Combination treatment for melanoma
Inventors: Leonard Zon, Richard White
Invention Types: Therapeutics
Research Areas: Dermatology, Oncology/Hematology
Keywords: Animal Model (zebra fish)For More Information Contact: Wong, Adrienne
Oncogenic BRAF mutations are present in a majority of melanomas and have been implicated in malignant growth of melanoma cells. Dr. Leonard Zon has discovered methods for treatment of melanoma using an inhibitor of dihydroorotate dehydrogenase (DHODH) and a combination therapy that involves an inhibitor of oncogenic BRAF combined with an inhibitor of DHODH. Dr. Zon's lab has also developed assays for identifying compounds useful for the treatment of melanoma. The methods comprise screening for compounds or agents that inhibit neural crest progenitor formation in a zebra fish model of melanoma.
Dr. Zon's lab determined by gene expression analysis that melanoma cells adopt a fate similar to multipotent neural crest progenitors. In studies, they used zebrafish embryos to identify the initiating transcriptional events that occur upon activation of oncogenic BRAF(V600E) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V660E) and which lack p53 have been found to have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate.
In particular, they discovered that BRAF(V600E):p53-/- embryos exhibit an abnormal expansion in the number of crestin+ progenitors. Furthermore, in the adult, BRAF(V600E):p53-/- virtually all tumor cells, but no normal cells, are positive for crestin. Thus, they concluded that suppressors of neural crest progenitors may have utility in the treatment of melanoma.
They then developed a screen to identify inhibitors of the crestin+ lineage during development, allowing for identification of compounds or agents useful for melanoma treatment. Dr. Zon's lab screened a library of 2,000 chemicals for suppressors of neural crest development in BRAF(V600E):p53-/- zebrafish and successfully identified compounds useful in the treatment of melanoma.
- Methods for treatment of melanoma using an inhibitor of dihydroorotate dehydrogenase (DHODH) and a combination therapy that involves an inhibitor of oncogenic BRAF combined with an inhibitor of DHODH.
- Screen to identify inhibitors of the crestin+ li
- Melanoma represents one of the rarer forms of skin cancer and underlies the majority of skin cancer-related deaths and despite many years of intensive laboratory and clinical research, there are still limited treatments for melanoma.
- One effective c
Key Publications: • White RM, Cech J, Ratanasirintrawoot S, et al. DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature. 2011 Mar 24;471(7339):518-22.
• Kaufman CK, Mosimann C, Fan ZP, et al. A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation. Science. 2016 Jan 29:351(6272):aad2197
• HeilmannS, Ratnakumar K, Langdon E, et al. A quantitative system for studying metastasis using transparent zebrafish. Cancer Res. 2015 Oct 15;75(20):4272-4282.
Related Publications: • Neiswender JV, Kortum RL, Bourque C, et al. KIT suppresses BRAFV699E-mutant melanoma by attenuating ocogenic RAS/MAPK signaling. Cancer Res. 2017 Nov 1;77(21):5820-5830.
• Pat. US10016402B2