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Melanoma News
ANTI-MELANOMA ACTIVITY OF NBD PEPTIDE
In an in vitro human melanoma model, a cell-permeable peptide spanning the NEMO binding domain (NBD) of IKK-beta disrupts the IKK heterotrimer (IKK-alpha + IKK-beta + NEMO/IKK-gamma), inhibits NFkB activity and leads to melanoma cell apoptosis via caspase-3 activation.
Source: Ianaro A, Cancer Lett 2008, Epub ahead of print
FAK AND MELANOMA AGGRESSIVENESS
In a murine melanoma model, the Y925F mutation of FAK (focal adhesion kinase) suppresses metastasis, which correlates with decreased extracellular matrix dependent proliferative capability, adhesive, migrational, and invasive capabilities: these findings suggest that the FAK Y925 residue is a potential therapeutic target.
Source: Kaneda T, Cancer Lett 2008, 270:354-61
GALECTIN-3: A NOVEL MELANOMA ONCOGENE
In a xenograft model of human melanoma, knockdown of Galectin-3 (a beta-galactoside-binding protein involved in cell migration/apoptosis) significantly impairs metastasis formation/growth in vivo, likely by interfering with melanoma angiogenesis/vasculogenic mimicry.
Source: Mourad-Zeidan AA, Am J Pathol 2008, Epub ahead of print
NFkB: NOT ALWAYS AN ONCOGENE
Despite the general belief that NFkB is an oncogene that promotes cancer aggressiveness and resistance to therapy, the Authors of this report demonstrate that this transcription factor can sensitize melanoma cells to TRAIL-mediated apoptosis, likely by inhibiting the expression of anti-apoptotic factor XIAP.
Source: Thayaparasingham B, Oncogene 2008, Epub ahead of print
ANTI-MELANOMA ACTIVITY of IL-2 PLUS FAMOTIDINE
In a small series of patients (n=16), short intravenous pulses of interleukin-2 (IL-2) combined with famotidine (an H2 receptor antagonist that may increase LAK cells activity by increasing IL-2 internalization) shows anti-melanoma activity in the metastatic setting, with a 19% overall response rate (95% CI: 6-44%).
Source: Quan WD, Cancer Biother Radiopharm 2008, 23:641-6
PLEXIN C1: A NOVEL MELANOMA SUPPRESSOR GENE
Plexin C1 (a receptor for Semaphorin 7A) inhibits cell migration by inactivating cofilin (an actin-binding protein involved in cell motility); moreover, plexin C1 is often downregulated in melanomas. This study identifies plexin C1 as a potential inhibitor of melanoma progression.
Source: Scott GA, J Invest Dermatol 2008, Epub ahead of print
GAS1: A NOVEL MELANOMA SUPPRESSOR GENE
In a genome-wide shRNA screening study, GAS1 has been identified as a novel melanoma suppressor gene. GAS1 suppresses metastasis in a spontaneous metastasis assay, promotes apoptosis following dissemination of cells to secondary sites, and is frequently downregulated in human melanoma specimens and cell lines.
Source: Gobeil S, Genes Dev 2008, 22:2932-40
CDKN2A GERMLINE MUTATION AND NON-MELANOMA CANCER RISK
In the largest study to date analyzing cancer risk in melanoma families positive for the same CDKN2A mutation (p16 Leiden founder mutation), the relative risk (RR) of cancer other than melanoma and non-melanoma skin cancer is 4.4 (95%CI: 3.3-5.6), which is mainly attributable to the increased risk for pancreatic cancer (RR=46.6; 95%CI: 24.7-76.4).
Source: De Snoo FA, Clin Cancer Res 2008, 14:7151-7
NON SENTINEL LYMPH NODE STATUS PREDICTS PATIENTS' SURVIVAL
After positive sentinel node biopsy, metastatic non sentinel lymph nodes (NSLN) are found in 15-20% of completion lymphadenectomies. This study shows that NSLN status is an independent predictor of patients' survival, which corroborates previously published findings (e.g. Roka et al, 2008; Cascinelli et al, 2006).
Source: Ariyan C, Ann Surg Oncol 2008, Epub ahead of print
siRNA: COMBINING BCL2 TARGETING WITH IMMUNOSTIMULATION
In a mouse melanoma model, systemic delivery of Bcl2-specific short interfering RNA (siRNA) with 5'-triphosphate ends (3p-siRNA) causes massive apoptosis of melanoma cells in lung metastases in vivo: this is due to both pro-apoptotic effects of BCL2 knockdown and the immunostimulatory properties of 3p-siRNA molecules.
Source: Poeck H, Nat Med 2008, Epub ahead of print
PAR1 SILENCING INHIBITS MELANOMA GROWTH IN VIVO
In a human xenograft melanoma model, systemic delivery of liposome-incorporated small interfering RNA targeting protease-activated receptor-1 (PAR1) leads to inhibition of melanoma growth and metastasis formation.
