Combination Treatment for Melanoma
Methods for treating melanoma using an inhibitor of dihydroorotate dehydrogenase (DHODH) and a combination therapy
Technology Overview
Oncogenic BRAF mutations are present in most melanomas and have been implicated in the malignant growth of melanoma cells. Researchers at Boston Children’s Hospital have discovered methods for treating 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. The lab has also developed assays for identifying compounds useful for the treatment of melanoma. The methods include screening for compounds or agents that inhibit neural crest progenitor formation in a zebrafish model of melanoma.
Through gene expression analysis, the lab determined 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 the 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 the identification of compounds or agents useful for melanoma treatment. The 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.
Further Details:
- 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 the emergence of neural crest identity during melanoma initiation. Science. 2016 Jan 29:351(6272):aad2197
- Heilmann S, Ratnakumar K, Langdon E, et al. A quantitative system for studying metastasis using transparent zebrafish. Cancer Res. 2015 Oct 15;75(20):4272-4282.
Benefits
- Melanoma is involved in the majority of skin cancer-related deaths and despite many years of intensive laboratory and clinical research, there are still limited treatments for melanoma.
Applications
- 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+ lineage.
Patents
