Melanoma Molecular Maps Projects

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Ocular melanoma

More than 95% of all ocular melanomas occur intraocularly, the remainder arising in conjunctiva. These two sub-types of ocular melanoma are completely different from each other in their molecular biology and natural history.


INTRAOCULAR MELANOMA

Overview

Intraocular melanomas arise from melanocytes in the uvea. The uvea is a vascular, pigmented tissue comprising: (A) the cup-shaped choroid, which lies between the retina and the sclera; (B) the ciliary body, a muscular ring of tissue, which lines the rim of the choroid, adjusting the lens focus; and (C) the iris, which lies anterior to the lens, altering the pupil size. About 90% of uveal melanomas involve choroid, with about 5% arising in the ciliary body and 5% developing in the iris.


Epidemiology

Uveal melanomas account for about 5-10% of all melanomas. They rarely present before adulthood, the incidence increasing with age to peak at around sixty years [1]. There is no sex preponderance. Risk factors include: fair skin, blue or grey iris color, increased number of cutaneous naevi, congenital ocular melanocytosis, and neurofibromatosis. The role of sunlight is disputed.


Clinical features

Choroidal and ciliary body melanomas cause exudative retinal detachment, which results in blurred or distorted vision, visual field loss and flashing lights. In addition, ciliary body melanomas press on the lens to cause astigmatism and cataract. Iris melanomas usually form a visible nodule. All type of uveal melanoma can show diffuse growth, which can cause glaucoma by obstructing aqueous fluid outflow through the drainage meshwork in the anterior chamber angle. Uveal melanomas can spread extraocularly along small blood vessels and nerves exiting the sclera. Optic nerve invasion is rare. Advanced melanomas can make the eye blind and painful as a result of retinal detachment, glaucoma and inflammation. About 30-40% of all uveal melanomas are asymptomatic at the time of detection, being discovered as a result of routine ocular examination.


Pathology

The two uveal melanoma cell types are spindle and epithelioid, with most tumors being of mixed cell type. Lymphocytes and macrophages are often present, although the numbers vary greatly from tumor to tumor. Periodic-acid-Schiff staining shows a variety of interstitial tissue patterns, such as so-called “closed loops” [2]. The microvascular density is variable [3]. In Caucasians, most uveal melanomas are amelanotic or lightly pigmented, with choroidal and ciliary body melanomas appearing dark brown or grey only because of the overlying pigment epithelium. Uveal melanomas tend to show chromosomal abnormalities such as partial or total loss of chromosome 3 (i.e., monosomy 3), gains in chromosome 8 (e.g., trisomy or isochromosome 8q), and gains in chromosome 6 (e.g., isochromosome 6p) [4, 5]. Uveal melanomas metastasize via the blood stream (i.e., hematogenously); lymphatic spread to regional nodes is very rare, occurring only if the tumor has spread extraocularly to involve conjunctiva [6]. Metastatic disease involves the liver in more than 90% of patients, other relatively common sites being skin, lung, and bone. Most patients with metastases die within a year of the onset of symptoms [6].


Prognostic factors

The most accurate predictor of metastatic disease in uveal melanoma is detection of monosomy 3 [7]. Almost all tumors with this cytogenetic abnormality are fatal as compared to less than 5% of tumors without chromosome 3 deletion. Chromosome 8 gains are associated with monosomy 3 and apparently occur at a later stage in tumor development, so that their presence indicates a worse prognosis. Chromosome 6p gains rarely coincide with monosomy 3 and, therefore, indicate a good survival probability [5]. Monosomy 3 is believed to develop at a very early stage in tumor growth [8]; however, tumor heterogeneity can occur, with implications for biopsy [9]. Epithelioid cell type indicates a poor prognosis, firstly because it correlates strongly with monosomy 3 and perhaps because in the presence of monosomy 3 it indicates more rapid growth. Other histological factors indicating an increased risk of metastasis include: closed loops; lymphocytic infiltrates; macrophages; and high microvascular density. Basal tumor diameter correlates with poor survival, firstly, because large tumours are more likely to show monosomy 3 and, secondly, because of lead-time bias. Tumor thickness is not significant in multivariate analyses Ciliary body involvement correlates with monosomy 3 and with poor survival, although these associations are unexplained. Extraocular spread is associated with increased mortality, mostly because it indicates that the underlying intraocular tumor is more malignant.


Staging

The present TNM (Tumor, Node and Metastasis) staging system is based on basal tumor diameter, tumor thickness, ciliary body involvement and extraocular spread [10]. It is currently being revised. It is not widely used by ocular oncologists. An alternative approach is being evaluated, which uses a neural network to: (A) take account of normal life-expectancy as determined by age and sex; (B) determines whether or not the tumor has metastatic potential; (C) stages lethal tumors to deal with lead-time bias; and (D) adjusts for tumor growth rate.


Ocular therapy

For many years, it was believed that ocular treatment was life-saving, especially with large uveal melanomas, which were, therefore, treated more radically, by enucleation. Eye-conserving treatments such as radiotherapy were considered risky. In 1978, Zimmerman hypothesized that enucleation accelerated metastatic death and this suggestion prompted measures such as pre-enucleation radiotherapy [11]. In the USA, the Collaborative Ocular Melanoma Study (COMS) reported that it found no difference in survival: (A) between pre-enucleation radiotherapy and enucleation alone; and (B) between brachytherapy and enucleation [12, 13]. A recent re-appraisal indicated that the COMS was essentially inconclusive, because of insufficient data [14]. Small melanomas were considered to be relatively benign and were often left untreated for months or years until growth was observed [15]. There is growing circumstantial evidence that monosomy 3 uveal melanomas start to metastasize at a very early stage, perhaps even when they are indistinguishable from naevi [16]. The implication of this view is that ocular treatment is only palliative, except perhaps with very small tumors. The problem is that only about 25% of small melanomas have metastatic potential. Several centers have recently started performing biopsy on small melanomas, to determine whether or not monosomy 3 is present; however, biopsy does not always produce an adequate sample and sometimes causes vitreous hemorrhage and other complications. Fluorescence in situ hybridization (FISH) is most widely used but being replaced by multiplex ligation probe amplification (MLPA) and other methods that provide more information from smaller samples. In most centers, the first choice of therapy for uveal melanomas is brachytherapy, delivered using an iodine or ruthenium plaque [17]. Proton beam is available in only a few centers, where it is used either in selected cases, when brachytherapy is not possible, or for all patients (e.g. Lausanne, Boston). A few centers advocate stereotactic radiotherapy. There are appreciable ocular complications after radiotherapy, with loss of vision and the eye itself. Such morbidity has been attributed to collateral damage to healthy ocular tissues. Recent evidence indicates that in many patients, the ocular morbidity occurs because the irradiated tumor can become toxic to the eye, as a result of exudation and the release of angiogenic factors [18]. These are treatable with methods such as: intraocular injections of steroids and/or anti-angiogenic agents; trans-pupillary thermotherapy or photodynamic therapy of the melanoma or local excision of the tumor, either trans-retinally or trans-sclerally. Primary enucleation now tends to be performed only if the tumor involves optic nerve or if it is very large, exceeding 17 mm in basal diameter. In practice, ocular conservation is attempted in about 70% of patients and successful in about 90% of these [19].


Screening for metastases

Systemic screening is performed mostly in the hope of detecting resectable hepatic metastases [6]. Methods include liver imaging, such as ultrasonography, and biochemical liver function tests, which are performed every six or twelve months, indefinitely [20]. Chest radiography is not useful, except when metastasis has been detected. Positron emission tomography (PET) is useful for determining the extent of systemic disease, for example, if partial hepatectomy is being considered [21]. There is no consensus as to whether screening should be performed in all patients or only in those with increased risk.


