The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma

Fodor, Klara; Dobos, Nikoletta; Steiber, Zita; Oláh, Gábor; Sipos, Éva; Székvölgyi, Lóránt; Halmos, Gábor

doi:10.18632/oncotarget.27431

Cited by 11 publications

(10 citation statements)

References 52 publications

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“…AEZS-108 is an analog of the Luteinizing Hormone-Releasing Hormone (LHRH) consisting of doxorubicin conjugated to a synthetic peptide containing LHRH that is used against cells expressing the LHRH-receptor. More importantly, the authors identified upregulation of MASPIN/SERPINB5, a tumor suppressor gene for UM [ 297 , 298 ], as well as downregulation of proteins related to angiogenesis, such as HIF-1α and VEGF, as cause of AEZS-108 efficacy [ 299 ]. Given to the pivotal role of angiogenesis in the metastatization of UM [ 195 ], the regulation of HIF-1α /VEGF axis by AEZS-108 is of particular relevance.…”

Section: Uveal Melanomamentioning

confidence: 99%

Hypoxia-dependent drivers of melanoma progression

D’Aguanno

Mallone

Marenco

et al. 2021

J Exp Clin Cancer Res

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Hypoxia, a condition of low oxygen availability, is a hallmark of tumour microenvironment and promotes cancer progression and resistance to therapy. Many studies reported the essential role of hypoxia in regulating invasiveness, angiogenesis, vasculogenic mimicry and response to therapy in melanoma. Melanoma is an aggressive cancer originating from melanocytes located in the skin (cutaneous melanoma), in the uveal tract of the eye (uveal melanoma) or in mucosal membranes (mucosal melanoma). These three subtypes of melanoma represent distinct neoplasms in terms of biology, epidemiology, aetiology, molecular profile and clinical features.In this review, the latest progress in hypoxia-regulated pathways involved in the development and progression of all melanoma subtypes were discussed. We also summarized current knowledge on preclinical studies with drugs targeting Hypoxia-Inducible Factor-1, angiogenesis or vasculogenic mimicry. Finally, we described available evidence on clinical studies investigating the use of Hypoxia-Inducible Factor-1 inhibitors or antiangiogenic drugs, alone or in combination with other strategies, in metastatic and adjuvant settings of cutaneous, uveal and mucosal melanoma.Hypoxia-Inducible Factor-independent pathways have been also reported to regulate melanoma progression, but this issue is beyond the scope of this review.As evident from the numerous studies discussed in this review, the increasing knowledge of hypoxia-regulated pathways in melanoma progression and the promising results obtained from novel antiangiogenic therapies, could offer new perspectives in clinical practice in order to improve survival outcomes of melanoma patients.

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Section: Uveal Melanomamentioning

confidence: 99%

Hypoxia-dependent drivers of melanoma progression

D’Aguanno

Mallone

Marenco

et al. 2021

J Exp Clin Cancer Res

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“…Recent research has sought to further evaluate the presence of LHRH and the effects of cytotoxic LHRH analogs – such as AEZS-108 and AN-207 – on cell lines [28-30]. Unfortunately, problematic cell lines (including OCM3 and OCM1), originally thought to be derived from UM tumors but later shown to be of skin melanoma origin, were used, limiting their applicability to UM (Table 4) [31-37].…”

Section: Evidence For Sex Hormone Receptor Expression In Nevi/um Tumorsmentioning

confidence: 99%

“…However, since UM primary tumors were also found to express LHRH, further work to validate the findings in confirmed UM cell lines with GNAQ/GNA11 mutations should be done. AEZS-108, a chemotherapy drug which consists of [D-Lys6]-LHRH linked to 1 molecule of doxorubicin (DOX), significantly reduced OCM3 cell viability by 36.3% after 24 h and by 84.7% after 48 h. AEZS-108 may prevent ECM degradation, angiogenesis, and migration of tumor cells via the regulation of MASPIN, HIF1A, and their target genes [28, 30]. These LHRH analogs are discussed further in detail in the section Sex Hormones as Potential Targets for Therapy in UM.…”

Section: Evidence For Sex Hormone Receptor Expression In Nevi/um Tumorsmentioning

confidence: 99%

Is Uveal Melanoma a Hormonally Sensitive Cancer? A Review of the Impact of Sex Hormones and Pregnancy on Uveal Melanoma

