The goal of this proposal is to identify the earliest melanoma precursors and to study the mechanisms of intraepidermal melanoma progression. Recent studies have identified a field effect comprised of genetically abnormal melanocytes in the non-lesional skin adjacent to primary melanomas. Evidence suggests that these field cells may be a source of local recurrences. The field effect appears to be confined to melanomas with a lentiginous growth pattern i.e. an intraepidermal growth pattern in which melanocytes are arranged as single units within the basilar epidermis such as acral and lentigo maligna melanomas. These melanoma types frequently have activating genetic alterations in the KIT signaling pathway. Since KIT has an essential role in melanocyte migration and homing of melanoblasts to the basal dermis, the hypothesis is that KIT pathway activation represents the initiating event that is subsequently followed by the acquisition of additional genetic alterations required to form clinically and histologically detectable lesions. To test this hypothesis, the candidate has developed a xenograft model of early human melanoma progression. Specifically, she will study the intraepidermal migration of genetically engineered melanocytes and melanoma cells expressing relevant KIT mutations seeded into human skin reconstructs grafted onto immunodeficient mice. In parallel, the candidate will evaluate the impact of KIT inhibitors on intraepidermal melanoma progression. These studies will provide an explanation for the tendency of certain melanoma types to recur after apparently complete excision and will offer the possibility to use KIT inhibitors to treat early melanoma.

Public Health Relevance

Melanoma is a malignant tumor arising from melanocytes. Melanomas have a high tendency to recur despite apparently clear surgical margins. We hypothesize that the origin of melanoma recurrences are cells that carry a mutation on a gene (KIT). Our studies will provide an explanation for the tendency of certain melanoma types to recur after apparently complete excision and will offer the possibility to use KIT inhibitors to treat early melanoma. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the Critique section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA155035-03
Application #
8515973
Study Section
Subcommittee G - Education (NCI)
Program Officer
Perkins, Susan N
Project Start
2011-08-04
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$122,040
Indirect Cost
$9,040
Name
University of California San Francisco
Department
Dermatology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Posch, Christian; Vujic, Igor; Monshi, Babak et al. (2016) Searching for the Chokehold of NRAS Mutant Melanoma. J Invest Dermatol 136:1330-6
Sanlorenzo, M; Vujic, I; Posch, C et al. (2016) Oncogenic KIT mutations in different exons lead to specific changes in melanocyte phospho-proteome. J Proteomics 144:140-7
Posch, Christian; Sanlorenzo, Martina; Vujic, Igor et al. (2016) Phosphoproteomic Analyses of NRAS(G12) and NRAS(Q61) Mutant Melanocytes Reveal Increased CK2α Kinase Levels in NRAS(Q61) Mutant Cells. J Invest Dermatol 136:2041-8
Vujic, Igor; Sanlorenzo, Martina; Esteve-Puig, Rosaura et al. (2016) Acyl protein thioesterase 1 and 2 (APT-1, APT-2) inhibitors palmostatin B, ML348 and ML349 have different effects on NRAS mutant melanoma cells. Oncotarget 7:7297-306
Posch, Christian; Moslehi, Homayoun; Sanlorenzo, Martina et al. (2016) Pharmacological inhibitors of c-KIT block mutant c-KIT mediated migration of melanocytes and melanoma cells in vitro and in vivo. Oncotarget :
Sanlorenzo, Martina; Vujic, Igor; Daud, Adil et al. (2015) Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression. JAMA Dermatol 151:1206-12
Sanlorenzo, Martina; Vujic, Igor; Posch, Christian et al. (2015) The risk of melanoma in pilots and cabin crew: UV measurements in flying airplanes. JAMA Dermatol 151:450-2
Sanlorenzo, Martina; Wehner, Mackenzie R; Linos, Eleni et al. (2015) The risk of melanoma in airline pilots and cabin crew: a meta-analysis. JAMA Dermatol 151:51-8
Vujic, Igor; Sanlorenzo, Martina; Posch, Christian et al. (2015) Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer. Oncotarget 6:969-78
Posch, Christian; Cholewa, Brian D; Vujic, Igor et al. (2015) Combined Inhibition of MEK and Plk1 Has Synergistic Antitumor Activity in NRAS Mutant Melanoma. J Invest Dermatol 135:2475-83

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