In the preceding funding period we have identified recurrent mutations and copy number increases of KIT in 30-40% of melanomas arising on chronically sun-damaged skin (CSD), acral sites. Emerging clinical evidence indicates that these genetic alterations are a strong indicator for clinical responses to already approved KIT inhibitors. By contrast, KIT alterations are absent in melanoma arising on the non-CSD skin, which frequently harbor BRAF mutations, identifying them as biologically distinct. Differences in mutation spectra, chromosomal aberrations, and clinical and histopathological presentation implicate the KIT pathway as an important contributor in acral, mucosal, and CSD melanoma types. Despite these advances, the oncogenic alterations in the majority of these melanomas are currently not known as they infrequently harbor BRAF mutations. Preliminary studies implicate additional genes downstream of KIT as candidate genes, including the scaffolding protein GAB2, the protein phosphatase SHP2, amplification of the two p70S6 kinase genes as additional targets for somatic activation. We hypothesize that together these findings indicate a wider role for KIT pathway activation in these melanoma types, which would have therapeutic and diagnostic implications. We will validate the contribution of genetic alterations in the KIT pathway to the malignant phenotype and response to therapy and aim to discover additional alterations. Our studies will involve comprehensive genomic characterization of archival tissues to identify genetic alterations and determine in which combination they occur (aim 1), functional analyses in vitro models representing the most common of the findings in human tumors to characterize their effect on sensitivity and resistance to targeted agents (aim 2), and tumor samples from patients with KIT alterations who were treated with KIT inhibitors, to determine factors of primary and secondary resistance to treatment in a clinical setting (aim 3).

Public Health Relevance

Characterization of the somatic genetic alterations in melanoma and their role in oncogenesis, therapeutic targets or biomarkers for resistance to specific therapies is of direct clinical relevance for the treatment and management of patients with metastatic melanoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA025874-33
Application #
8627551
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
33
Fiscal Year
2014
Total Cost
$572,333
Indirect Cost
$255,987
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Qin, Jie; Rajaratnam, Rajathees; Feng, Li et al. (2015) Development of organometallic S6K1 inhibitors. J Med Chem 58:305-14
Bastian, Boris C (2014) The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol 9:239-71
Simpson, R Mark; Bastian, Boris C; Michael, Helen T et al. (2014) Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma. Pigment Cell Melanoma Res 27:37-47
Vultur, A; Villanueva, J; Krepler, C et al. (2014) MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene 33:1850-61
Wähler, Kathrin; Ludewig, Anja; Szabo, Patrick et al. (2014) Rhenium Complexes with Red-Light-Induced Anticancer Activity. Eur J Inorg Chem 2014:807-811
Wiesner, Thomas; He, Jie; Yelensky, Roman et al. (2014) Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun 5:3116
Yeh, Iwei; Mully, Thaddeus W; Wiesner, Thomas et al. (2014) Ambiguous melanocytic tumors with loss of 3p21. Am J Surg Pathol 38:1088-95
Wang, Tao; Ge, Yingbin; Xiao, Min et al. (2014) SECTM1 produced by tumor cells attracts human monocytes via CD7-mediated activation of the PI3K pathway. J Invest Dermatol 134:1108-18
Dörr, Markus; Meggers, Eric (2014) Metal complexes as structural templates for targeting proteins. Curr Opin Chem Biol 19:76-81
Botton, Thomas; Yeh, Iwei; Bastian, Boris C (2014) Melanoma BRAF fusions--letter. Clin Cancer Res 20:6631

Showing the most recent 10 out of 331 publications