Identifying New Drug Targets for Chemoresistant and MYC-Driven Cancers

One of the biggest challenges to cancer treatment is the eventual resistance of cancer cells to drug therapy. Cisplatin, once touted as a drug capable of treating a wide range of cancers, is one such drug therapy whose efficacy is limited due to an eventual resistance of the cells to the drug. The first part of my project involved a high throughput siRNA screen carried out in ovarian cancer and neuroblastoma cells to identify genes and pathways that could sensitize the cells to Cisplatin. The genes identified by the screen were then confirmed in a broader panel of ovarian and neuroblastoma cancer cells. The assay involved transfection of siRNAs into cancer cells in the presence or absence of Cisplatin and then measurement of cell viability. In a parallel approach to targeting aggressive and chemoresistant cells, tumor cell with over-expressed/amplified MYC were targeted. MYC, an oncogene responsible for maintaining cell stability by regulating cell proliferation and death, has been implicated in both tumor formation and resistance. Our lab employed functional genomics to identify a group of druggable targets that, when inhibited, work synergistically with over-expressed/amplified MYC to cause significant cell death. These genes are also referred to as MYC-synthetic lethal genes. The synthetically lethal interactions of the genes with over-expressed/amplified MYC were validated by inhibition of the genes with drugs, followed by cell viability assays. The results from this research project provide significant insights into how chemoresistant and aggressive cancers like ovarian cancer and neuroblastoma could be effectively treated.