Targeted chemotherapy for triple-negative breast cancers via LHRH receptor

Föst, Crispin; Duwe, Francesca; Hellriegel, Martin; Schweyer, Stefan; Emons, Günter; Gründker, Carsten

doi:10.3892/or.2011.1188

Cited by 19 publications

(14 citation statements)

References 25 publications

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“…Treatment of triple-negative, LHRH receptor positive MDA-MB-231, HCC1806 and HCC1937 human breast cancer cells with AEZS-108 resulted in apoptotic cell death as reflected by caspase-3 cleavage. The antitumor effects were confirmed in vivo , as AEZS-108 significantly inhibited the growth of the triple-negative breast cancers, HCC1806 and MDA-MB-231, xenografted into nude mice, without any apparent toxic side effects [ 1 ]…”

Section: Discussionmentioning

confidence: 99%

“…The hypothesis of a ‘magic bullet’ that could specifically eradicate cancers was conceived in 1898 by Paul Ehrlich, but remained undeveloped for decades. Following the discovery that tumor cells express certain specific extra- or intracellular proteins, the concept of using receptor proteins as potential targets for “magic bullets” became applicable to tumor therapy [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

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Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs, AEZS 108 and AEZS 125

et al. 2014

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BackgroundTriple negative breast cancer (TNBC) is a distinct subtype of breast cancer burdened with a dismal prognosis due to the lack of effective therapeutic agents. Receptors for LHRH (luteinizing hormone-releasing hormone) can be successfully targeted with AEZS-108 [AN-152], an analog of LHRH conjugated to doxorubicin. Our study evaluates the presence of this target LHRH receptor in human specimens of TNBC and investigates the efficacy and toxicity of AEZS-108 in vivo. We also studied in vitro activity of AEZS-125, a new LHRH analog conjugated with the highly potent natural compound, Disorazol Z.Methods69 human surgical specimens of TNBC were investigated for LHRH-R expression by immunohistochemistry. Expression of LHRH-R in two TNBC cell lines was evaluated by real time RT-PCR. Cytotoxicity of AEZS-125 was evaluated by Cell Titer Blue cytoxicity assay. LHRH- receptor expression was silenced with an siRNA in both cell lines. For the in vivo experiments an athymic nude mice model xenotransplanted with the cell lines, MDA-MB-231 and HCC 1806, was used. The animals were randomised to three groups receiving solvent only (d 1, 7, 14, i.v.) for control, AEZS-108 (d 1, 7, 14, i.v.) or doxorubicin at an equimolar dose (d 1, 7, 14, i.v.).ResultsIn human clinical specimens of TNBC, expression of the LHRH-receptor was present in 49% (n = 69).HCC 1806 and MDA-MB-231 TNBC cells expressed mRNA for the LHRH-receptor. Silencing of the LHRH-receptor significantly decreased the cytotoxic effect of AEZS-108. MDA-MB-231 and HCC 1806 tumors xenografted into nude mice were significantly inhibited by treatment with AEZS-108; doxorubicin at equimolar doses was ineffective.As compared to AEZS 108, the Disorazol Z – LHRH conjugate, AEZS-125, demonstrated an increased cytotoxicity in vitro in HCC 1806 and MDA-MB-231 TNBC; this was diminished by receptor blockade with synthetic LHRH agonist (triptorelin) pretreatment.ConclusionThe current study confirms that LHRH-receptors are expressed by a significant proportion of TNBC and can be successfully used as homing sites for cytotoxic analogs of LHRH, such as AEZS-108 and AEZS-125.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs, AEZS 108 and AEZS 125

et al. 2014

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“…High LHRH receptor expression is found in diverse tumor types, including: prostate [7], breast [2, 8, 9, 12], ovarian [10, 11], endometrial [1, 8, 11], pancreatic [12], bladder [13], colorectal [14], melanoma [15], renal cancers of clear cell and chromophilic papillary histology [16] and non-Hodgkin lymphoma [18]. Malignant cells typically display LHRH-receptor overexpression relative to their normal counterparts, except anterior pituitary basophil cells.…”

Section: Introductionmentioning

confidence: 99%

Novel LHRH-receptor-targeted cytolytic peptide, EP-100: first-in-human phase I study in patients with advanced LHRH-receptor-expressing solid tumors