Miller¹,

Schoenfield²,

Abdel-Rahman³

et al. 2021

Ocul Oncol Pathol

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Background: Despite a higher incidence and worse prognosis of uveal melanoma (UM) in men, there have been many case reports of pregnant patients with aggressive UM. This has led researchers to explore the influence of sex hormones and pregnancy on the development and progression of UM and hormones as potential therapeutic targets. Summary: A systematic literature review was conducted. More work is needed to elucidate the basis of sex differences in UM incidence and survival. The evaluation of germline BAP1 mutation would be beneficial in patients with UM presenting at a young age. Importantly, multiple studies reported no significant difference between the 5-year survival and 5-year metastasis-free survival rates between nonpregnant women with UM and pregnant women with UM. Multiple case-control studies disagree on how parity affects risk of UM. However, most studies agree that oral contraceptives and hormone replacement therapy have no effect on the incidence of UM. Current treatment strategies for pregnant patients with UM are discussed. Looking forward, this review reports recent research on targeted receptor-based chemotherapy, which is based on evidence of estrogen receptor (ER), estrogen-related receptor alpha (ERRα), and luteinizing hormone-releasing hormone (LHRH) receptor expression in UM. Key Messages: Based on review of the literature, UM is not a contraindication to oral contraceptives, hormone replacement therapy, or pregnancy. Globe-sparing radiation can be used as a treatment option for pregnant patients. Due to the presence of ER on a subset of unselected UM, its potential for adjunctive targeted therapy with agents like tamoxifen should be explored. Lessons from cutaneous melanoma regarding tissue ratios of estrogen receptors (ERα:ERβ) should be applied to assess their therapeutic predictive value. In addition, ERRα-targeted therapeutics and LHRH analogs are worthy of further exploration in UM.

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“…It is expected that, by binding to its receptor, the GnRH derivative may specifically carry the cytotoxic drug to cancer cells without affecting normal cells. AEZS-108 (also known as AN-152), a bioconjugate consisting of a GnRH derivative covalently linked to doxorubicin via an ester bond, was developed, and its anticancer activity was investigated in different types of tumors [ 282 , 283 , 284 ]. This peptide cytotoxin was reported to exert a significant antiproliferative/proapoptotic activity in PCa, and specifically in CRPC cells, in vitro and in preclinical studies [ 285 , 286 , 287 ].…”

Section: Androgen and Gonadotropin-releasing Hormone Receptors: Molecular Targets For Therapeutic Strategies In Crpcmentioning

confidence: 99%

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

Fontana

Limonta

2021

Cells

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Understanding the molecular mechanisms underlying prostate cancer (PCa) progression towards its most aggressive, castration-resistant (CRPC) stage is urgently needed to improve the therapeutic options for this almost incurable pathology. Interestingly, CRPC is known to be characterized by a peculiar hormonal landscape. It is now well established that the androgen/androgen receptor (AR) axis is still active in CRPC cells. The persistent activity of this axis in PCa progression has been shown to be related to different mechanisms, such as intratumoral androgen synthesis, AR amplification and mutations, AR mRNA alternative splicing, increased expression/activity of AR-related transcription factors and coregulators. The hypothalamic gonadotropin-releasing hormone (GnRH), by binding to its specific receptors (GnRH-Rs) at the pituitary level, plays a pivotal role in the regulation of the reproductive functions. GnRH and GnRH-R are also expressed in different types of tumors, including PCa. Specifically, it has been demonstrated that, in CRPC cells, the activation of GnRH-Rs is associated with a significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic activity. This antitumor activity is mainly mediated by the GnRH-R-associated Gαi/cAMP signaling pathway. In this review, we dissect the molecular mechanisms underlying the role of the androgen/AR and GnRH/GnRH-R axes in CRPC progression and the possible therapeutic implications.

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The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma

Cited by 11 publications

References 52 publications

Hypoxia-dependent drivers of melanoma progression

Hypoxia-dependent drivers of melanoma progression

Is Uveal Melanoma a Hormonally Sensitive Cancer? A Review of the Impact of Sex Hormones and Pregnancy on Uveal Melanoma

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

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