Therapy for metastatic melanoma: the past, present, and future

Finn, Laura; Markovic, Svetomir N.; Joseph, Richard W.

doi:10.1186/1741-7015-10-23

Cited by 189 publications

(199 citation statements)

References 85 publications

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“…Chemotherapy has only a slight impact on the survival of patients with metastatic melanoma (Hersey et al, 2009;Davar et al, 2011). Until 2011, only two drugs were approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma, decarbazine and interleukin 2, but neither was capable of increasing the overall median survival of melanoma patients (Finn et al, 2012). A phase 3 trial comparing the selective inhibitor of the BRAF mutated protein (vemurafenib) with decarbazine in a group of previously untreated melanoma patients demonstrated a significant improvement in the response rate after six months of treatment (84% versus 64%), as well as a reduction in the risk of death (Lemech et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Analysis of the BRAF V600E mutation in primary cutaneous melanoma

Inumaru¹,

Gordo²,

Junior

et al. 2014

Genet. Mol. Res.

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ABSTRACT. BRAF V600E is the most common mutation in cutaneous melanomas, and has been described in 30-72% of such cases. This mutation results in the substitution of valine for glutamic acid at position 600 of the BRAF protein, which consequently becomes constitutively activated. The present study investigated the BRAF V600E mutation frequency and its clinical implications in a group of 77 primary cutaneous melanoma patients treated in a cancer reference center in Brazil. Mutation analysis 2841 BRAF V600E mutation of primary cutaneous melanomas in Brazil ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 13 (2): 2840-2848 (2014) was accomplished by polymerase chain reaction, restriction fragment length polymorphism, and automated DNA sequencing. The chi-squared and Fischer exact tests were used for comparative analyses. The BRAF V600E mutation was detected in 54/77 (70.1%) melanoma subjects. However, no statistically significant association was found between the presence of the mutation and clinical or prognostic parameters. Our results demonstrated that the BRAF V600E mutation is a common event in melanomas, representing an important molecular target for novel therapeutic approaches in such tumors.

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Section: Discussionmentioning

confidence: 99%

Analysis of the BRAF V600E mutation in primary cutaneous melanoma

Inumaru¹,

Gordo²,

Junior

et al. 2014

Genet. Mol. Res.

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“…The high frequency of these genetic modifications underscores a critical role for BRAF mutation in melanoma oncogenesis (1), as well as providing an actionable target for molecular therapeutic approaches in this disease. Indeed, these considerations have been strikingly validated by the recent U.S. Food and Drug Administration approval of the first highly selective BRAF V600E inhibitor, vemurafenib, for patients with metastatic melanoma (7). Despite this clinical success, however, durable responses to vemurafenib are rare and most patients invariably relapse with drug-resistant disease within 6 to 8 months (8).…”

Section: Introductionmentioning

confidence: 99%

Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib

Acquaviva

Smith

Jimenez

et al. 2014

Molecular Cancer Therapeutics

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Activating BRAF kinase mutations serve as oncogenic drivers in over half of all melanomas, a feature that has been exploited in the development of new molecularly targeted approaches to treat this disease. Selective BRAF V600E inhibitors, such as vemurafenib, typically induce initial, profound tumor regressions within this group of patients; however, durable responses have been hampered by the emergence of drug resistance. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90, in melanoma lines harboring the BRAF V600E mutation. Ganetespib exposure resulted in the loss of mutant BRAF expression and depletion of mitogen-activated protein kinase and AKT signaling, resulting in greater in vitro potency and antitumor efficacy compared with targeted BRAF and MAP-ERK kinase (MEK) inhibitors. Dual targeting of Hsp90 and BRAF V600E provided combinatorial benefit in vemurafenibsensitive melanoma cells in vitro and in vivo. Importantly, ganetespib overcame mechanisms of intrinsic and acquired resistance to vemurafenib, the latter of which was characterized by reactivation of extracellular signal-regulated kinase (ERK) signaling. Continued suppression of BRAF V600E by vemurafenib potentiated sensitivity to MEK inhibitors after acquired resistance had been established. Ganetespib treatment reduced, but not abolished, elevations in steady-state ERK activity. Profiling studies revealed that the addition of a MEK inhibitor could completely abrogate ERK reactivation in the resistant phenotype, with ganetespib displaying superior combinatorial activity over vemurafenib. Moreover, ganetespib plus the MEK inhibitor TAK-733 induced tumor regressions in vemurafenib-resistant xenografts. Overall these data highlight the potential of ganetespib as a single-agent or combination treatment in BRAF V600E -driven melanoma, particularly as a strategy to overcome acquired resistance to selective BRAF inhibitors. Mol Cancer Ther; 13(2); 353-63. Ó2014 AACR.

