Malignant melanoma is one of the most aggressive types of human cancers. Its ability to metastasize in combination with resistance to conventional anticancer chemotherapy makes melanoma extremely difficult to cure. As a consequence, the median survival of patients with metastatic melanoma is merely 8.5 months. One of the prominent events in metastatic melanomas is increase in the amounts of the protein C-MYC. C- MYC is a transcription factor. High amounts of C-MYC have been associated with multiple types of human cancers predominantly at more advanced, aggressive stages. Accordingly, C-MYC has been demonstrated essential for growth of many types of experimental tumors in mice including melanoma. None the less, despite wide recognition of the central role of C-MYC in tumor development, only a single drug targeting C-MYC is currently being tested in clinical trials. The major goal of our proposal is to develop anti-C-MYC pharmaceutical agents capable of elimination of melanoma either alone or in combination with existent anti-cancer drugs. To this end, by applying different experimental assays, we have screened a set of 34,000 individual chemicals for those capable of elimination of C-MYC in cancerous cells or inhibition of its function. We were able to identify a lead compound, AM7, that decreases tumor growth in mice without noticeable side effects such as distress or weight loss. Mechanistically, we have identified that AM7 does not decrease C-MYC mRNA or protein levels but inhibits the ability of C-MYC to interact with SWI/SNF complexes. In the present application, we propose a research plan aiming at identifying molecular mechanisms of AM7 activity and establishing the use of AM7 as a novel melanoma treatment strategy.
Malignant melanoma is one of the most aggressive forms of cancer: the survival rate of metastatic melanoma patients is approximately 8.5 months. Currently, there is no comprehensive melanoma therapy available. Our proposal aims at development of novel anti-melanoma therapeutics targeting C-MYC ? a protein which is most commonly up-regulated in human malignancies and yet, the one that has never been targeted by drugs at advanced phases of clinical trials. We have identified a lead compound that can be developed into the anticancer drug and have a potential to significantly improve management of malignant melanoma in long term.
| Fink, Emily E; Moparthy, Sudha; Bagati, Archis et al. (2018) XBP1-KLF9 Axis Acts as a Molecular Rheostat to Control the Transition from Adaptive to Cytotoxic Unfolded Protein Response. Cell Rep 25:212-223.e4 |