Curtis

Sarantopoulos

Northfelt

et al. 2014

Cancer Chemother Pharmacol

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PurposeTo conduct a phase I study determining the safety, pharmacokinetics and preliminary efficacy of EP-100, a novel anticancer drug consisting of natural luteinizing-hormone-releasing hormone (LHRH) ligand linked to a cationic membrane-disrupting peptide.MethodsPatients with advanced, solid tumors, positive for LHRH receptor by immunohistochemistry (IHC), received EP-100 weekly or twice weekly for 3 of 4 weeks in a 28 day cycle. A modified Fibonacci 3 + 3 dose-escalation schema was used. Initial cohorts received EP-100 once weekly (cohorts 1–7, 0.6–7.8 mg/m2, n = 21). Later cohorts received doses twice weekly (cohorts 7–11, 7.8–40 mg/m2, n = 16).ResultsLHRH-receptor expression was confirmed by IHC in 52 of 89 consented patients; 37 patients received at least 1 dose. Cohorts receiving doses of 5.2 mg/m2 and above achieved therapeutic levels from in vitro studies Clearance was rapid (mean half-life 7.1 ± 3.8 to 15.9 ± 3.6 min). The maximum-tolerated dose was not reached at the highest dose evaluated (40 mg/m2 twice weekly). Grade 2 increase in alanine aminotransferase/serum aspartate aminotransferase in one patient resolved, did not recur upon re-treatment, and was not observed in other patients. The only drug-related adverse event was transient infusion-related dermatologic reactions (10 patients). No complete or partial tumor responses were observed; seven patients had stable disease of 16 weeks.ConclusionsEP-100 was well tolerated in patients with advanced, LHRH-receptor-expressing solid tumors. The recommended phase 2 dose is 40 mg/m2 twice weekly for 3 of 4 weeks per cycle.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-014-2424-x) contains supplementary material, which is available to authorized users.

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“…The finding of GnRH/GnRH-R expression in these tumors, as well as in nonmalignant tissues [4]–[7], disclosed the possibility for cells of extrapituitary tissues to be directly affected by GnRH analogues. Different studies demonstrated the inhibitory effect of GnRH agonists on the growth of various neoplasms including prostate cancer (PCa) cells [6], [8]–[14]. Nevertheless, some authors reported that GnRH agonists are ineffective when used alone while counteract or even suppress hormone- or growth factor-stimulated cell proliferation [15]–[19].…”

Section: Introductionmentioning

confidence: 99%

Leuprorelin Acetate Long-Lasting Effects on GnRH Receptors of Prostate Cancer Cells: An Atomic Force Microscopy Study of Agonist/Receptor Interaction

et al. 2013

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High cell-surface GnRH receptor (GnRH-R) levels have been shown to have a major influence on the extent of GnRH agonist-mediated tumor growth inhibition. The ability of the GnRH agonist leuprorelin acetate (LA) to induce a post-transcriptional upregulation of GnRH-R at the plasma membrane of androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer (PCa) cells has been previously demonstrated by Western blotting. Here we performed single molecule force spectroscopy by using Atomic Force Microscopy (AFM), which has proven to be a powerful tool allowing for investigation of living cell surface biological features, such as the so far unclear GnRH agonist/receptor interaction. Thus, in the hormone-insensitive PC-3 cells, we characterized the strength of the LA-receptor binding, and the amount and distribution of the functional receptor molecules on the cell surface. The effect of a long and continuous treatment (up to 30 days) with the agonist (10−11 and 10−6 M) on the same parameters was also investigated. A GnRH-R increase was observed, reaching the maximum (∼80%) after 30 days of treatment with the highest dose of LA (10−6 M). The analogue-induced increase in GnRH-R was also demonstrated by Western blotting. In addition, two different receptor bound strengths were detected by AFM, which suggests the existence of two GnRH-R classes. A homogeneous distribution of the unbinding events has been found on untreated and treated PC-3 cell surfaces. The persistence of high receptor levels at the membrane of these living cells may warrant the maintenance of the response to LA also in androgen-unresponsive PCa. Moreover, the determination of ligand/receptor bond strength could shed light on the poorly understood event of LA/GnRH-R interaction and/or address structural/chemical agonist optimizations.

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Targeted chemotherapy for triple-negative breast cancers via LHRH receptor

Cited by 19 publications

References 25 publications

Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs, AEZS 108 and AEZS 125

Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs, AEZS 108 and AEZS 125

Novel LHRH-receptor-targeted cytolytic peptide, EP-100: first-in-human phase I study in patients with advanced LHRH-receptor-expressing solid tumors

Leuprorelin Acetate Long-Lasting Effects on GnRH Receptors of Prostate Cancer Cells: An Atomic Force Microscopy Study of Agonist/Receptor Interaction

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