Impact: There is a huge need for drugs to treat advanced and metastatic solid cancers. Cells in such cancers usually have aberrant genomes with highly amplified oncogenes. Drugs have been developed to target certain amplified oncogenes as proteins, but this has been difficult in many cases. Our idea is to target the amplified DNA itself by exploiting fundamental differences in its chromosomal organization compared to normal DNA. Recent analysis showed that 20-60% of common solid tumors contain amplified DNA in the form of small, circular chromosomes called extrachromosomal DNA (ecDNA). These autonomous genetic elements, previously called “double minutes”, are typically 0.2-2MB in length, present at 2-100copies per cancer cell and absent from normal cells. They lack centromeres and segregate inefficiently at mitosis, resulting in copy number fluctuations that allow rapid evolution of cancer genotype. ecDNA is a highly abnormal state of chromosome organization that is specific to cancer cells. We propose it constitutes a druggable vulnerability and have identified a candidate target based on its DepMap dependency scores and cell biology.
Research Objectives: Develop an enzyme assay suited for inhibitor screening on the candidate target and test inhibitor scaffolds from in silico prediction or/and HTS screens. In parallel, develop cell-based assays for genetic depletion of the candidate target and test if it is selectively required for mitosis in cancer cells with high ecDNA copy number.
Funding
Funding Duration
July 1, 2021 - June 30, 2022