Systemic therapy

There is a growing desire for adjuvant systemic therapy in high risk uveal melanoma patients; however, no randomized, prospective studies have yet shown any benefit. Obstacles to such studies include the rarity of uveal melanoma and the limited number of ocular oncology centers, which perform cytogenetic studies on a routine basis, required to distinguish between lethal and non-lethal tumors. Long term survival has been reported after apparently complete resection of hepatic metastases. Encouraging results have also occurred after intra-hepatic chemotherapy. Systemic chemotherapy has generally been disappointing [6].


CONJUNCTIVAL MELANOMA

Overview

Most conjunctival melanomas arise in the bulbar (or ‘ocular’) conjunctiva, usually at the limbus (i.e., edge of the cornea) and most often temporally [22]. A minority develop in the caruncle (i.e. fleshy pink tissue at the nasal end of the conjunctiva) or in the palpebral conjunctiva (i.e., inner surface of eyelid). Knowledge on conjunctival melanomas is diminished by the fact that most patients are referred to an ocular oncology centre only after initial treatment by general ophthalmologists, who may not perform adequate treatment and who often provide incomplete baseline data.


Epidemiology

Conjunctival melanomas account for less than 5-10% of all ocular melanomas. They usual present in adulthood [22]. There is no sex preponderance. The most important risk factor for invasive melanoma is, perhaps confusingly, referred to as ‘primary acquired melanosis (PAM) with atypia’. This is essentially ‘conjunctival melanocytic dysplasia’, culminating in ‘in situ melanoma’ and, ultimately, invasive melanoma [23]. Some melanomas are believed to arise from naevi [23].


Clinical features

Conjunctival melanomas can be nodular or diffuse, that is, thick with discrete margins or thin and wide with indistinct edges. Many are mixed (i.e., nodulo-diffuse). There may be extensive intra-epithelial disease, consisting either of the pre-existing melanocytic dysplasia, or secondary pagetoid spread from the melanoma. The tumor color can be black, grey, brown, tan, pink or white. A minority of tumors are multinodular. Spread can occur to adjacent eyelid skin, naso-lacrimal duct, orbit, eye, nasal sinuses and intracranial cavity. Metastatic spread can occur to regional lymph nodes and systemically. There is circumstantial evidence that seeding can occur iatrogenically, if tumor biopsy or excision is not performed properly [24].


Pathology

Primary acquired melanosis (PAM) requires histology with immunohistochemistry to distinguish: (A) racial melanosis (i.e., increased melanin production from melanocytes that are normal in shape, location and number); (B) ‘PAM without atypia’, which consists of melanocytic hyperplasia, with the melanocytes showing an increased density, without atypia or displacement from the basal layer; and (C) ‘PAM with atypia’, consisting of melanocytic dysplasia, i.e., melanocytes with cellular atypia infiltrating with increasing density, partial or the entire conjunctival epithelial thickness. Invasive melanoma shows spread into the lamina propria of the conjunctiva. Invasive melanoma can be associated with diffuse infiltration either within the conjunctival epithelium, subepithelially and into adjacent tissues.


Prognostic factors

The overall ten-year mortality is reported to be 25-30% [25-27]. Risk factors for metastatic spread are: involvement of non-bulbar conjunctiva, especially caruncle; local tumor recurrence; multi-focal tumors; increased tumor thickness; high mitotic rate; epithelioid tumor cell type; and lymphatic invasion.


Staging

The present TNM staging system categorizes conjunctival melanomas as: T1, bulbar tumors; T2, bulbar tumors involving cornea; T3, involvement of non-bulbar conjunctiva; and T4, involvement of eyelid skin, eye, orbit, nasal sinuses or brain. This system has several limitations. First, there is no evidence that corneal involvement is associated with a worse prognosis for survival. Second, it ignores basal tumor diameter, which is important. Third, it takes no account of quadrant, whereas nasal tumors have a worse prognosis than temporal disease. Fourth, it assumes that any non-bulbar conjunctival disease indicates a poor prognosis, whereas caruncular involvement is particularly serious. Finally, in T4, it stages all routes of spread equally, whereas intracranial disease is likely to have a worse prognosis than eyelid involvement. The TNM system is currently being revised and should correct most of these weaknesses in the new version.


Ocular therapy

Nodular tumors are treated by local excision with adjunctive brachytherapy or cryotherapy. If unresectable, such tumors can be treated with brachytherapy or some form of external beam radiotherapy. Intra-epithelial disease is treated with mitomycin C drops or some other form of topical chemotherapy. Exenteration is reserved for uncontrollable disease.


Screening for metastases

The role of sentinel lymph node biopsy is controversial [28] Not all patients with systemic metastases have clinical evidence of regional lymph node involvement. Other systemic screening is the same as for cutaneous melanoma.


Systemic therapy

Systemic therapy for metastatic disease from conjunctival melanomas is the same as for metastases from cutaneous primaries.





CLINICAL PRACTICE GUIDELINES



TABLE 1: Summary of evidence and recommendations for choroidal and conjunctival precursor melanocytic lesions (*).




TABLE 2-A: Summary of evidence for choroidal melanoma (*).




TABLE 2-B: Summary of recommendations for choroidal melanoma (*).




TABLE 3: Summary of evidence and recommendations for conjunctival melanoma (*).


TABLE 4: Summary of evidence and recommendations for eyelid melanoma, orbital melanoma and psychological aspects of ocular melanoma (*).


TABLE 5: Levels of evidence used in the above Tables. Grades of recommendations (A: excellent, B: good, C: satisfactory, D: poor) are based on level of evidence, consistency across studies, clinical impact and applicability.








TNM STAGING SYSTEM FOR OCULAR MELANOMA



FIGURE 1: AJCC TNM staging of conjunctival melanoma


FIGURE 2: AJCC TNM staging of uveal melanoma (choroid)


FIGURE 3: AJCC TNM staging of uveal melanoma (iris and ciliary body)




REFERENCES

[1] Singh AD et al, Uveal melanoma: epidemiologic aspects. In: Singh AD et al, eds. Clinical Ophthalmic Oncology. Philadelphia: Saunders Elsevier, 2007

[2] Frenkel S et al, Demonstrating circulation in vasculogenic mimicry patterns of uveal melanoma by confocal indocyanine green angiography. Eye 2008, 22:948-52

[3] Toivonen P et al, Microcirculation and tumor-infiltrating macrophages in choroidal and ciliary body melanoma and corresponding metastases. Invest Ophthalmol Vis Sci 2004, 45: 1-6

[4] Scholes AG et al, Monosomy 3 in uveal melanoma: correlation with clinical and histologic predictors of survival. Invest Ophthalmol Vis Sci 2003, 44: 1008-11

[5] Parrella P et al, Allelotype of posterior uveal melanoma: implications for a bifurcated tumor progression pathway. Cancer Res 1999, 59: 3032-7

[6] Singh AD et al, Uveal malignant melanoma: metastasis. In: Singh AD et al, eds. Clinical ophthalmic oncology. Philadelphia: Saunders Elsevier, 2007

[7] Damato B et al, Cytogenetics of uveal melanoma: a seven-year clinical experience. Ophthalmology 2007, 114: 1925-31

[8] Tschentscher F et al, Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities. Cancer Res 2003, 63: 2578-84

[9] Sandinha T et al, Correlation of heterogeneity for chromosome 3 copy number with cell type in choroidal melanoma of mixed-cell type. Invest Ophthalmol Vis Sci 2006, 47: 5177-80

