Viewing Study NCT01281722



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Last Modification Date: 2024-10-26 @ 10:30 AM
Study NCT ID: NCT01281722
Status: UNKNOWN
Last Update Posted: 2011-01-24
First Post: 2011-01-20

Brief Title: Role of SLURP-1 in Melanoma and Melanoma Stem Cells
Sponsor: National Taiwan University Hospital
Organization: National Taiwan University Hospital

Study Overview

Official Title: None
Status: UNKNOWN
Status Verified Date: 2011-01
Last Known Status: RECRUITING
Delayed Posting: No
If Stopped, Why?: Not Stopped
Has Expanded Access: False
If Expanded Access, NCT#: N/A
Has Expanded Access, NCT# Status: N/A
Acronym: None
Brief Summary: Melanoma is the most aggressive skin cancer with a propensity to metastasize and is resistant to most of the current therapeutic regimens Incidence rate of melanoma in patients with MDM Mal De Maleda with SLURP-1 mutation is much higher than normal counterpart SLURP-1 lymphocyte antigen 6urokinase-type plasminogen activator receptor related protein-1 is an allosteric agonist to the nicotinic acetylcholine receptor nAchR and it regulates epidermal homeostasis and T-cell function The preliminary results of comparing human peripheral blood mononuclear cells PBMCs from 4 affected and 15 unaffected members from the family with MDM revealed that T-cell activation was impaired in PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation 2 of affected members developed melanoma Since there is currently no effective treatment for metastatic melanoma identifying novel molecular mechanisms may lead to development of new treatments for metastatic melanomas

Previous study showed that melanoma stem cells MSCs are crucial in melanoma pathogenesis 1Melanoma contains ABCB5 CD133 and ABCG2 positive cells had enhanced tumorigenic potential 2Higher frequencies of cells capable of initiating melanoma xenografts when using IL2Rγ-- NOD SCID mice These data confirmed the interaction between T cells and MSCs

In this project we will investigate the roles of SLURP-1 in melanoma and MSCs Investigating and verifying the interaction between T-cells from patients with MDM and melanoma cells to confirm the SLURP-1 function of tumorigenesis in xenotransplant mice IL2Rγ-- NOD SCID model To reveal the role of SLURP-1 silencing in melanoma cell lines by using not only A2058 A375 and MeWo mwlanima cell lines but also ABCB5 melanoma cells and ABCB5- melanoma cells through the tumorigenesis apoptosisangiogenesis proliferation melanosphere formation assays

The aim of this project is to investigate the roles and molecular mechanisms of SLURP-1 in melanoma carcinogenesis which may improve the development of novel treatments for melanoma
Detailed Description: Cutaneous melanoma is an aggressive neoplasm refractory to traditional therapies especially at the metastatic stage Furthermore its incidence is continuously increasing during the last decade 1 Melanomas develop through a multistep process that from normal melanocytes proceeds to nevi and to radial and vertical growth phase tumors 2 During this process melanomas are characterized by certain well-defined genetic alterations as well as frequent chromosomal aberrations associated with tumor progression 3 However the molecular mechanisms involved in the carcinogenesis and progression of melanoma are complex and not entirely clear 4 Because of the intractability of metastatic melanomas with only 14 of the patients survive for 5 years and no effective treatments 2 understanding the underlying molecular mechanisms involved in melanoma and identifying molecular markers may lead to improvements in therapeutic approaches for metastatic melanomas

Mal de Meleda MDM OMIM 248300 is a rare autosomal recessive disorder characterized by erythema and hyperkeratosis of the palms and soles extending to the dorsal aspects of the hands and feet known as transgrediens and perioral erythema and psoriasiform plaques on the elbows and knees 5-7 Homozygous mutations of the SLURP1 gene previously known as ARS component B encoding lymphocyte antigen 6urokinase-type plasminogen activator receptor related protein-1 SLURP-1 have been identified as the cause of MDM 8-10 Mutations of the SLURP1 gene affect the expression integrity and stability of SLURP-1 on the upper layer of the epidermis and in cultured mature keratinocytes 11 Other studies also demonstrated that SLURP-1 acts as a positive allosteric ligand for 7-nAchR in keratinocytes eliciting proapoptotic activity and differentiation 1213 As well as in epidermis and keratinocytes the expression of SLURP-1 has been found in T cells B cells dendritic cells and macrophages 14-15 Malignant melanoma MM has been reported to be the predominant cutaneous malignancy occurring in the hyperkeratotic area in patients with MDM 16 The incidence of MM in MDM is significantly higher than in the general population17 At least six cases of MM have been reported in patients with MDM27-29 two of the reported cases were siblings 18 The possible explanations of the higher incidence of MM in patients with MDM include i lack of proapoptotic effect of SLURP-1 ii defective T-cell activation and tumour monitoring or iii prolonged inflammation in hyperkeratotic skin

