Melanoma has been one ofthe fastest rising malignancies in the last four decades with cases increasing from below three per 100,000 people to above 13 (18.9 if only whites are counted). The following discoveries have been made that serve as the basis for this program project: 1) Mutations in genes ofthe MAP kinase pathway are frequent in melanoma and mutually exclusive. Mutations are most frequent in BRAF (50%) followed by NRAS (15%) and c-kit (4%). 2) Within each mutation group there are sub-groups due to additional critical mutations. 3) The biological characteristics of melanomas including their progression and metastasis are driven by both tumor and microenvironment forces. 4) Small molecule inhibitors for tumor-associated kinases lead to powerful effects on melanoma cells both in vitro and in vivo. Our first objective is to identify somatic alterations in growth factor mediated signaling pathways and determine whether they are targets for therapy. Our group (Project 2, Bastian) has recently identified c-kit mutations in melanoma, particularly in acral and mucosal melanomas, that are mutually exclusive to BRAF and NRAS mutations, and emerging trial data suggest that drugs targeting c-kit induce significant clinical responses in some patients with these mutations. Several lines of evidence point towards a wider role ofthe c-kit signaling pathway is specific types of melanoma and we will perform detailed genetic and functional analyses to analyze the pathway for additional therapeutic targets and factors of primary and secondary resistance to ckit directed therapies (Project 2, Bastian). Two other genes that function downstream of c-kit encoding isoforms of the p70S6 kinase, critical regulators of protein synthesis and cell growth, are also amplified in many melanomas. Therefore, we will characterize the biochemical properties of p70S6K and develop potent and specific inhibitors to this kinase (Project 3, Marmorstein). Our complementary second objective that focuses on therapy resistance in melanoma is to identify sub-populations of tumor cells that are drivers for tumor progression and evaluate combination therapeutic strategies that target this tumor cell sub-population in addition to the bulk of tumor cells. Our group (Project 1, Herlyn) has identified melanoma cells with high self-renewing capacity that are very slowly cycling but have a high proliferative reserve. They are characterized by expression ofthe histone 3 K4 demethylase JARID1B. In this proposal we will characterize the signaling mechanisms mediating therapy resistance in JARID1B+ cells and biochemically analyze the JARID1B protein to develop and evaluate therapeutic strategies using inhibitors to JARID1B and/or JARIDIB-dependant signaling (Project 3, Marmorstein and Project 1, Herlyn).

Public Health Relevance

The major objective of this long-standing program project is to better understand the biology of melanoma development from a normal melanocytes to a mole and the progression to primary and metastatic melanoma. In the past, we have delineated each progression stage with monoclonal antibodies and have developed models in culture and experimental animals that mimic the disease as we experience it in patients. In this renewal application we continue to work on the biology of melanoma with a major emphasis on using the accumulated information to develop new strategies for therapy. Forthis reason, we have expanded the project, which includes now a structural biologist and a chemist to develop inhibitors for two key enzymes for this malignancy. This multi-disciplinary program has been a long-term center for novel approaches in melanoma research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA025874-33
Application #
8627549
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (J1))
Program Officer
Sathyamoorthy, Neeraja
Project Start
1990-04-06
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
33
Fiscal Year
2014
Total Cost
$1,438,284
Indirect Cost
$367,779
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

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