Updates in Therapy for Advanced Melanoma

Singh, Bhavana; Salama, April K.S.

doi:10.3390/cancers8010017

Cited by 41 publications

(55 citation statements)

References 90 publications

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“…In order to overcome both drug resistance development and side effects, the challenge for basic researchers and clinicians will be the development of novel combination therapies (immune/immune or immune/target specific therapies) for the achievement of both long-term and safe responses (56–58). …”

Section: Current Therapies For Advanced Melanomamentioning

confidence: 99%

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

et al. 2016

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Cutaneous melanoma is an aggressive tumor; its incidence has been reported to increase fast in the past decades. Melanoma is a heterogeneous tumor, with most patients harboring mutations in the BRAF or NRAS oncogenes, leading to the overactivation of the MAPK/ERK and PI3K/Akt pathways. The current therapeutic approaches are based on therapies targeting mutated BRAF and the downstream pathway, and on monoclonal antibodies against the immune checkpoint blockade. However, treatment resistance and side effects are common events of these therapeutic strategies. Increasing evidence supports that melanoma is a hormone-related cancer. Melanoma incidence is higher in males than in females, and females have a significant survival advantage over men. Estrogens exert their effects through estrogen receptors (ERα and ERβ) that affect cancer growth in an opposite way: ERα is associated with a proliferative action and ERβ with an anticancer effect. ERβ is the predominant ER in melanoma, and its expression decreases in melanoma progression, supporting its role as a tumor suppressor. Thus, ERβ is now considered as an effective molecular target for melanoma treatment. 17β-estradiol was reported to inhibit melanoma cells proliferation; however, clinical trials did not provide the expected survival benefits. In vitro studies demonstrate that ERβ ligands inhibit the proliferation of melanoma cells harboring the NRAS (but not the BRAF) mutation, suggesting that ERβ activation might impair melanoma development through the inhibition of the PI3K/Akt pathway. These data suggest that ERβ agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant melanomas. In an era of personalized medicine, pretreatment evaluation of the expression of ER isoforms together with the concurrent oncogenic mutations should be considered before selecting the most appropriate therapeutic intervention. Natural compounds that specifically bind to ERβ have been identified. These phytoestrogens decrease the proliferation of melanoma cells. Importantly, these effects are unrelated to the oncogenic mutations of melanomas, suggesting that, in addition to their ERβ activating function, these compounds might impair melanoma development through additional mechanisms. A better identification of the role of ERβ in melanoma development will help increase the therapeutic options for this aggressive pathology.

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Section: Current Therapies For Advanced Melanomamentioning

confidence: 99%

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

et al. 2016

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“…In contrast to the direct cytotoxic effects of chemotherapy, checkpoint blockade relies on antigen-specific T cell responses by blunting tumor-induced immunoregulatory mechanisms 9 . This form of treatment has provided durable, long-lasting responses in many melanoma patients including cutaneous and mucosal melanoma subtypes, largely due to the persistence and adaptability of the immune system.…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, checkpoint blockade has been investigated in the context of UM, with agents targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), such as ipilimumab and tremelimumab, 9 though clinical response rates to these regimens were largely unimpressive (< 10%) with no significant benefit to OS in UM patients 7,8 . Importantly, the low response rates in UM sharply contrast with relatively higher response rates to immunotherapy in CM patients, where several agents have now been FDA-approved based on a clear survival advantage or an encouraging response rate 9 . This tremendous disparity in the success of these treatment regimens suggests of the distinct immunological features and resistance mechanisms harbored by UM metastases.…”

Section: Introductionmentioning

confidence: 99%

Parallel profiling of immune infiltrate subsets in uveal melanoma versus cutaneous melanoma unveils similarities and differences: A pilot study

et al. 2017

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The low response rates to immunotherapy in uveal melanoma (UM) sharply contrast with reputable response rates in cutaneous melanoma (CM) patients. To characterize the mechanisms responsible for resistance to immunotherapy in UM, we performed immune profiling in tumors from 10 metastatic UM patients and 10 metastatic CM patients by immunohistochemistry (IHC). Although there is no difference in infiltrating CD8+ T cells between UM and CM, a significant decrease in programmed death-1 (PD-1)-positive lymphocytes was observed and lower levels of programmed death ligand-1 (PD-L1) in UM metastases compared with CM metastases. Tumors from metastatic UM patients showed a lower success rate of tumor-infiltrating lymphocyte (TIL) growth compared with metastatic CM (45% vs. 64% success), with a significantly lower quantity of UM TIL expanded overall. These studies suggest that UM and CM are immunologically distinct, and provide potential explanation for the impaired success of immunotherapy in UM.

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“…Cutaneous melanoma (CM) is a potentially aggressive form of skin cancer and its incidence continues to rise with over 250,000 new cases annually worldwide [1]. CM accounts for the majority of skin cancer-related deaths [1].…”

Section: Introductionmentioning

confidence: 99%

“…CM accounts for the majority of skin cancer-related deaths [1]. A large variance in survival rates, depending on the extent of disease, exists [2].…”

Section: Introductionmentioning

confidence: 99%

Introducing MARCo: Histoserological Findings of a Multi-Organic Paraneoplastic Syndrome in Cutaneous Melanoma Patients

Ranjbar

Mohi

Pföhler

et al. 2016

Dermatol Ther (Heidelb)

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IntroductionCutaneous melanoma (CM) is an aggressive skin cancer entity, causing most skin cancer-related deaths. Autoimmune disorders have been described as potential paraneoplastic complications. The purpose of this study was to elucidate the possibility of a combinatory paraneoplastic affection of the retina and cochlea in patients with CM.MethodsSera samples from CM patients were used for indirect immunofluorescence on histological retinal and cochlear sections. Furthermore, the serum specimen of a patient with symptomatic affection of both organs was analyzed by multiplex ELISA (enzyme-linked immunosorbent assay) for various cytokines including CD163 (cluster of differentiation 163).ResultsEleven patients were diagnosed with CM. Autoantibodies against structures of the inner ear were confirmed in all patients who were tested positive for antiretinal antibodies as well. CD163 was significantly elevated in the double-symptomatic patient, who developed metastatic disease.ConclusionParaneoplastic disease of CM can affect more than one organ and this affect may be correlated with the individual prognosis. Therefore, a thorough anamnesis is needed to avoid missing potential symptoms.

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Updates in Therapy for Advanced Melanoma

Cited by 41 publications

References 90 publications

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

Parallel profiling of immune infiltrate subsets in uveal melanoma versus cutaneous melanoma unveils similarities and differences: A pilot study

Introducing MARCo: Histoserological Findings of a Multi-Organic Paraneoplastic Syndrome in Cutaneous Melanoma Patients

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