designed for receptor-mediated targeted chemotherapy and consists of an LHRH carrier linked to doxorubicin. Preclinical studies demonstrate that the uptake of AEZS-108 is achieved by receptor-mediated endocytosis. Results of Phase I and II clinical trials in patients with gynecological cancers demonstrated anticancer activity without cardiotoxicity even in highly pretreated patients. Phase I/II studies in castration-resistant prostate cancer and chemotherapy refractory bladder cancer are in progress. Targeted chemotherapy with a cytotoxic analog of LHRH, such as AEZS-108, is therefore being considered for Phase III studies in advanced endometrial cancers positive for LHRH receptor. LHRH receptors are also present in human colon cancers, melanomas, lymphomas, and sarcomas, and treatment of these cancers with AEZS-108 should also be undertaken. Before such treatment with AEZS-108 is begun, the status of tumoral LHRH receptors of patients must be determined.

Original languageEnglish
Pages (from-to)891-899
Number of pages9
JournalExpert Opinion on Investigational Drugs
Volume21
Issue number6
DOIs
StatePublished - Jun 1 2012

Fingerprint

LHRH Receptors
Gonadotropin-Releasing Hormone
Neoplasms
Endometrial Neoplasms
Prostatic Neoplasms
Urinary Bladder Neoplasms
Drug Therapy
Therapeutics
Ovarian Neoplasms
Precision Medicine
Poisons
Castration
lysine(6)-doxorubicin LHRH
Pancreatic Neoplasms
Sarcoma
Doxorubicin
Colorectal Neoplasms
Melanoma
Lymphoma
Clinical Trials

Keywords

  • AEZS-108
  • Bladder cancer
  • Breast cancer
  • Doxorubicin
  • Endometrial cancer
  • LHRH-receptor-positive cancers
  • Ovarian cancer
  • Personalized medicine
  • Prostatic cancer
  • Targeted chemotherapy

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

AEZS-108 : A targeted cytotoxic analog of LHRH for the treatment of cancers positive for LHRH receptors. / Engel, Joerg; Emons, Guenter; Pinski, Jacek; Schally, Andrew V.

In: Expert Opinion on Investigational Drugs, Vol. 21, No. 6, 01.06.2012, p. 891-899.

Research output: Contribution to journalArticle

@article{8445ae74fdbe42139b30bdcef0ea7113,
title = "AEZS-108: A targeted cytotoxic analog of LHRH for the treatment of cancers positive for LHRH receptors",
abstract = "Introduction: Receptors for the luteinizing hormone-releasing hormone [LHRH, also known as gonadotropin-releasing hormone (GnRH)] can be regarded as an ideal target for a personalized medicine approach in cancer therapy. LHRH receptors are expressed in about 80{\%} of human endometrial and ovarian cancers, 86{\%} of prostate cancer, and about 50{\%} of breast cancers including triple-negative breast cancer, as well as bladder, colorectal, and pancreatic cancers, sarcomas, lymphomas, melanomas, and renal cell carcinomas. Apart from the pituitary and reproductive organs, other organs and hematopoietic stem cells express LHRH receptors. Thus, a targeted cytotoxic LHRH analog such as AEZS-108 (formerly known as AN-152), in which doxorubin is linked to the LHRH agonist [D-Lys 6]LHRH, appears to be a suitable drug for targeted chemotherapy of cancers expressing receptors for LHRH, which would be more efficacious and less toxic than standard systemic chemotherapy. Areas covered: This review discusses the development of AEZS-108, its targeting mechanism, preclinical studies, and clinical trials in patients with endometrial, ovarian, prostatic, and bladder cancers. We emphasize its development as a personalized medicine approach. The studies reviewed demonstrate the effects of the cytotoxic LHRH analog, AEZS-108, mediated by LHRH receptors, in in vivo models of LHRH-receptor-positive human endometrial, ovarian, breast, prostatic, colorectal, pancreatic, and bladder cancers xenografted into nude mice. Intravenous administration of AEZS 108 inhibits the growth of LHRH-receptor-positive tumors better than equimolar doses of the cytotoxic agent doxorubicin and is far less toxic. AEZS 108 has no antitumor activity in cancers negative to LHRH receptor. This strongly supports the concept of targeting cytotoxic chemotherapy to tumor cells expressing LHRH receptors. Early clinical trials have demonstrated the efficacy of AEZS-108. A Phase I trial assessed the maximum tolerated dose and pharmacokinetics and pharmacodynamics of AEZS-108 given once every 3 weeks in patients with gynecological cancers. Two Phase II studies in heavily pretreated ovarian and recurrent endometrial cancers showed good clinical activity after a maximum of six courses of AEZS-108 as a single agent. Ongoing clinical studies with AEZS-108 in men with castration-resistant prostate cancer and patients with chemotherapy refractory bladder cancer had shown early signs of clinical efficacy. Side effects are moderate and easily manageable. In particular, no pituitary or cardiac toxicity is observed. Expert opinion: AEZS-108 is a cytotoxic analog designed for receptor-mediated targeted chemotherapy and consists of an LHRH carrier linked to doxorubicin. Preclinical studies demonstrate that the uptake of AEZS-108 is achieved by receptor-mediated endocytosis. Results of Phase I and II clinical trials in patients with gynecological cancers demonstrated anticancer activity without cardiotoxicity even in highly pretreated patients. Phase I/II studies in castration-resistant prostate cancer and chemotherapy refractory bladder cancer are in progress. Targeted chemotherapy with a cytotoxic analog of LHRH, such as AEZS-108, is therefore being considered for Phase III studies in advanced endometrial cancers positive for LHRH receptor. LHRH receptors are also present in human colon cancers, melanomas, lymphomas, and sarcomas, and treatment of these cancers with AEZS-108 should also be undertaken. Before such treatment with AEZS-108 is begun, the status of tumoral LHRH receptors of patients must be determined.",
keywords = "AEZS-108, Bladder cancer, Breast cancer, Doxorubicin, Endometrial cancer, LHRH-receptor-positive cancers, Ovarian cancer, Personalized medicine, Prostatic cancer, Targeted chemotherapy",
author = "Joerg Engel and Guenter Emons and Jacek Pinski and Schally, {Andrew V}",
year = "2012",
month = "6",
day = "1",
doi = "10.1517/13543784.2012.685128",
language = "English",
volume = "21",
pages = "891--899",
journal = "Expert Opinion on Investigational Drugs",
issn = "1354-3784",
publisher = "Taylor and Francis Ltd.",
number = "6",

