Treatment of advanced melanoma - A changing landscape

Hepner, Adriana; Salgues, Alessandra Corte Real; Anjos, Carlos A Dos; Sahade, Marina; Camargo, Veridiana Pires de; Garicochea, Bernardo; Shoushtari, Alexander N.; Postow, Michael A.; Fernandes, Gwendolyn; Munhoz, Rodrigo Ramella

doi:10.1590/1806-9282.63.09.814

Cited by 17 publications

(14 citation statements)

References 45 publications

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“…There is an increasing interest in developing new melanoma therapies based on the modulation of JAK-STAT pathway [ 236 ]. Although there is no specific drug approved aiming JAK-STAT downstream components, immunotherapies against receptors that may initiate this signaling cascade have been used as main therapy or co-adjuvant in classical chemotherapies [ 237 ].…”

Section: Janus Kinase-signal Transducer and Activator Of Transcriptiomentioning

confidence: 99%

Exploring major signaling cascades in melanomagenesis: a rationale route for targetted skin cancer therapy

et al. 2018

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Although most melanoma cases may be treated by surgical intervention upon early diagnosis, a significant portion of patients can still be refractory, presenting low survival rates within 5 years after the discovery of the illness. As a hallmark, melanomas are highly prone to evolve into metastatic sites. Moreover, melanoma tumors are highly resistant to most available drug therapies and their incidence have increased over the years, therefore leading to public health concerns about the development of novel therapies. Therefore, researches are getting deeper in unveiling the mechanisms by which melanoma initiation can be triggered and sustained. In this context, important progress has been achieved regarding the roles and the impact of cellular signaling pathways in melanoma. This knowledge has provided tools for the development of therapies based on the intervention of signal(s) promoted by these cascades. In this review, we summarize the importance of major signaling pathways (mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)-Akt, Wnt, nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB), Janus kinase (JAK)-signal transducer and activator of transcription (STAT), transforming growth factor β (TGF-β) and Notch) in skin homeostasis and melanoma progression. Available and developing melanoma therapies interfering with these signaling cascades are further discussed.

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Section: Janus Kinase-signal Transducer and Activator Of Transcriptiomentioning

confidence: 99%

Exploring major signaling cascades in melanomagenesis: a rationale route for targetted skin cancer therapy

et al. 2018

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“…Malme-3M cells were engineered to stably knockdown IRAK-M (Malme-3M shRNA IRAK-M ) or express scramble RNA (Malme-3M shRNA control ). Azacytidine or vehicle control were administered when the tumor reached~10 mm 2 . Azacytidine, which induces IRAK-M in Malme-3M shRNA control cells, reduced the tumor growth kinetics as compared with vehicle control-treated mice (Fig.…”

Section: Irak-m Provokes Calpain-mediated Melanoma Cell Deathmentioning

confidence: 99%

“…elanoma is one of the deadliest forms of cancer and is the fifth and seventh most common cancer for men and women, respectively 1 . Patients with advanced disease have a median survival of 6-12 months 2 . The recent development of several treatment options for melanoma including targeted and immunotherapies have resulted in remarkable antitumor responses.…”

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confidence: 99%

Induction of IRAK-M in melanoma induces caspase-3 dependent apoptosis by reducing TRAF6 and calpastatin levels

et al. 2020

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Melanoma represents the most serious type of skin cancer. Although recent years have seen advances using targeted and immunotherapies, most patients remain at high risk for tumor recurrence. Here we show that IRAK-M, a negative regulator of MyD88 signaling, is deficient or low in melanoma and expression levels correlate with patient survival. Inducing IRAK-M expression using genetic approaches or epigenetic modifiers initiates apoptosis by prompting its interaction with TRAF6 via IRAK-M's C-terminal domain. This complex recruits and degrades calpastatin which stimulates calpain activity and triggers caspase-3-dependent but caspase-8,−9-independent apoptosis. Using a drug screen, we identified compounds that induced IRAK-M expression. Administration of IRAK-M-inducing drugs reduced tumor growth in mice but was ineffective against IRAK-M knock-down tumors. These results uncover a previously uncharacterized apoptosis pathway, emphasize IRAK-M as a potential therapeutic target and suggest that the anticancer activity of certain drugs could do so through their ability to induce IRAK-M expression.

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“…Despite the impressive clinical responses, only a small fraction of patients obtain a durable response, and the emergence of acquired resistance appears a major problem for both treatments (Matthews et al ., ; Nazarian et al ., ). To overcome this failure, the emerging therapies are increasingly considering combinatorial treatments based on different mechanisms of action (Hepner et al ., ; Shtivelman et al ., ; Volpe et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Joint action of miR‐126 and MAPK/PI3K inhibitors against metastatic melanoma

et al. 2019

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Emerging data support the rationale of combined therapies in advanced melanoma. Specifically, the combined use of drugs with different mechanisms of action can reduce the probability of selecting resistant clones. To identify agents active against melanoma cells, we screened a library of 349 anti‐cancer compounds, currently in clinical use or trials, and selected PIK ‐75, an inhibitor of the phosphatidylinositol 3‐kinase/protein kinase B ( PI 3K/ AKT ) pathway, as the ‘top active’ drug. PIK ‐75 was then used alone or in combination with vemurafenib, the first BRAF inhibitor approved for patients with melanoma harboring BRAF mutations. We identified a combined dose of PIK ‐75 and vemurafenib that inhibited both the PI 3K/ AKT and mitogen‐activated protein kinase pathways, thereby overcoming any compensatory activation. In view of the important tumor suppressor function induced by restoring expression of microRNA (miR)‐126 in metastatic melanoma cells, we examined whether miR‐126 has a synergistic role when included in a triple combination alongside PIK ‐75 and vemurafenib. We found that enforced expression of miR‐126 (which alone can reduce tumorigenicity) significantly increased PIK ‐75 activity when used as either a single agent or in combination with vemurafenib. Interestingly, PIK ‐75 proved to be effective against early passage cell lines derived from patients’ biopsies and on melanoma cell lines resistant to either vemurafenib or dabrafenib, thus suggesting that it potentially has the capability to overcome drug resistance. Finally, the synergistic role played by miR‐126 in combination with vemurafenib and/or PIK ‐75 was demonstrated in vivo in mouse xenograft models, in which tumor growth inhibition was associated with increased apoptosis. These results not only show the efficacy of PIK ‐75 and vemurafenib co‐treatment but also indicate that restoration of miR‐126 expression in advanced melanoma can enhance their antitumor activity, which may possibly allow dose reduction to decrease adverse events without reducing the therapeutic benefits.

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Treatment of advanced melanoma - A changing landscape

Cited by 17 publications

References 45 publications

Exploring major signaling cascades in melanomagenesis: a rationale route for targetted skin cancer therapy

Exploring major signaling cascades in melanomagenesis: a rationale route for targetted skin cancer therapy

Induction of IRAK-M in melanoma induces caspase-3 dependent apoptosis by reducing TRAF6 and calpastatin levels

Joint action of miR‐126 and MAPK/PI3K inhibitors against metastatic melanoma

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