Source: Villares GJ, Cancer Res 2008, 68:9078-86
MFGE8 AND MELANOMA PROGRESSION
In a murine melanoma model, milk fat globule EGF-8 (MFGE8) enhances tumorigenicity and metastatic capacity through Akt- and Twist-dependent pathways. MFGE8 augments melanoma cell resistance to apoptosis, triggers an epithelial-to-mesenchymal transition (EMT) and stimulates immune suppression.
Source: Jinushi M, Cancer Res 2008, 68:8889-98
ADAM-10 SHOWS ANTI-MELANOMA ACTIVITY
ADAM-10 (a disintegrin-metalloprotease family member) causes the shedding of CD44 (the receptor for hyaluronic acid, HA) from the surface of melanoma cells: since soluble CD44 interferes with the proliferation-promoting interaction between HA and membrane-bound CD44, ADAM-10 activation might represent a novel anti-melanoma therapeutic strategy.
Source: Anderegg U, J Invest Dermatol 2008, Epub ahead of print
LIF AND MELANOMA BONE METASTASIS
In a xenograft model, inhibition of leukemia inhibitory factor (LIF) expression by RNA interference decreases melanoma-induced osteolysis in vivo, which suggests that LIF might be a novel therapeutic target for the treatment of melanoma metastatic disease to the bones.
Source: Maruta S, Clin Exp Metastasis 2008, Epub ahead of print
p16INK4a AND BRAF AS CHEMOSENSITIVITY MARKERS
p16INK4a expression and absence of activated BRAF are independent predictors of chemosensitivity in patients (n=30) treated with isolated limb infusion (with melphalan and actinomycin-D) for in transit melanoma metastases.
Source: Gallagher SJ, Neoplasia 2008, 10:1231-9
NFKB1/p50 AND MELANOMA ANGIOGENESIS
Nuclear expression of the NF-kappaB subunit p50 correlates with melanoma progression and poor 5-year patient survival: in this study, the Authors report that p50 favors melanoma angiogenesis/progression at least in part by enhancing IL-6 expression.
Source: Karst AM, Int J Cancer 2008, Epub ahead of print
EBI-3 AND ANTI-MELANOMA IMMUNOSURVEILLANCE
In a murine melanoma model, EBV-induced gene 3 (EBI-3, which codes for a soluble type I receptor homologous to the p40 subunit of IL-12) reveals immunosuppressive properties that make EBI-3 a potential target for anti-melanoma immunotherapy.
Source: Sauer KA, J Immunol 2008, 181:6148-57
UVEAL VERSUS CONJUNCTIVAL MELANOMA CLINICAL OUTCOME
In a population-based study, longer survival was observed after primary conjunctival melanoma (CM) than after primary uveal melanoma (UM), which reflects the smaller average size of CM. However, after adjusting for tumor size, CM is more deadly than UM, possibly because of lymphatic dissemination occurring with CM.
Source: Kujala E, Acta Ophthalmol 2008, Epub ahead of print
NOTCH1 AND MELANOMA DEVELOPMENT
Notch1 signaling is elevated in human melanoma samples and cell lines and is required for Akt and hypoxia to transform melanocytes in vitro; Notch1 facilitates melanoma development also in a xenograft model.
Source: Bedogni B, J Clin Invest 2008, Epub ahead of print
B-1 LYMPHOCYTES FAVOR MELANOMA PROGRESSION
A subset of B cells (termed B-1 population) might favor melanoma metastatic potential in vivo, likely through the homophilic interaction mediated by the cell surface glycoprotein MUC18.
Source: Staquicini FI, Cancer Res 2008, 68:8419-28
SYNERGISM BETWEEN INTERFERON AND BORTEZOMIB
Interferon-alpha (IFN) and bortezomib display significant antitumor activity compared with either agent alone in both the B16 murine model of melanoma and in athymic mice bearing human A375 xenografts.
Source: Lesinski GB, Cancer Res 2008, 68:8351-60
LOCUS POLYMORPHISMS AND MELANOMA RISK
In large European series of cases (>2,000) and controls (>40,000), two polymorphisms at loci 1p36 and 1q42 are associated with basal cell carcinoma (BCC) but not cutaneous melanoma.
Source: Stacey SN, Nat Genet 2008, Epub ahead of print
NEW FOLLOW-UP GUIDELINES FOR MELANOMA
Using the disease recurrence data from a large series (n=4,748), investigators from the Sydney Melanoma Unit propose this follow up schedule: stage I annually, stage IIA 6-monthly for 2 years and then annually, stage IIB-IIC 4-monthly for 2 years, 6-monthly in the third year and annually thereafter.
