Expression of Receptors for Luteinizing Hormone-Releasing Hormone (LH-RH) in Prostate Cancers following Therapy with LH-RH Agonists

Liu, Stephen V.; Schally, Andrew V.; Hawes, Debra; Xiong, Shigang; Fazli, Ladan; Gleave, Martin; Cai, Jie; Groshen, Susan; Brands, F.; Engel, Juergen; Pinski, Jacek

doi:10.1158/1078-0432.ccr-10-1113

Cited by 44 publications

(28 citation statements)

References 24 publications

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“…Such a strategy may overcome off-target toxicity in tandem with continuous efficacy due to persistent expression of the GnRH-R on prostate cancer cells, despite prolonged exposure to GnRH agonists (6). A better understanding of prostate cancer Figure 6.…”

Section: Discussionmentioning

confidence: 99%

“…This idea is based on the evidence that certain cell surface receptors in malignant cells are either mutated or overexpressed (e.g., EGFR, HER2/neu, GnRH-R), compared with normal cells (4)(5)(6) and that these alterations provide "druggable" opportunities. We recently demonstrated the successful targeting of gonadotropin-releasing hormone receptor (GnRH-R) in GnRH-R-positive prostate cancer using a conjugate of a GnRH peptide linked to the cytotoxic drug gemcitabine (7).…”

Section: Introductionmentioning

confidence: 99%

“…The GnRH-R is primarily located in the pituitary gland (10, 11) but upregulation of its expression has been reported in prostate, breast, and other cancers (10,12) which persists despite prolonged exposure to GnRH agonists (6). Interestingly, an antiproliferative role has also been reported for GnRH, providing additional opportunities for the treatment of tumors by directly affecting cancer cells apart from the pituitary (13,14).…”

Section: Introductionmentioning

confidence: 99%

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Peptide–Drug Conjugate GnRH–Sunitinib Targets Angiogenesis Selectively at the Site of Action to Inhibit Tumor Growth

et al. 2016

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The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogues of a clinically established antiangiogenic compound (sunitinib), from which a lead candidate (SAN1) was conjugated to the targeting peptide [D-Lys 6 ]-GnRH, generating SAN1GSC. Conjugation of SAN1 did not disrupt any of its antiangiogenic or cytotoxic properties in GnRH-R-expressing prostate and breast tumor cells. Daily SAN1GSC treatments in mouse xenograft models of castration-resistant prostate cancer resulted in significant tumor growth delay compared with equimolar SAN1 or sunitinib alone. This efficacy correlated with inhibited phosphorylation of AKT and S6, together with reduced Ki-67 and CD31 expression. The superior efficacy of the peptide-drug conjugate was also attributed to the finding that higher amounts of SAN1 were delivered to the tumor site ($4-fold) following dosing of SAN1GSC compared with equimolar amounts of nonconjugated SAN1. Importantly, treatment with SAN1GSC was associated with minimal hematotoxicity and cardiotoxicity based on measurements of the left ventricular systolic function in treated mice. Our results offer preclinical proof-of-concept for SAN1GSC as a novel molecule that selectively reaches the tumor site and downregulates angiogenesis with negligible cardiotoxicity, thus encouraging its further clinical development and evaluation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peptide–Drug Conjugate GnRH–Sunitinib Targets Angiogenesis Selectively at the Site of Action to Inhibit Tumor Growth

et al. 2016

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“…While expression of LHRH receptors may not be common in normal, nonpituitary tissue, these receptors are highly expressed on malignant tissue, including cancers of the lung, ovary, endometrium, bladder, kidney, breast, colon, and prostate (7)(8)(9)(10)(11)(12)(13)(14)(15). We have previously reported that expression of LHRH receptor on prostate cancer cells persists despite prolonged exposure to LHRH agonists (16).…”