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“…The monoclonal antibody ipilimumab is active in patients with advanced melanoma and brain metastases [7] , but is effective in only some patients [6][7][8] . The BRAF kinase inhibitors vemurafenib and dagrafenib (GSK2118436) are active in patients with BRAF V600E mutated melanoma and appear to have activity in the brain, although a small number of patients have been treated to date [9] .…”

Section: Introductionmentioning

confidence: 99%

Combinatorial treatment with carboxyamidotriazole- orotate and temozolomide in sc-implanted human LOX IMVI melanoma xenografts

Karmali

Maxuitenko

Gorman

et al. 2012

JST

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Background: Carboxyamidotriazole orotate (CTO) is the orotic acid salt of 5-amino-1(4-(4-chlorobenzoyl)-3, 5-dichlorobenzyl)-1, 2, 3-triazole-4-carboxamide (CAI). CTO possesses increased solubility as compared to CAI as the free base. The antiproliferative and antimetastatic effects of CTO are related to inhibition of receptor-operated, calcium-channel-mediated calcium influx. CTO can inhibit calcium-sensitive signal transduction in the VEGF and the PI3K pathways, inhibition of FGF-2-induced tyrosine kinase, VEGF-mediated activation of phospholipase Cy, generation of IP3 and nitric oxide synthase activation, and induction of apoptosis in imatinib mesylate resistant CML cells by downregulating bcr-abl.Methods: Different combinations of CTO and temozolomide were first tested in female athymic NCr-nu/nu mice to evaluate tolerance of the combination. The tolerated combinations were then tested to evaluate the antitumor activity against subcutaneously implanted human LOX IMVI melanoma xenografts. Results:Oral CTO at doses of 513 or 342 mg/kg/dose Q1D×14 resulted in inhibition of tumor growth (p<0.001 and p=0.004). Oral TEM at doses of 90 and 60 mg/kg/dose Q4D×3 resulted in dose-dependent inhibition of tumor growth (p<0.001 and p<0.001). Oral CTO at 513 or 342 mg/kg/dose in combination with temozolomide 90 mg/kg/dose resulted in comparable tumor inhibition to temozolomide alone. However, oral CTO at 513 mg/kg/dose in combination with temozolomide 60mg/kg/dose resulted in additive antitumor activity compared to each drug alone. Also, CTO at 342 mg/kg/dose in combination with temozolomide 60mg/kg/dose had more than additive antitumor activity and was statistically different from the group treated with temozolomide 60 mg/kg/dose alone (p=0.001). Conclusions:These results suggest that this combination of previously configured therapeutic doses of temozolomide with CTO enhances the sensitivity of temozolomide and may permit use of lower temozolomide doses to obtain an optimum antitumor effect in combination therapy. This dose-dilution combinatorial strategy fulfills the need for increased tumor sensitivity and efficacy. Additionally, this strategy reduces drug resistance and toxicity associated with dose dense strategy of temozolomide treatment in this melanoma model.

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Therapy for metastatic melanoma: the past, present, and future

Cited by 189 publications

References 85 publications

Analysis of the BRAF V600E mutation in primary cutaneous melanoma

Analysis of the BRAF V600E mutation in primary cutaneous melanoma

Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib

Combinatorial treatment with carboxyamidotriazole- orotate and temozolomide in sc-implanted human LOX IMVI melanoma xenografts

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