[10] Kujala E et al, Tumor, node, metastasis classification of malignant ciliary body and choroidal melanoma evaluation of the 6th edition and future directions. Ophthalmology 2005, 112: 1135-44

[11] Zimmerman LE et al, Does enucleation of the eye containing a malignant melanoma prevent or accelerate the dissemination of tumour cells. Br J Ophthalmol 1978, 62: 420-5

[12] Hawkins BS, The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma: IV. Ten-year mortality findings and prognostic factors. COMS report number 24. Am J Ophthalmol 2004, 138: 936-51

[13] Collaborative Ocular Melanoma Study Group, The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report No. 28. Arch Ophthalmol 2006, 124: 1684-93

[14] Damato B, Legacy of the collaborative ocular melanoma study. Arch Ophthalmol 2007, 125: 966-8

[15] Melia BM et al, Factors predictive of growth and treatment of small choroidal melanoma. Arch Ophthalmol 1997, 115: 1537-44

[16] Singh AD et al, eds. Clinical ophthalmic oncology. Philadelphia: Saunders Elsevier, 2007

[17] Damato B, Treatment of primary intraocular melanoma. Expert Rev Anticancer Ther 2006, 6: 493-506

[18] Damato B, Vasculopathy after treatment of uveal melanoma. In: Joussen AM et al, eds. Retinal vascular disease. Berlin: Springer-Verlag, 2007

[19] Damato B, et al, Conservation of eyes with choroidal melanoma by a multimodality approach to treatment: an audit of 1632 patients. Ophthalmology 2004, 111: 977-83

[20] Eskelin S et al, Screening for metastatic malignant melanoma of the uvea revisited. Cancer 1999, 85: 1151-9

[21] Finger PT et al, Whole body PET/CT imaging for detection of metastatic choroidal melanoma. Br J Ophthalmol 2004, 88: 1095-7

[22] Damato B et al, Clinical mapping of conjunctival melanomas. Br J Ophthalmol 2008, 92:1545-9

[23] Seregard S, Conjunctival melanoma. Surv Ophthalmol 1998, 42: 321-50

[24] Shields CL, Conjunctival melanoma. Br J Ophthalmol 2002, 86: 127

[25] Shields CL, Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Trans Am Ophthalmol Soc 2000, 98: 471-92

[26] Anastassiou G et al, Prognostic value of clinical and histopathological parameters in conjunctival melanomas: a retrospective study. Br J Ophthalmol 2002, 86: 163-7

[27] Paridaens AD et al, Prognostic factors in primary malignant melanoma of the conjunctiva: a clinicopathological study of 256 cases. Br J Ophthalmol 1994, 78: 252-9

[28] Tuomaala S et al, Metastatic pattern and survival in disseminated conjunctival melanoma: implications for sentinel lymph node biopsy. Ophthalmology 2004, 111: 816-21



Author(s)

Bertil Damato (Liverpool, UK). Update: 01-29-2008

Sarah Coupland (Liverpool, UK). Update: 01-29-2008

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PAR-1 AND MASPIN
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MACRO-H2A
The histone variant macroH2A suppresses melanoma progression through regulation of CDK8.
Source: Kapoor A, Nature 2010, 468:1105-9.

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CXCL9 induces chemotaxis, chemorepulsion and endothelial barrier disruption through CXCR3-mediated activation of melanoma cells.
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EXCISION MARGINS
In this meta-analysis of randomized controlled trials, excision margins affect both disease-free and disease-specific survival, which questions the common belief that narrow excision margins are as safe as wide margins in the management of primary melanoma.
Source: Mocellin S, Ann Surg 2011, 253:238-43.

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BRAF INHIBITOR RESISTANCE
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RASSF1A
RASSF1A suppresses melanoma development by modulating apoptosis and cell cycle progression.
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MOLECULAR STAGING
Molecular upstaging based on paraffin-embedded sentinel lymph nodes confirms prognostic utility in melanoma patients.
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SUNSCREEN TRIAL
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PTP4A3 PHOSPHATASE
High PTP4A3 phosphatase expression correlates with metastatic risk in uveal melanoma patients.
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MENIN: NEW MELANOMA SUPPRESSOR
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C-KIT AND MELANOMA RISK
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LYMPH NODE RATIO
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Ipilimumab (anti-CTLA4 antibody) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma (n=502).
Source: Robert C, N Engl J Med 2011, Epub ahead of print.

PHASE III TRIAL OF VEMURAFENIB
Vemurafenib (PLX4032, BRAF inhibitor) produced improved rates of overall and progression-free survival in patients with previously untreated metastatic melanoma with the BRAF V600E mutation.
Source: Chapman PB, N Engl J Med 2011, Epub ahead of print.

PHASE III TRIAL OF VACCINE + IL2
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Source: Schwartzentruber DJ, N Engl J Med 2011, 364:2119-27.

PHASE II TRIAL OF DASATINIB
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Contact: mmmpteam@mmmp.org

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HUMAN ARGINASE
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Source: Lam TL, Pigment Cell Melanoma Res 2010, Epub ahead of print.

PLEXIN B1
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Source: McClelland L, Pigment Cell Melanoma Res 2011, 24:165-74.

mTOR AND PROGNOSIS
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TRAIL GENE THERAPY
Efficient melanoma cell killing and reduced melanoma growth was observed in mice using a selective replicating adenovirus armed with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
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IMATINIB + VATALANIB
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Source: Singh T, Carcinogenesis 2011, 32:86-92.

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Source: CollabRx.

BRG1 AND PROGRESSION
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UCN-01 TRIAL
In this phase II trial (n=33), although well tolerated, UCN-01 (7-hydroxystaurosporine, a cell cycle inhibitor) as a single agent did not have sufficient clinical activity to warrant further study in refractory metastatic melanoma.
Source: Li T, Invest New Drugs 2010, Epub ahead of print.

ELASTIN PEPTIDES
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Source: Gopal YN, Cancer Res 2010, 70:8736-47.

IL-21 TRIAL
In a phase I trial of subcutaneous interleukin-21, the cytokine was well tolerated and showed some antitumor activity in patients with advanced melanoma.
Source: Schmidt H, Clin Cancer Res 2010, 16:5312-9.

MIRNA-200 FAMILY
MicroRNA-200 family members differentially regulate morphological plasticity and mode of melanoma cell invasion.
Source: Elson-Schwab I, PLoS One 2010, 5(10) pii: e13176.

KLOTHO AND PROGRESSION
Loss of Klotho during melanoma progression leads to increased filamin cleavage, increased Wnt5A expression, and enhanced melanoma cell motility.
Source: Camilli TC, Pigment Cell Melanoma Res 2011, 24:175-86.

LONAFARNIB AND SORAFENIB
The farnesyl transferase inhibitor lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells.
Source: Niessner H, J Invest Dermatol 2011, 131:468-79.

RIBONUCLEOTIDE REDUCTASE
siRNA knockdown of ribonucleotide reductase inhibits melanoma cell line proliferation alone or synergistically with temozolomide.
Source: Zuckerman JE, J Invest Dermatol 2011, 131:453-60.

TARGETED THERAPY ADVISOR
Over the next few months the MMMP website is going to provide users with a free access to an unprecedented tool for the personalized treatment of melanoma based on the automated analysis of the data collected in the Targeted Therapy Database.
Source: The MMMP Team.

HSP90 INHIBITORS
A novel class of specific Hsp90 small molecule inhibitors (including PF-4470296 and PF-3823863) demonstrate in vitro and in vivo anti-tumor activity in human melanoma cells.
Source: Mehta PP, Cancer Lett 2011, 300:30-9.