Source: Francken AB, Br J Surg 2008, 95:1401-7
GRP78: A NOVEL DRUG RESISTANCE MOLECULE FOR MELANOMA
Inhibition of glucose regulated protein 78 (GRP78) expression by RNA interference sensitizes human melanoma cells to both cisplatin and doxorubicin in vitro.
Source: Jiang CC, Carcinogenesis 2008, Epub ahead of print
TBX3 ENHANCES MELANOMA PROGRESSION
T-box (TBX) transcription factors/repressors are often overexpressed in cancer; in this melanoma model, TBX3 promotes melanoma progression by inhibiting both p21/CIP1 (cell senescence) and E-cadherin (cell adhesion) expression.
Source: Rodriguez M, Cancer Res 2008, 68:7872-81
HMW-MAA BASED IMMUNOTHERAPY WORKS IN MICE
In this animal model, vaccination with a peptide derived from HMW-MAA (high molecular weight melanoma associated antigen) significantly impairs the in vivo growth of melanoma, even when malignant cells are not engineered to express HMW-MAA.
Source: Maciag PC, Cancer Res 2008, 68:8066-75
SYNTENIN PROMOTES MELANOMA METASTASIS
Acting as a scaffold protein, Syntenin/MDA9 interacts with the oncoprotein c-SRC and promotes the formation of an active c-SRC/FAK complex, which ultimately enhances melanoma cell motility/migration and metastatic capability.
Source: Boukerche H, PNAS 2008, Epub ahead of print
HIGH RESPONSE RATES ACHIEVED WITH CHEMORADIATION + ADOPTIVE CELL THERAPY
In a series of 50 patients with metastatic melanoma, intensive myeloablative chemotherapy + total body irradiation followed by autologous adoptive cell therapy and interleukin-2 yielded an encouraging 52% to 72% tumor response rate.
Source: Dudley ME, J Clin Oncol 2008, Epub ahead of print
STAT3 INHIBITION LEADS TO MELANOMA REGRESSION IN MICE
In a syngeneic melanoma mouse model, pharmacological inhibition of STAT3 with WP1066 leads to tumor regression: this is accompanied by reduced production of immunosuppressive factors (TGF-beta, RANTES, MCP-1, VEGF), inhibition of Treg proliferation and increased cytotoxic immune responses of T cells.
Source: Kong LY, Clin Cancer Res 2008, 14:5759-68
MGLUR1 SUSTAINS BOTH MELANOMA DEVELOPMENT AND PROGRESSION
In a transgenic mouse model, ectopic expression of metabotropic glutamate receptor subtype 1 (mGluR1) in melanocytes induces melanoma formation. Subsequent inactivation of the mGluR1 transgene in melanoma-bearing mice inhibits melanoma growth, supporting the role of mGluR1 as a novel therapeutic target.
Source: Ohtani Y, Oncogene 2008, Epub ahead of print
POSITRON EMISSION TOMOGRAPHY (PET) CANNOT REPLACE SENTINEL NODE BIOPSY (SNB)
In a recent study, investigators found that PET scan (combined with computed tomography, CT) has low accuracy in detecting SLN metastasis, which leaves SNB the best method to assess SLN status [1]. These findings are in line with a recent review of the literature on this subject [2].
Source: [1] Singh B, Melanoma Res 2008, 18:346-52. [2] El-Maraghi RH, J Am Coll Radiol 2008, 5:924-31
ORAL CONTRACEPTIVES AND MELANOMA RISK
Although meta-analyses have ruled out a significant melanoma risk in women assuming oral contraceptives (Karagas MR et al, Br J Cancer 2002; Lens M et al, Cancer Causes Control 2008, 19:437-42), a recent study raises new concerns about the use of estrogens (including oral contraceptives and hormone replacement therapy), the effect on melanoma risk being cumulative dose dependent.
Source: Koomen ER et al, Ann Oncol 2008, Epub ahead of print
HER3: PROGNOSTIC FACTOR AND THERAPEUTIC TARGET FOR MELANOMA
In this study, protein expression of HER3/HerbB3 (EGFR family of receptor tyrosine kinases; ligands: neuregulin-1 to -4) is an independent negative prognostic factor in patients with melanoma. Moreover, in preclinical models, anti-HER3 strategies (e.g. RNA interference, monoclonal antibody) show anti-melanoma effects alone and synergic activity in combination with dacarbazine.
Source: Reschke M et al, Clin Cancer Res 2008, 14:5188-97
ADJUVANT PEGYLATED INTERFERON IMPROVES DISEASE-FREE NOT OVERALL SURVIVAL
The results of the EORTC 18991 trial show that PEG-IFN (as compared to placebo) increases disease free but not overall survival in patients with stage III melanoma. At subgroup analysis, this survival advantage is maintained in patients with N1 disease (microscopic metastasis, as detected by sentinel node biopsy), but not in those with N2 disease (palpable lymph node metastasis).