The previous study showed that peripheral blood mononuclear cells PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation This was restored by the addition of 05 μg mL-1 recombinant human SLURP-1 protein 19 Previous study showed that a putative monoclonal antibody that recognized ABCB5 was used to isolate melanoma stem cells MSCs 20 In this study the investigators will investigate the roles of SLURP-1 in melanoma cells including MSC and also its interaction between melanoma cells and T-cells

Aims

1 To evaluate the significance and correlation of SLURP-1 expression in melanoma cells and melanoma metastasis in human tissues and mouse metastasis models
2 To assess the function of the SLURP-1 protein in melanoma cells and melanoma stem cells
3 To investigate the interaction between T-cells with SLURP-1 mutation and melanoma cells MSCs
4 Confirm the biological effects of SLURP-1 on melanoma cells MSCs
5 To investigate the relationship between SLURP-1 overexpression and melanoma cancer biology

References

1 Gray-Schopfer V Wellbrock C Marais R Melanoma biology and new target therapy Nature 2007 445 851-7
2 Miller AJ Mihm MC Melanoma N Engl J Med 2006 355 51-65
3 Jonsson G et al Genomic profiling of malignant melanoma using tiling-resolution array CGH Oncogene 2007 6 4738-48
4 Bemis LT Chen R Amato CM et al MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines Cancer Res 2008 68 1362-8
5 Lucker GP Van De Kerkhof PC Steijlen PM The hereditary palmoplantar keratoses an updated review and classification Br J Dermatol 1994 1311-14
6 Bergman R Bitterman-Deutsch O Fartasch M et al Mal de Meleda keratoderma with pseudoainhum Br J Dermatol 1993 128207-12
7 Jee SH Lee YY Wu YC et al Report of a family with mal de Meleda in Taiwan a clinical histopathological and immunological study Dermatologica 1985 17130-7
8 Fischer J Bouadjar B Heilig R et al Mutations in the gene encoding SLURP-1 in Mal de Meleda Hum Mol Genet 2001 10875-80
9 Ward KM Yerebakan O Yilmaz E et al Identification of recurrent mutations in the ARS component B gene encoding SLURP-1 in two families with mal de Meleda J Invest Dermatol 2003 12096-8
10 Mastrangeli R Donini S Kelton CA et al ARS component B structural characterization tissue expression and regulation of the gene and protein SLURP-1 associated with mal de Meleda Eur J Dermatol 2003 13560-70
11 Favre B Plantard L Aeschbach L et al SLURP1 is a late marker of epidermal differentiation and is absent in mal de Meleda J Invest Dermatol 2007 127301-8
12 Grando SA Basic and clinical aspects of non-neuronal acetylcholine biological and clinical significance of non-canonical ligands of epithelial nicotinic acetylcholine receptors J Pharmacol Sci 2008 106174-9
13 Arredondo J Chernyavsky AI Webber RJ et al Biological effects of SLURP-1 on human keratinocytes J Invest Dermatol 2005 1251236-41
14 Moriwaki Y Yoshikawa K Fukuda H et al Immune system expression of SLURP-1 and SLURP-2 two endogenous nicotinic acetylcholine receptor ligands Life Sci 2007 802365-8
15 Kawashima K Yoshikawa K Fujii YX et al Expression and function of genes encoding cholinergic components in murine immune cells Life Sci 2007 802314-19
16 Nakajima K Nakano H Takiyoshi N et al Papillon-Lefèvre syndrome and malignant melanoma A high incidence of melanoma development in Japanese palmoplantar keratoderma patients Dermatology 2008 21758-62
17 Sartore L Bordignon M Bassetto F et al Melanoma in skin affected with keratoderma palmoplantaris hereditaria mal de Meleda treatment with excision and grafting J Am Acad Dermatol 2009 61161-3
18 Mozzillo N Nunziata CA Caraco C et al Malignant melanoma developing in an area of hereditary palmoplantar keratoderma mal de Meleda J Surg Oncol 2003 84229-33
19 Tjiu JW Lin PJ Wu WH et al SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda Br J Dermatol 2010 Sep 21
20 Schatton T Murphy GF Frank NY et al Identification of cells initiating human melanomas Nature 2008 Jan 174517176345-9

Study Oversight

Has Oversight DMC: None
Is a FDA Regulated Drug?: None
Is a FDA Regulated Device?: None
Is an Unapproved Device?: None
Is a PPSD?: None
Is a US Export?: None
Is an FDA AA801 Violation?: None