SAGOPILONE TRIAL
In a phase II trial of sagopilone (a novel epothilone analog) in metastatic melanoma, tumor responses were observed even in previously treated patients.
Source: DeConti RC, Br J Cancer 2010, 103:1548-53.

FREG PEPTIDE
The fibroblast growth factor-2 (FGF-2) derived peptide FREG inhibits melanoma growth by inhibiting FGF-2-dependent angiogenesis.
Source: Aguzzi MS, Mol Ther 2010, Epub ahead of print.

MELANOMA CHEMORESISTANCE
The expression of over 90 genes encoding proteins involved in drug resistance was correlated with melanoma sensitivity to different chemotherapeutics.
Source: Parker KA, J Clin Pathol 2010, 63:1012-20.

IFN-GAMMA AND VACCINE
In this preclinical model, peptide vaccines can eradicate large, established tumors in circumstances under which the inhibitory activities of interferon (IFN) gamma are curtailed.
Source: Cho HI, Blood 2011, 117:135-44.

NESTIN, CD133 AND CTC
In melanoma patients, circulating tumor cells (CTC) express stem cell-associated markers NESTIN and CD133; higher expression of NESTIN on CTC might represent an index of poor prognosis.
Source: Fusi A, J Invest Dermatol 2011, 131:487-94.

CDKN2A MUTATION CARRIERS
MC1R variants, hair color, and number of nevi are jointly associated with melanoma risk in CDKN2A mutation carriers.
Source: Demenais F, J Natl Cancer Inst 2010, 102:1568-83.

hTERTC27 VIRAL COCKTAIL
In C57BL/6 mice, melanoma growth can be inhibited by subcutaneous administration of hTERTC27 (a 27 kDa C-terminal polypeptide of human telomerase reverse transcriptase) viral cocktail that induces NK cell activation.
Source: Huo L, PLoS One 2010, 5:e12705.

CASPASE-3, XIAP AND TRAIL
Caspase-3 cleaves XIAP in a positive feedback loop to sensitize melanoma cells to TRAIL-induced apoptosis.
Source: Hörnle M, Oncogene 2010, Epub ahead of print.

DHA-PACLITAXEL vs DTIC
In a phase III trial of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma, no significant survival difference was found.
Source: Bedikian AY, Ann Oncol 2010, Epub ahead of print.

ADAM-15
Metalloproteinase ADAM15 is downregulated in melanoma metastasis compared to primary melanoma.
Source: Ungerer C, Biochem Biophys Res Commun 2010, 401:363-9.

ALPHAVIRUS REPLICON PARTICLES
Alphavirus replicon particles expressing TRP-2 provide potent therapeutic effect on melanoma through activation of humoral and cellular immunity.
Source: Avogadri F, PLoS One 2010, 5: e12670.

miR-125b
MicroRNA miR-125b is downregulated in primary cutaneous melanomas that produced early metastases (T2, N1, M0) compared with the sentinel lymph node-negative (T2, N0, M0) melanomas.
Source: Glud M, Melanoma Res 2010, 20:479-84.

EMMPRIN
EMMPRIN promotes melanoma cells malignant properties through a HIF-2 alpha mediated upregulation of VEGF-receptor-2.
Source: Bougatef F, PLoS One 2010, 5:e12265.

PLX4032 STRIKING ANTI-MELANOMA ACTIVITY
In a phase I-II trial (n=82), treatment of metastatic melanoma carrying the V600E BRAF mutation with PLX4032 (also known as RG7204, an orally available inhibitor of mutated BRAF), resulted in complete or partial tumor regression in the majority of patients.
Source: Flaherty KT, N Engl J Med 2010, 363:809-19.

PLX4720 IN MUTANT N-RAS MELANOMA
In mutant N-RAS melanoma cells, PLX4720 (inhibitor of oncogenic B-RAF) can induce hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis.
Source: Kaplan FM, Oncogene 2010, Epub ahead of print.

ANTIBODY C11C1
Monoclonal antibody C11C1 targeting domain 5 of high molecular weight kininogen inhibits metastasis of syngeneic murine melanoma in vivo and vasculogenesis in vitro.
Source: Khan ST, Cancer Immunol Immunother 2010, 59:1885-93.

NUCLEOTIDE EXCISION REPAIR (NER)
Cisplatin-induced DNA damage is recognized and repaired by the NER pathway; NER genes are upregulated in melanoma, which might explain cisplatin resinstance.
Source: Bowden NA, Cancer Res 2010, 70:7918-26.

SURVIVIN
Anti-apoptotic factor survivin enhances motility of melanoma cells by supporting AKT/PKB activation and integrin-alpha-5 upregulation.
Source: McKenzie JA, Cancer Res 2010, 70:7927-37.

CREB AND AP-2 ALPHA
CREB inhibits AP-2alpha expression to promote the malignant phenotype of melanoma.
Source: Melnikova VO, PLoS One 2010, 5:e12452.

FATTY ACID SYNTHASE
Inhibition of fatty acid synthase (FASN) in melanoma cells activates the intrinsic pathway of apoptosis.
Source: Zecchin KG, Lab Invest 2010, Epub ahead of print.

ANTI-MELANOMA PEPTIDE
In a murine in vivo model, a novel melanoma-targeting peptide screened by phage display exhibits antitumor activity.
Source: Matsuo AL, J Mol Med 2010, 88:1255-64.

CHEST X-RAY AND FOLLOW-UP
In this study the routine use of surveillance CXR did not provide clinically useful information in the follow-up of patients with melanoma.
Source: Brown RE, Surgery 2010, 148:711-6.

VATALANIB CLINICAL TRIAL
In a phase 2 trial in metastatic melanoma patients, Vatalanib stabilized disease in a proportion of patients, although overall survival was disappointing.
Source: Cook N, Eur J Cancer 2010, 46:2671-3.

ALDH POSITIVE CELLS
Aldehyde dehydrogenase (ALDH) positive melanoma cells have enhanced tumorigenicity over ALDH negative cells and superior self-renewal ability.
Source: Boonyaratanakornkit JB, J Invest Dermatol 2010, 130:2799-808.

ULCERATION AND IFN-ALPHA
Adjuvant interferon (IFN) was a significant independent predictor of survival among patients with ulcerated primary melanoma, but not among patients without ulceration, which suggests that ulceration might be a marker of responsiveness to IFN.
Source: McMasters KM, Ann Surg 2010, 252:460-5.

SMAD7
SMAD7 restricts melanoma invasion by restoring N-cadherin expression and establishing heterotypic cell-cell interactions in vivo.
Source: DiVito KA, Pigment Cell Melanoma Res 2010, 23:795-808.

MGMT METHYLATION
MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome.
Source: Hassel JC, Br J Cancer 2010, 103:820-6.

TENASCIN-C
Tenascin-C promotes melanoma progression by maintaining the ABCB5-positive side population.
Source: Fukunaga-Kalabis M, Oncogene 2010, 29:6115-24.

PTEN AND RAS
PTEN inactivation can drive the genesis and promote the metastatic progression of RAS-activated Ink4a/Arf-deficient melanomas.
Source: Nogueira C, Oncogene 2010, 29:6222-32.

PIRIN AND MIGRATION
A small-molecule inhibitor (triphenyl compound) shows that pirin (nuclear protein of unknown function) regulates migration of melanoma cells.
Source: Miyazaki I, Nat Chem Biol 2010, 6:667-73.

PHX-3 PRECLINICAL ACTIVITY
2-aminophenoxazine-3-one (Phx-3) prevents pulmonary metastasis of mouse B16 melanoma cells in mice, likely by activating both intrinsic and extrinsic apoptotic pathways.
Source: Hongo T, J Pharmacol Sci 2010, 114:63-8.