Source: Eggermont AM et al, Lancet 2008, 372:117-26
NSAID & MELANOMA RISK/PROTECTION
A large cohort study (n = 63,809) showed no association between non-steroidal anti-inflammatory drugs (NSAID) use and melanoma risk (after adjusting for melanoma risk factors and indications for NSAID use). Moreover, NSAID use was not associated with tumor invasion, tumor thickness or risk of metastasis . NSAID do not appear to be good candidates for the chemoprevention of melanoma.
Source: Asgari MM et al, J Natl Cancer Inst 2008, Epub ahead of print
SENTINEL NODEL BIOPSY MAY IMPROVE SURVIVAL
Unlike the prospective randomized MSLT-I trial, a retrospective larger case-match-control study performed using data from the SEER database indicates that sentinel nodel biopsy improves the overall survival of patients with 0.75-3.5 mm thick melanoma.
Source: Gimotty P et al, J Clin Oncol 2008, 26 (May 20 suppl), Abstract 9005
TREMELIMUMAB (ANTI-CTLA4 ANTIBODY) IN ADVANCED MELANOMA
In a phase III RCT comparing the efficacy of first line anti-CTLA4 antibody Tremelimumab to physician's choice (Dacarbazine or Temozolomide) for the treatment of advanced/metastatic melanoma, investigators found no improvement in overall survival.
Source: Ribas A et al, J Clin Oncol 2008, 26 (May 20 suppl), Abstract LBA9011
ADJUVANT VACCINATION FOR STAGE II MELANOMA
In the largest adjuvant phase III RCT to date in stage II melanoma (EORTC 18961), investigators compared the efficacy and toxicity of ganglioside GM2-KLH21 vaccination to observation. The findings of this trial show that adjuvant GM2-KLH21 vaccination is ineffective and could even be detrimental in stage II melanoma patients.
Source: Eggermont AM et al, J Clin Oncol 2008, 26 (May 20 suppl), Abstract 9004
SUNBELT MELANOMA TRIAL: FINAL RESULTS
The final results of this multicenter prospective randomized trial failed to demonstrate a benefit for adjuvant high-dose interferon alpha (IFN) for patients with a single positive sentinel lymph node (SLN). Among patients with melanoma cells detected in the SLN by RT-PCR analysis, there was no significant benefit to completion lymph node dissection (CLND) or CLND + IFN.
Source: McMasters KM et al, J Clin Oncol 2008, 26 (May 20 suppl), Abstract 9003
NEWS FROM MOLECULAR EPIDEMIOLOGY STUDIES
Two recently published molecular epidemiology studies conducted on two large European series have shed further light on melanoma susceptibility genes. Besides confirming the relationship between melanocortin 1 receptor (MC1R) variants and risk of developing cutaneous melanoma, a highly significant association has been also found with polymorphisms at the tyrosinase (TYR), TYR related protein 1 (TYRP1) and aoguti signaling protein (ASIP) genes [1] and with sequence variants on chromosome 20q11.22 [2].
Source: [1] Gudbjartsson DF et al, Nat Genetics 2008, Epub ahead of print
[2] Brown KM et al, Nat Genetics 2008, Epub ahead of print
BIOCHEMOTHERAPY NOT RECOMMENDED BY CANADIAN GUIDELINES
The Melanoma Disease Site Group of Cancer Care Ontario's Program in Evidence-Based Care does not recommend the use of biochemotherapy (defined as a therapeutic regimen that includes chemotherapy [either single-agent or combination] and interleukin-2 [IL-2]) for the treatment of metastatic melanoma because of the inconsistent results of the available studies with regard to benefit (response, time to progression, and survival) and consistently high toxicity rates.
Source: Verma S et al, Curr Oncol 2008, 15:85-89
UNDER THE SPOTLIGHT: MELANOMA-PROMOTING MICRORNA
The promyelocytic leukemia zinc finger (PLZF) transcription factor has been found to act as a repressor of two microRNA (mir-221 and mir-222) by direct binding to their putative regulatory region. PLZF silencing in melanomas unblocks mir-221 and mir-222, which in turn controls the progression of the neoplasia through down-modulation of p27/Cip1/Kip1 and c-KIT receptor, leading to enhanced proliferation and differentiation blockade of the melanoma cells, respectively. In vitro and in vivo functional studies, including the use of antisense "antagomir" oligonucleotides, confirmed the key role of the two oncomirs in regulating the progression of human melanoma. These findings suggest that targeted therapies suppressing mir-221/mir-222 may be a novel anti-melanoma strategy.
Source: Felicetti F et al, Cancer Res 2008, 68:2745-54