}

TY - JOUR

T1 - AEZS-108

T2 - A targeted cytotoxic analog of LHRH for the treatment of cancers positive for LHRH receptors

AU - Engel, Joerg

AU - Emons, Guenter

AU - Pinski, Jacek

AU - Schally, Andrew V

PY - 2012/6/1

Y1 - 2012/6/1

N2 - Introduction: Receptors for the luteinizing hormone-releasing hormone [LHRH, also known as gonadotropin-releasing hormone (GnRH)] can be regarded as an ideal target for a personalized medicine approach in cancer therapy. LHRH receptors are expressed in about 80% of human endometrial and ovarian cancers, 86% of prostate cancer, and about 50% of breast cancers including triple-negative breast cancer, as well as bladder, colorectal, and pancreatic cancers, sarcomas, lymphomas, melanomas, and renal cell carcinomas. Apart from the pituitary and reproductive organs, other organs and hematopoietic stem cells express LHRH receptors. Thus, a targeted cytotoxic LHRH analog such as AEZS-108 (formerly known as AN-152), in which doxorubin is linked to the LHRH agonist [D-Lys 6]LHRH, appears to be a suitable drug for targeted chemotherapy of cancers expressing receptors for LHRH, which would be more efficacious and less toxic than standard systemic chemotherapy. Areas covered: This review discusses the development of AEZS-108, its targeting mechanism, preclinical studies, and clinical trials in patients with endometrial, ovarian, prostatic, and bladder cancers. We emphasize its development as a personalized medicine approach. The studies reviewed demonstrate the effects of the cytotoxic LHRH analog, AEZS-108, mediated by LHRH receptors, in in vivo models of LHRH-receptor-positive human endometrial, ovarian, breast, prostatic, colorectal, pancreatic, and bladder cancers xenografted into nude mice. Intravenous administration of AEZS 108 inhibits the growth of LHRH-receptor-positive tumors better than equimolar doses of the cytotoxic agent doxorubicin and is far less toxic. AEZS 108 has no antitumor activity in cancers negative to LHRH receptor. This strongly supports the concept of targeting cytotoxic chemotherapy to tumor cells expressing LHRH receptors. Early clinical trials have demonstrated the efficacy of AEZS-108. A Phase I trial assessed the maximum tolerated dose and pharmacokinetics and pharmacodynamics of AEZS-108 given once every 3 weeks in patients with gynecological cancers. Two Phase II studies in heavily pretreated ovarian and recurrent endometrial cancers showed good clinical activity after a maximum of six courses of AEZS-108 as a single agent. Ongoing clinical studies with AEZS-108 in men with castration-resistant prostate cancer and patients with chemotherapy refractory bladder cancer had shown early signs of clinical efficacy. Side effects are moderate and easily manageable. In particular, no pituitary or cardiac toxicity is observed. Expert opinion: AEZS-108 is a cytotoxic analog designed for receptor-mediated targeted chemotherapy and consists of an LHRH carrier linked to doxorubicin. Preclinical studies demonstrate that the uptake of AEZS-108 is achieved by receptor-mediated endocytosis. Results of Phase I and II clinical trials in patients with gynecological cancers demonstrated anticancer activity without cardiotoxicity even in highly pretreated patients. Phase I/II studies in castration-resistant prostate cancer and chemotherapy refractory bladder cancer are in progress. Targeted chemotherapy with a cytotoxic analog of LHRH, such as AEZS-108, is therefore being considered for Phase III studies in advanced endometrial cancers positive for LHRH receptor. LHRH receptors are also present in human colon cancers, melanomas, lymphomas, and sarcomas, and treatment of these cancers with AEZS-108 should also be undertaken. Before such treatment with AEZS-108 is begun, the status of tumoral LHRH receptors of patients must be determined.