CASEIN KINASE 1 ALPHA
Suppression of casein kinase 1 alpha in melanoma cells induces a switch in beta-catenin signaling to promote metastasis.
Source: Sinnberg T, Cancer Res 2010, 70:6999-7009.

METHYL SULFONE
Methyl sulfone induces loss of metastatic properties and reemergence of normal phenotypes in a metastatic cloudman S-91 (M3) murine melanoma cell line.
Source: Caron JM, PLoS One 2010, 5:e11788.

TANESPIMYCIN TRIAL
A Phase II trial of 17-AAG (tanespimycin, a HSP90 inhibitor) in patients with metastatic melanoma was prematurely interrupted due to drug inefficacy.
Source: Pacey S, Invest New Drugs 2010, Epub ahead of print.

TYROSINE PHOSPHATASE INHIBITOR
Tyrosine phosphatase inhibitor-3 sensitizes melanoma and colon cancer to biotherapeutics and chemotherapeutics.
Source: Kundu S, Mol Cancer Ther 2010, 9:2287-96.

SUNBED USE
Sunbed use during adolescence and early adulthood is associated with increased risk of early-onset melanoma.
Source: Cust AE, Int J Cancer 2010, Epub ahead of print.

MMP13 AND CELL CYCLE
In vitro studies of migration and proliferation show that matrix metallo-proteinase-13 (MMP13) mediates cell cycle progression in melanocytes and melanoma cells.
Source: Meierjohann S, Mol Cancer 2010, 9:201.

KLF6 MELANOMA SUPPRESSOR
In melanoma cells, the tumor suppressor gene at 10p15 appears to be KLF6. Signaling from the collagen I-rich extracellular matrix appears to be involved in the tumor suppressive activity of KLF6.
Source: Huh SJ, J Natl Cancer Inst 2010, 102:1131-47.

TGFB AND GLI2
GLI2, a mediator of the Hedgehog pathway, is as a transcriptional target of TGF-beta signaling and is directly involved in driving melanoma metastasis in this preclinical study.
Source: Alexaki VI, J Natl Cancer Inst 2010, 102:1148-59.

MMP1 POLYMORPHISMS
Polymorphisms of the matrix metallopeptidase 1 gene have been associated with the risk of developing melanoma.
Source: Wang LE, Eur J Cancer 2010, Epub ahead of print.

TELOMERE THERAPY
In human xenograft model, investigators could obtain the inhibition of melanoma angiogenesis by using telomere homolog oligonucleotides.
Source: Coleman C, J Oncol 2010; 2010:928628.

EPHB4 RECEPTOR
The EphB4 receptor promotes the growth of melanoma cells expressing the ephrin-B2 ligand.
Source: Yang NY, Pigment Cell Melanoma Res 2010, 23:684-7.

AKT AND MUTATED BRAF
Intrinsically resistant metastatic melanoma cells displayed elevated Akt phosphorylation and were rendered susceptible to PLX4720 by Akt3 knockdown.
Source: Shao Y, Cancer Res 2010, 70:6670-81.

miR-148 AND MITF
miR-148 regulates MITF expression in melanocytes and melanoma cells: loss of this regulation, either by mutations or by shortening of the 3'UTR sequence, might promote melanoma formation and/or progression.
Source: Haflidadottir BS, PLoS One 2010, 5:e11574.

YM529/ONO-5920
Nitrogen-containing bisphosphonate, YM529/ONO-5920, inhibits tumor metastasis in mouse melanoma through suppression of the Rho/ROCK pathway.
Source: Tanimori Y, Clin Exp Metastasis 2010, 27:529-38.

IRF4 VARIANTS
In a European-Australian case-control study, interferon regulatory factor 4 (IRF4) variants have age-specific effects on nevus count and predispose to melanoma.
Source: Duffy DL, Am J Hum Genet 2010, 87:6-16.

GLUTAMINE METABOLISM
Targeting glutamine metabolism sensitizes some melanoma cell lines to TRAIL-induced death in vitro.
Source: Qin JZ, Biochem Biophys Res Commun 2010, 398:146-52.

ANTI-bFGF ANTIBODIES
Monoclonal antibodies targeting basic fibroblast growth factor (bFGF) inhibit the growth of B16 melanoma in vivo and in vitro.
Source: Li D, Oncol Rep 2010, 24:457-63.

CIGLITAZONE AND CXCL1
Ciglitazone (a well known PPARgamma agonist) negatively regulates CXCL1 signaling through MITF to suppress melanoma growth.
Source: Botton T, Cell Death Differ 2010, Epub ahead of print.

MELANOMA INITIATING CELLS
Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271; they rarely express TYR, MART1 and MAGE, which might explain the failure of immunotherapies directed against these antigens.
Source: Boiko AD, Nature 2010, 466:133-7.

S100B, LDH AND SENTINEL NODE STATUS
Serum S100B and LDH are not useful in predicting the sentinel node status in melanoma patients (n=259).
Source: Egberts F, Anticancer Res 2010, 30:1799-805.

JNK AND DOXYCYCLINE
Activation of c-Jun N-terminal kinase is essential for mitochondrial membrane potential change and apoptosis induced by doxycycline in melanoma cells.
Source: Shieh JM, Br J Pharmacol 2010, 160:1171-84.

S100B AND P53
The calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma.
Source: Lin J, J Biol Chem 2010, 285:27487-98.

R-RAS AND MIGRATION
R-Ras regulates migration through an interaction with filamin A in melanoma cells.
Source: Gawecka JE, PLoS One 2010, 5:e11269.

GANGLIOSIDE GD3
Ganglioside GD3 enhances adhesion signals and augments malignant properties of melanoma cells by recruiting integrins to glycolipid-enriched microdomains.
Source: Miyazaki S, J Biol Chem 2010, 285:27213-23.

CURCUMIN ANALOG FLLL32
The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity.
Source: Bill MA, Mol Cancer 2010, 9:165.

SORAFENIB AND REGIONAL CHEMO
In an animal model of regional chemotherapy, sorafenib in combination with melphalan or temozolomide was more effective than either treatment alone in slowing tumor growth.
Source: Augustine CK, Mol Cancer Ther 2010, 9:2090-101.

NMB AND IMMUNITY
DC-HIL/glycoprotein Nmb promotes growth of melanoma in mice by inhibiting the activation of tumor-reactive T cells.
Source: Tomihari M, Cancer Res 2010, 70:5778-87.

RESVERATROL AND CHEMORESISTANCE
In a murine model, resveratrol induces cell cycle disruption and apoptosis in chemoresistant B16 melanoma.
Source: Gatouillat G, J Cell Biochem 2010, 110:893-902.

BEVACIZUMAB PLUS EVEROLIMUS
In a phase II trial, bevacizumab (anti-VEGF antibody) plus everolimus (anti-mTOR drug) was found to have moderate activity and was well tolerated in the treatment of patients with metastatic melanoma.
Source: Hainsworth JD, Cancer 2010, 116:4122-9.

BORTEZOMIB PLUS CHEMO
In a phase II trial, proteasome inhibitor bortezomib combined with paclitaxel and carboplatin showed no clinical activity against metastatic melanoma.
Source: Croghan GA, Cancer 2010, 116:3463-8.

DESMOPLASTIC MELANOMA
In the so far largest study (n=252), desmoplastic melanoma was associated with lower sentinel node positivity rate, but the combined type was associated with worse prognosis.
Source: Murali R, Cancer 2010, 116:4130-8.

