Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV600 mutations

Spain, Lavinia; Julve, Maximilian; Larkin, James

doi:10.1517/14656566.2016.1168805

Cited by 34 publications

(32 citation statements)

References 37 publications

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“…It is a cancer with one of the biggest rise in incidence 3,4 , and the overall 5-year survival rate is less than 10% for patients with stage IV disease 5, 6 . There have been major advances in the treatment of advanced melanoma including Ipilimumab, an antibody to cytotoxic T-lymphocyte-associated-antigen-4 (CTLA-4), and BRAF inhibitor [7][8][9] . However, the anti-CTLA-4 antibody shows benefit in less than 50% of patients 10 .…”

mentioning

confidence: 99%

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

Yoshida

Koodie

Jacobsen

et al. 2020

Sci Rep

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β-1,4-N-Acetyl-Galactosaminyltransferase 1 (B4GALNT1) encodes the key enzyme B4GALNT1 to generate gangliosides GM2/GD2. GM2/GD2 gangliosides are surface glycolipids mainly found on brain neurons as well as peripheral nerves and skin melanocytes and are reported to exacerbate the malignant potential of melanomas. In order to elucidate the mechanism, we performed functional analyses of B4GALNT1-overexpressing cells. We analyzed ganglioside pattern on four melanoma and two neuroblastoma cell lines by high performance liquid chromatography (HPLC). We overexpressed B4GALNT1 in GM2/GD2-negative human melanoma cell line (SH4) and confirmed production of GM2/GD2 by HPLC. They showed higher anchorage independence growth (AIG) in colony formation assay, and exhibited augmented motility. In vitro, cell proliferation was not affected by GM2/GD2 expression. In vivo, GM2/GD2-positive SH4 clones showed significantly higher tumorigenesis in NOD/ Scid/IL2Rγ-null mice, and immunostaining of mouse CD31 revealed that GM2/GD2 induced remarkable angiogenesis. No differences were seen in melanoma stem cell and Epithelial-Mesenchymal Transition markers between GM2/GD2-positive and -negative SH4 cells. We therefore concluded that B4GALNT1, and consequently GM2/GD2, enhanced tumorigenesis via induction of angiogenesis, AIG, and cell motility. RNA-Seq suggested periostin as a potential key factor for angiogenesis and AIG. These findings may lead to development of novel therapy for refractory melanoma.abundant in the nervous system, especially brain neurons 14 . They also exist in peripheral nerves and skin melanocytes 15,16 . These molecules are reported to have important biological functions, such as intercellular communication, cell cycling, cell growth, adhesion, differentiation, and cell motility [17][18][19] . Gangliosides are not only detected at high levels in tumors of neuroectodermal cell origin but also related to the biological and clinical behavior of many kinds of tumors 20 . Recently, some analysis revealed that patients with higher expression of B4GALNT1 and GM2/GD2 correlated with poorer prognosis in renal cell carcinoma (TCGA data set; Human Protein Atlas), neuroblastoma 21 , and melanoma 22 . Thus, B4GALNT1 gene is considered to be key tumor-associated antigens [23][24][25][26][27] , indicating that their expression is a meaningful marker for metastatic condition and are potential therapeutic targets for melanoma.Our findings indicate the involvement of B4GALNT1 and GM2/GD2 in tumor establishment and progression as well as a potential direction of therapeutic approach via controlling B4GALNT1, and consequently GM2/GD2 expression in cancers such as melanoma. Scientific RepoRtS |(2020) 10:1199 | https://doi.Generation of GM2/GD2-positive SH4 melanoma clones. The SH4 cells were transfected with expression vectors with or without B4GALNT1 gene cassette, to establish GM2/GD2-positive and -negative SH4 clones. Two GM2/GD2-high clones were selected by single cell isolation (#4 and #5, Fig. S2A). These two clones showed significa...

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confidence: 99%

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

Yoshida

Koodie

Jacobsen

et al. 2020

Sci Rep

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“…92,93 BRAF -mutant melanomas show high levels of MAPK pathway activation and are clearly dependent on BRAF-induced MAPK pathway activation given the efficacy of BRAF and MEK inhibitors. 94 …”

Section: Mechanisms Of Growth Arrestmentioning

confidence: 99%

Melanocytic nevi and melanoma: unraveling a complex relationship

2017

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Approximately 33% of melanomas are derived directly from benign, melanocytic nevi. Despite this, the vast majority of melanocytic nevi, which typically form as a result of BRAFV600E-activating mutations, will never progress to melanoma. Herein, we synthesize basic scientific insights and data from mouse models with common observations from clinical practice to comprehensively review melanocytic nevus biology. In particular, we focus on the mechanisms by which growth arrest is established after BRAFV600E mutation. Means by which growth arrest can be overcome and how melanocytic nevi relate to melanoma are also considered. Finally, we present a new conceptual paradigm for understanding the growth arrest of melanocytic nevi in vivo termed stable clonal expansion. This review builds upon the canonical hypothesis of oncogene-induced senescence in growth arrest and tumor suppression in melanocytic nevi and melanoma.

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“…Combinations that modulate distinct pathways may provide an opportunity for improved responses (18). For example, the combination of an MEK inhibitor (trametinib) with an RAF inhibitor (dabrafenib) is now an approved therapy for BRAF mutation-positive metastatic melanoma (19). A similarly attractive alternative strategy for AML, supported by emerging data, is the use of molecularly guided drug combinations, such as quizartinib and azacitidine, which inhibit FLT3 and DNA methyltransferase activities, respectively (20).…”

Section: Significancementioning

confidence: 99%

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

Kurtz

Eide

Kaempf

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies.

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Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV600 mutations

Cited by 34 publications

References 37 publications

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

Melanocytic nevi and melanoma: unraveling a complex relationship

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

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