Section: Introductionmentioning

confidence: 99%

“…In this limited study of 17 patients, 3 achieved a partial or complete response and 4 achieved stable disease. Given the persistent expression of LHRH receptors in prostate cancer cells (16) and the lack of expression on most normal tissues, AEZS-108 represents a promising targeted therapeutic agent for CRPC. Because the experience with AEZS-108 was limited to female patients, we designed a dose-escalation study of AEZS-108 in men with CRPC before launching a phase II trial (NCT01240629).…”

Section: Introductionmentioning

confidence: 99%

Phase I, Dose-Escalation Study of the Targeted Cytotoxic LHRH Analog AEZS-108 in Patients with Castration- and Taxane-Resistant Prostate Cancer

Liu

Tsao‐Wei

Xiong

et al. 2014

Clinical Cancer Research

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Purpose: AEZS-108, formerly AN-152, is a cytotoxic hybrid molecule consisting of a luteinizing hormone-releasing hormone (LHRH) agonist moiety covalently coupled to doxorubicin, allowing it to deliver doxorubicin selectively to cells expressing LHRH receptors. LHRH receptors are expressed on the cell membrane of many tumors, including prostate cancer. This phase I study determined the maximum tolerated dose (MTD) of AEZS-108 in men with taxane-and castration-resistant prostate cancer (CRPC) while providing additional information on the safety profile and efficacy of this agent.Experimental Design: AEZS-108 was administered as an intravenous infusion every 21 days until progression or unacceptable toxicity in cohorts of 3 or 6 patients until the MTD was reached. Blood was collected for capture of circulating tumor cells (CTC) to visualize internalization of AEZS-108, an autofluorescent molecule.Results: The MTD of AEZS-108 in this cohort was 210 mg/m 2 , which was lower than that seen in a phase I study conducted in women with endometrial or ovarian cancers. The dose-limiting toxicity was persistent neutropenia. Three patients had a PSA response with an additional 10 patients maintaining PSA stable disease. Of the 10 patients evaluable by RECIST criteria, 9 achieved stable disease. AEZS-108 internalization in CTCs was routinely visualized using its autofluorescence. Conclusion: These findings show that AEZS-108 has an acceptable safety profile and a signal of efficacy, lowering PSA in heavily pretreated patients with prostate cancer, and that internalization of AEZS-108 in prostate cancer CTCs may be a viable pharmacodynamic marker. A phase II study in men with prostate cancer is ongoing. Clin Cancer Res; 20(24); 6277-83. Ó2014 AACR.

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Discovery of LHRH and development of LHRH analogs for prostate cancer treatment

2017

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The discovery, isolation, elucidation of structure, synthesis, and initial testing of the neuropeptide hypothalamic luteinizing hormone-releasing hormone (LHRH), which regulates reproduction, is briefly described. The design, synthesis, and experimental and clinical testing of agonistic analogs of LHRH is extensively reviewed focusing on the development of new methods for the treatment of prostate cancer. Subsequent development of antagonistic analogs of LHRH is then faithfully recounted with special emphasis on therapy of prostate cancer and BPH. The concepts of targeted therapy to peptide receptors on tumors are re-examined and the development of the cytotoxic analogs of LHRH and their status is reviewed. The endeavor to develop better therapies for prostate cancer, based on LHRH analogs, guided much of our work.

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Expression of Receptors for Luteinizing Hormone-Releasing Hormone (LH-RH) in Prostate Cancers following Therapy with LH-RH Agonists

Cited by 44 publications

References 24 publications

Peptide–Drug Conjugate GnRH–Sunitinib Targets Angiogenesis Selectively at the Site of Action to Inhibit Tumor Growth

Peptide–Drug Conjugate GnRH–Sunitinib Targets Angiogenesis Selectively at the Site of Action to Inhibit Tumor Growth

Phase I, Dose-Escalation Study of the Targeted Cytotoxic LHRH Analog AEZS-108 in Patients with Castration- and Taxane-Resistant Prostate Cancer

Discovery of LHRH and development of LHRH analogs for prostate cancer treatment

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