IMEXON PLUS DTIC
In a phase I-II trial, imexon (a reactive oxygen species - ROS - generator) plus dacarbazine was associated with 30% disease stabilization rate; encouraging survival data suggest further evaluation.
Source: Weber JS, Cancer 2010, 116:3683-91.

RG7204 (PLX4032)
RG7204, a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models (including melanoma xenograft).
Source: Yang H, Cancer Res 2010, 70:5518-27.

EPAC AND MIGRATION
Exchange protein directly activated by cyclic AMP increases melanoma cell migration by a Ca2+-dependent mechanism and is a potential target to suppress melanoma metastasis.
Source: Baljinnyam E, Cancer Res 2010, 70:5607-17.

BRAF-V600E AND IMMUNITY
Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function.
Source: Boni A, Cancer Res 2010, 70:5213-9.

HLA AND PROGNOSIS
Among high-risk melanoma patients receiving adjuvant interferon alpha (IFN), HLA-Cw 06-positive patients have better relapse-free and overall survival.
Source: Gogas H, Cancer 2010, 116:4326-33.

VITAMIN A CHEMOSENSITIZATION
Vitamin A enhances antitumor effect of a green tea polyphenol on melanoma by upregulating the polyphenol sensing molecule 67-kDa laminin receptor.
Source: Lee JH, PLoS One 2010, 5:e11051.

PNPase AND miRNA221
Targeted overexpression of human polynucleotide phosphorylase (hPNPase) might provide an effective therapeutic strategy for miR-221-overexpressing and interferon(IFN)-resistant melanoma.
Source: Das SK, Proc Natl Acad Sci USA 2010, 107:11948-53.

TARGETING GRP78
In an in vitro model, downregulation of GRP78 by small-interfering RNA increased fenretinide- or bortezomib-induced apoptosis.
Source: Martin S, Pigment Cell Melanoma Res 2010, 23:675-82

TRAIL GENE THERAPY
Radiation-inducible human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy is a potential treatment for radioresistant uveal melanoma.
Source: Zhou Y, Pigment Cell Melanoma Res 2010, 23:661-74

QUERCETIN AND CHEMORESISTANCE
In an in vitro model, quercetin abrogates chemoresistance in melanoma cells by modulating deltaNp73.
Source: Thangasamy T, BMC Cancer 2010, 10:282

LONG-TERM SURVIVAL (LTS)
LTS can occur in select patients who achieve a complete response to chemotherapy: however, this occurs in only a minority of patients and is likely the result of indolent disease biology.
Source: Kim C, Oncologist 2010, 15:765-71

CTC ISOLATION BY SIZE
Isolation of circulating tumor cells based on cell size is feasible not only in patients with epithelial cancers but also in those with melanoma.
Source: De Giorgi V, J Invest Dermatol 2010, 130:2440-7

MDM2 POLYMORPHISMS
The MDM2 SNP309 is not associated with the risk and age of onset of melanoma, but might be a risk genotype for increased tumor Breslow thickness.
Source: Capasso M, J Hum Genet 2010, 55:518-24

CHEMICAL EXPOSURE AND MELANOMA RISK
In a case-control study, exposure to polychlorinated biphenyls is associated with high risk of melanoma (OR: 7.02; 95% CI: 2.30-21.43 for highest quartile) even after controlling for sun exposure.
Source: Gallagher RP, Int J Cancer 2010, Epub ahead of print

BRAF-MEK INHIBITION
In an in vitro study, combined BRAF/MEK inhibition results an effective strategy to prevent the emergence of drug resistance in BRAF-V600E-mutated melanomas.
Source: Paraiso KH, Br J Cancer 2010, 102:1724-30.

RAF PATHWAY
Screening a large cohort of patients showed that, although rare, recurrent rearrangements in the RAF pathway tend to occur in prostate cancer, gastric cancer and melanoma, suggesting that RAF and MEK inhibitors may be useful in a subset of gene fusion-harboring solid tumors.
Source: Palanisamy N, Nat Med 2010, 16:793-8.

microRNA PROFILE
High-throughput miRNA profiling showed that blood samples of melanoma patients and healthy individuals can be well differentiated from each other based on miRNA expression analysis.
Source: Leidinger P, BMC Cancer 2010, 10:262.

IKKB INHIBITION
In mice, mutant HRas initiation of tumorigenesis requires IKKbeta-mediated NFKB activity (ablation of IKKB inhibits melanoma development).
Source: Yang J, J Clin Invest 2010, 120:2563-74.

CURCUMIN-RELATED D6
The new alpha,beta-unsaturated ketone D6 is more effective in inhibiting melanoma cells growth when compared to curcumin.
Source: Pisano M, Mol Cancer 2010, 9:137.

INDOOR TANNING
A case-control study shows that, in a highly exposed population, frequent indoor tanning increases melanoma risk, regardless of age when indoor tanning begins.
Source: Lazovich D, Cancer Epidemiol Biomarkers Prev 2010, 19:1557-68.

ALDH PHENOTYPE
Aldehyde dehydrogenase (ALDH) activity does not distinguish tumor-initiating and/or therapy-resistant melanoma cells.
Source: Prasmickaite L, PLoS One 2010, 5:e10731.

RILUZOLE
The glutamate release inhibitor Riluzole decreases migration, invasion, and proliferation of melanoma cells.
Source: Le MN, J Invest Dermatol 2010, 130:2240-9.

JARID1B POSITIVE MELANOMA CELLS
Using the H3K4 demethylase JARID1B as biomarker, investigators have characterized a small subpopulation of slow-cycling melanoma cells required for continuous tumor growth.
Source: Roesch A, Cell 2010, 141:583-94.

NUCLEOTIDE EXCISION REPAIR
Melanoma cells retain capacity for nucleotide excision repair (NER), the loss of which probably does not commonly contribute to melanoma progression.
Source: Gaddameedhi S, Cancer Res 2010, 70:4922-30.

MELANOMA DORMANCY
In a mouse melanoma model, Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, reinforcing the theory that immune responses favor dormancy of disseminated tumor cells.
Source: Eyles J, J Clin Invest 2010, 120:2030-9.

MTAP AND INTERFERON
Expression of methylthioadenosine phosphorylase (MTAP) might represent a predictive marker for response to adjuvant interferon therapy in patients with skin melanoma.
Source: Meyer S, Exp Dermatol 2010, 19:e251-7.

TARGETING RAP1 GTPase
Preventing the activation or cycling of the Rap1 GTPase alters adhesion and cytoskeletal dynamics and blocks metastatic melanoma cell extravasation into the lungs.
Source: Freeman SA, Cancer Res 2010, 70:4590-601.

FOLLOW-UP FOR STAGE III MELANOMA
Based on the analysis of retrospective data, investigators suggest new guidelines for the follow up of patients with stage III melanoma.
Source: Romano E, J Clin Oncol 2010, 28:3042-7.

ANTI-BPAG1 AUTO-ANTIBODY
Serum levels of anti-BPAG1 auto-antibodies are higher in melanoma patients than in healthy volunteers and thus are proposed as novel melanoma diagnostic marker.
Source: Shimbo T, PLoS One 2010, 5:e10566.

SHIELDS PROGNOSTIC INDEX
The Shields index, a non-invasive analysis based on immunohistochemistry of lymphatics surrounding primary lesions, is proposed to predict outcome of melanoma patients.
Source: Emmett MS, BMC Cancer 2010, 10:208.

PLK1 INHIBITOR BI-2536
In a phase II trial of polo-like kinase 1 inhibitor BI 2536, no objective tumor response was observed in patients with different types of metastatic cancer, including melanoma.
Source: Schoffski P, Eur J Cancer 2010, 46:2206-15.