AB - Introduction: Receptors for the luteinizing hormone-releasing hormone [LHRH, also known as gonadotropin-releasing hormone (GnRH)] can be regarded as an ideal target for a personalized medicine approach in cancer therapy. LHRH receptors are expressed in about 80% of human endometrial and ovarian cancers, 86% of prostate cancer, and about 50% of breast cancers including triple-negative breast cancer, as well as bladder, colorectal, and pancreatic cancers, sarcomas, lymphomas, melanomas, and renal cell carcinomas. Apart from the pituitary and reproductive organs, other organs and hematopoietic stem cells express LHRH receptors. Thus, a targeted cytotoxic LHRH analog such as AEZS-108 (formerly known as AN-152), in which doxorubin is linked to the LHRH agonist [D-Lys 6]LHRH, appears to be a suitable drug for targeted chemotherapy of cancers expressing receptors for LHRH, which would be more efficacious and less toxic than standard systemic chemotherapy. Areas covered: This review discusses the development of AEZS-108, its targeting mechanism, preclinical studies, and clinical trials in patients with endometrial, ovarian, prostatic, and bladder cancers. We emphasize its development as a personalized medicine approach. The studies reviewed demonstrate the effects of the cytotoxic LHRH analog, AEZS-108, mediated by LHRH receptors, in in vivo models of LHRH-receptor-positive human endometrial, ovarian, breast, prostatic, colorectal, pancreatic, and bladder cancers xenografted into nude mice. Intravenous administration of AEZS 108 inhibits the growth of LHRH-receptor-positive tumors better than equimolar doses of the cytotoxic agent doxorubicin and is far less toxic. AEZS 108 has no antitumor activity in cancers negative to LHRH receptor. This strongly supports the concept of targeting cytotoxic chemotherapy to tumor cells expressing LHRH receptors. Early clinical trials have demonstrated the efficacy of AEZS-108. A Phase I trial assessed the maximum tolerated dose and pharmacokinetics and pharmacodynamics of AEZS-108 given once every 3 weeks in patients with gynecological cancers. Two Phase II studies in heavily pretreated ovarian and recurrent endometrial cancers showed good clinical activity after a maximum of six courses of AEZS-108 as a single agent. Ongoing clinical studies with AEZS-108 in men with castration-resistant prostate cancer and patients with chemotherapy refractory bladder cancer had shown early signs of clinical efficacy. Side effects are moderate and easily manageable. In particular, no pituitary or cardiac toxicity is observed. Expert opinion: AEZS-108 is a cytotoxic analog designed for receptor-mediated targeted chemotherapy and consists of an LHRH carrier linked to doxorubicin. Preclinical studies demonstrate that the uptake of AEZS-108 is achieved by receptor-mediated endocytosis. Results of Phase I and II clinical trials in patients with gynecological cancers demonstrated anticancer activity without cardiotoxicity even in highly pretreated patients. Phase I/II studies in castration-resistant prostate cancer and chemotherapy refractory bladder cancer are in progress. Targeted chemotherapy with a cytotoxic analog of LHRH, such as AEZS-108, is therefore being considered for Phase III studies in advanced endometrial cancers positive for LHRH receptor. LHRH receptors are also present in human colon cancers, melanomas, lymphomas, and sarcomas, and treatment of these cancers with AEZS-108 should also be undertaken. Before such treatment with AEZS-108 is begun, the status of tumoral LHRH receptors of patients must be determined.

KW - AEZS-108

KW - Bladder cancer

KW - Breast cancer

KW - Doxorubicin

KW - Endometrial cancer

KW - LHRH-receptor-positive cancers

KW - Ovarian cancer

KW - Personalized medicine

KW - Prostatic cancer

KW - Targeted chemotherapy

UR - http://www.scopus.com/inward/record.url?scp=84861040329&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861040329&partnerID=8YFLogxK

U2 - 10.1517/13543784.2012.685128

DO - 10.1517/13543784.2012.685128

M3 - Article

C2 - 22577891

AN - SCOPUS:84861040329

VL - 21

SP - 891

EP - 899

JO - Expert Opinion on Investigational Drugs

JF - Expert Opinion on Investigational Drugs

SN - 1354-3784

IS - 6

ER -