TOPOISOMERASE I AMPLIFICATION
Topoisomerase I amplification in melanoma is associated with more advanced tumours and poor prognosis.
Source: Ryan D, Pigment Cell Melanoma Res 2010, 23:542-53.

NOVEL SMAC MIMETICS
Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and Bortezomib.
Source: Lecis D, Br J Cancer 2010, 102:1707-16.

CHIMERIC ANTIGEN RECEPTORS (CAR)
Designer T cells with second generation GD3-specific CAR plus systemic interleukin-2 (IL2) can eradicate subcutaneous established GD3+ melanoma in nude mice.
Source: Lo AS, Clin Cancer Res 2010, 16:2769-80.

APREPITANT
The NK-1 receptor is expressed by human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on human melanoma cell lines.
Source: Munoz M, Lab Invest 2010, 90:1259-69.

BEVACIZUMAB + IFNalpha
In a pilot trial, patients with metastatic ocular melanoma were treated with bevacizumab and IFN-alpha, which were well tolerated and showed some clinical activity.
Source: Guenterberg KD, Am J Clin Oncol 2010, Epub ahead of print.

GITR ACTIVATION
Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell (Treg) stability and intra-tumor accumulation.
Source: Cohen AD, PLoS One 2010, 5:e10436.

ETARACIZUMAB
The findings of a pharmacodynamic (phase 0) study using etaracizumab (a monoclonal antibody targeting integrin alpha V beta3) in advanced melanoma have been reported.
Source: Moschos S, J Immunother 2010, 33:316-25.

CD147 SILENCING
Depletion of CD147 (a cell surface receptor for cyclophilin A) sensitizes human malignant melanoma cells to hydrogen peroxide-induced oxidative stress.
Source: Li J, J Dermatol Sci 2010, 58:204-10.

9.2.27PE IMMUNOTOXIN
9.2.27PE (Pseudomonas Exotoxin A) immunotoxin can efficiently cause cell death in malignant melanoma cells independent of their level of resistance to apoptosis and DTIC.
Source: Risberg K, J Immunother 2010, 33:272-8.

TARGETED INTERNAL RADIONUCLIDE THERAPY
Melanin targeting radionuclide therapy with a quinoxaline-derived molecule (ICF01012) has strong anti-tumoral efficacy in pigmented versus unpigmented melanomas.
Source: Bonnet M, Pigment Cell Melanoma Res 2010, Epub ahead of print

NRASQ61R and CRE-RECOMBINASE
Targeted delivery of mutationally activated NRAS (NRASQ61R) and Cre-recombinase to post-natal melanocytes induces melanoma in Ink4a/Arflox/lox mice.
Source: VanBrocklin MW, Pigment Cell Melanoma Res 2010, 23:531-41

microRNA DEREGULATED IN MELANOMA
miRNA-200c is consistently downregulated in melanocytes, melanoma cell lines and patient samples, whereas miRNA-205 and miRNA-23b are markedly reduced only in patient samples. miR-146a and miR-155 are upregulated in all analyzed patients but none of the cell lines.
Source: Philippidou D, Cancer Res 2010, 70:4163-73

131-I-LABELED BENZAMIDE
In a xenograft model, 131-I-labeled benzamide proved to be effective for targeted radiotherapy of human melanoma.
Source: Joyal JL, Cancer Res 2010, 70:4045-53

MIC-1 AND ANGIOGENESIS
Inhibition of macrophage inhibitory cytokine 1 (MIC-1) retards melanoma tumor vascular development, subsequently affecting tumor cell proliferation and apoptosis.
Source: Huh SJ, Am J Pathol 2010, 176:2948-57

3-BROMOPYRUVATE
3-bromopyruvate (BrPA) - an inhibitor of glucose metabolism - selectively kills melanoma cells with low levels of glutathione.
Source: Qin JZ, Biochem Biophys Res Commun 2010, 396:495-500

c-RET AND GDNF
Constitutively activated RET-carrying transgenic mice (RET-mice) spontaneously develop malignant melanoma and glial cell line-derived neurotrophic factor (GDNF)-mediated c-RET kinase activation is associated with melanoma pathogenesis.
Source: Ohshima Y, PLoS One 2010, 5:e10279

IGF1R INHIBITION
Disruption of insulin-like growth factor 1 receptot (IGF1R) signaling increases TRAIL-induced apoptosis in human melanoma cell lines.
Source: Karasic TB, Exp Cell Res 2010, 316:1994-2007

IL-24 AND ERLOTINIB
Interleukin-24 (IL-24) gene transfer sensitizes melanoma cells to erlotinib through modulation of the Apaf-1 and Akt signaling pathways.
Source: Deng WG, Melanoma Res 2010, Epub ahead of print

PROTEIN KINASE C ALPHA
RNA interference (RNAi)-mediated knockdown of protein kinase C-alpha (PKC-alpha) inhibits cell migration in MM-RU human metastatic melanoma cell line.
Source: Byers HR, Melanoma Res 2010, 20:171-8

NITRIC OXIDE SYNTHASE INHIBITION
Targeted inhibition of inducible nitric oxide synthase (iNOS)inhibits growth of human melanoma in vivo and synergizes with chemotherapy.
Source: Sikora AG, Clin Cancer Res 2010, 16:1834-44

CXCL4L1/PF-4var47-70
The COOH-terminal peptide of platelet factor-4 variant (CXCL4L1/PF-4var47-70) strongly inhibits angiogenesis and suppresses B16 melanoma growth in vivo.
Source: Vandercappellen J, Mol Cancer Res 2010, 8:322-34

FOXP3
Intratumoral forkhead box P3-positive regulatory T (Treg) cells predict poor survival in cyclooxygenase-2 (COX2) positive uveal melanoma.
Source: Mougiakakos D, Cancer 2010, 116:2224-33

TRIB2
Human TRIB2 is a repressor of FOXO that contributes to the malignant phenotype of melanoma cells.
Source: Zanella F, Oncogene 2010, 29:2973-82

IPILIMUMAB IMPROVES SURVIVAL
In a phase III RCT, anti-CTLA4 antibody ipilimumab (combined or not with gp100 vacination) significantly improves the survival of patients with advanced melanoma resistant to conventional chemotherapy (as compared to gp100 vaccination).
Source: Hodi FS, N Engl J Med 2010, 363:711-23

MELANOMA INITIATING CELLS AND CD271
Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271.
Source: Boiko AD, Nature 2010, 466:133-7

RCT OF THYMOSIN ALPHA 1
In a phase III RCT, thymosin increases tumor response rates but not overall survival as compared to DTIC + interferon (IFN) alpha.
Source: Maio M, J Clin Oncol 2010, 28:1780-7

LEPTIN AND MELANOMA GROWTH
The metabolic hormone leptin is a melanoma growth factor: a leptin-based autocrine loop may contribute to the proliferation of melanoma cells.
Source: Ellerhorst JA, Oncol Rep 2010, 23:901-7

IGFBP7 GENE THERAPY
Intratumoral injection of pEGFC1-IGFBP7 inhibits malignant melanoma growth in C57BL/6J mice by inducing apoptosis and downregulating VEGF expression.
Source: Chen RY, Oncol Rep 2010, 23:981-8

B-CELLS AND ANTI-MELANOMA IMMUNITY
B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice.
Source: DiLillo DJ, J Immunol 2010, 184:4006-16

PD-1 BLOCKADE + COMBINED IMMUNOTHERAPY
Blockade of programmed death ligand 1 (PD-1) enhances the therapeutic efficacy of combination immunotherapy against murine melanoma in vivo.
Source: Pilon-Thomas S, J Immunol 2010, 184:3442-9

BIOMARKERS FOR ANTI-ANGIOGENIC THERAPY
Using both a murine model and patient biopsies, investigators suggest that resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in melanoma.
Source: Helfrich I, J Exp Med 2010, 207:491-503

MC1R VARIANTS AND CDKN2A MUTATIONS
In a meta-analysis of the literature, MC1R variants significantly increase the penetrance of CDKN2A mutations in melanoma-prone families.
Source: Fargnoli MC, Eur J Cancer 2010, 46:1413-20

IL-24 PLUS DTIC
In a human in vitro model, the combination of interleukin-24 gene therapy and dacarbazine showed anti-melanoma synergism.
Source: Jiang G, Cancer Lett 2010, Epub ahead of print

CONDITIONAL SURVIVAL ANALYSIS (CSA)
Using the SEER database (n=8,647), investigators found that - 8 years after primary surgery - survival differences between low (T2-3N0M0) and high (T4N0M0 or T2-4N1-3M0) risk melanoma patients are no longer significant.
Source: Rueth NM, Ann Surg Oncol 2010, Epub ahead of print

PLEXIN-B1: MELANOMA SUPPRESSOR GENE ?
Plexin B1 can act as a tumor-suppressor protein in melanoma, in part through suppression of c-MET signaling: however, since it also activates AKT, plexin B1 may function as a tumor promoter in melanomas not driven by c-MET activation.
Source: Stevens L, J Invest Dermatol 2010, Epub ahead of print

PESTICIDES AND MELANOMA RISK
In the Agricultural Health Study cohort of licensed pesticide applicators, some pesticides were significantly associated with increased melanoma risk.
Source: Dennis LK, Environ Health Perspect 2010, Epub ahead of print

MITF-MDEL: NEW MELANOMA BIOMARKER
MITF-Mdel, a novel melanocyte/melanoma-specific isoform (splice variant) of microphthalmia-associated transcription factor-M, is proposed as a candidate biomarker for melanoma.
Source: Wang Y, BMC Med 2010, 8:14

4-METHYLUMBELLIFERONE (4-MU)
4-MU inhibits tumour cell growth and the activation of stromal hyaluronan synthesis by melanoma cell-derived factors.
Source: Edward M, Br J Dermatol 2010, Epub ahead of print

PD1 AND CTLA4 BLOCKADE
PD-1 and CTLA-4 combination blockade expands infiltrating T-cells and reduces regulatory T-cells (Treg) and myeloid suppressor cells within B16 melanoma tumors.
Source: Curran MA, Proc Natl Acad Sci USA 2010, 107:4275-80

ETV1: NEW MELANOMA ONCOGENE
ETV1 in combination with oncogenic NRAS(G12D) transformed primary melanocytes (which was dependent on MITF overexpression) and promoted tumor formation in mice.
Source: Jané-Valbuena J, Cancer Res 2010, 70:2075-84

IGFBP7 GENE THERAPY
In vivo transfection of pcDNA3.1-IGFBP7 inhibits melanoma growth in mice through apoptosis induction and VEGF downregulation.
Source: Chen RY, J Exp Clin Cancer Res 2010, 29:13

SELENIUM ANTI-MELANOMA ACTIVITY
In a mouse model, selenium inhibits melanoma metastasis through the induction of cell cycle arrest and cell death.
Source: Song H, Immune Netw 2009, 9:236-42

OCCULT NODAL METASTASIS
In a large series of patients with thin melanoma (n=1732), a scoring system and nomogram for the risk of nodal involvement was created using 3 variables: sex, age and Breslow tumor thickness.
Source: Faries MB, Arch Surg 2010, 145:137-42

CD4+ CYTOTOXIC T-CELLS
Tumor-reactive CD4(+) T-cells - especially in association with anti-CTLA4 antibody - develop cytotoxic activity and eradicate large established syngeneic melanoma after transfer into lymphopenic hosts.
Source: Quezada SA, J Exp Med 2010, 207:637-50

TRICHOSTATIN PLUS 5-AZA
Histone deacetylase inhibitor (HDACI) trichostatin A (TSA) and the DNA methyltransferase inhibitor (DNMTI) 5-azacytidine (5-AZA) show synergistic anti-melanoma activity in vitro.
Source: Essa S, J Steroid Biochem Mol Biol 2010, Epub ahead of print

S100B SERUM LEVELS
Elevated serum levels of protein S100B during the follow-up of patients with melanoma (n=46) showed a low positive predictive value (50%) for disease recurrence.
Source: Aukema TS, Ann Surg Oncol 2010, Epub ahead of print

NEW PROBE FOR PET
In a preclinical in vivo model, (18)F-MEL050 - a melanin selective compound - showed to perform better than standard (18)F-FDG as a PET probe.
Source: Denoyer D, J Nucl Med 2010, 51:441-7

IMIDAZOLE DERIVATIVE 7A
In a human in vitro model, pyrimidin-4-yl-1H-imidazole derivative 7a showed greater anti-melanoma activity than sorafenib and turned out to be a strong CRAF inhibitor.
Source: Lee J, Bioorg Med Chem Lett 2010, 20:1573-7

PLX4032: BRAF V600E SELECTIVE INHIBITOR
PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells.
Source: Halaban R, Pigment Cell Melanoma Res 2010, 23:190-200

NOW AVAILABLE: TARGETED THERAPY DATABASE
The MMMP website now hosts a new database coupled with an original model to match the patient's molecular profile with the available evidence on melanoma targeted therapy (drug ranking system).
Source: MMMP_Targeted Therapy Database

FIRST HUMAN EXPERIENCE OF siRNA + TARGETED NANOPARTICLES
The first phase I clinical trial involving the systemic administration of small interfering RNA (siRNA) to patients with solid cancers using targeted nanoparticles is ongoing. Evidence of inducing RNA intereference in a patient with melanoma has been provided.
Source: Davis ME, Nature 2010, Epub ahead of print

RESPONSE TO IPILIMUMAB
In a multicenter single-arm phase II trial of ipilimumab (monotherapy) for pretreated advanced melanoma (n=155), the best overall response rate was 5.8% and the disease control rate was 27%.
Source: O'Day SJ, Ann Oncol 2010, Epub ahead of print

GENOME-WIDE METHYLATION PROFILING
Genome-wide methylation and expression profiling identifies promoter characteristics affecting demethylation-induced gene upregulation in melanoma.
Source: Rubinstein JC, BMC Med Genomics 2010, 3:4

PD1 LIGAND AND PROGNOSIS
Tumor cell expression of programmed cell death-1 (PD1) ligand is an independent prognostic factor for patients with melanoma (n=59).
Source: Hino R, Cancer 2010, 116:1757-66

IPILIMUMAB AND LYMPHOCYTE COUNT
Absolute lymphocyte count determined in the peripheral blood after 2 cycles of ipilimumab correlates with improved survival of patients with advanced melanoma (n=53).
Source: Ku GY, Cancer 2010, 116:1767-75

POPULATION ATTRIBUTABLE FRACTION (PAF)
In a meta-analysis of 66 studies, the PAF for people with skin phototypes I/II, presence of freckling and blond hair color were 27%, 23% and 23%, respectively.
Source: Olsen CM, Int J Cancer 2010, Epub ahead of print

IFN-GAMMA + GGTI298
Human melanoma cells treated with IFN-gamma and geranylgeranyl transferase inhibitor GGTI-298 enhance generation and activity of melanoma-specific cytotoxic T cells.
Source: Sarrabayrouse G, PLoS One 2010, 5:e9043

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