Dr. Florian Muller
The University of Texas MD Anderson Cancer Center
Department of Cancer Systems Imaging
Cancer is a disease of the genome ultimately caused by genetic alterations in genes normally regulating cell proliferation and survival. In an effort to understand the inner anatomy of cancer, large-scale genomic profiling projects, such as TCGA, have been undertaken. Such efforts have painted an unprecedentedly detailed picture of genetic changes that occur in cancer yet the key challenge for the field remains how to turn this information into actionable therapies. Indeed, genetic events that have been successfully targeted to date are almost exclusively activating mutations in driver oncogenes and the vast majority of genetic alterations catalogued remain un-actionable in terms of therapeutic intervention. Genomic deletions are a frequent event in diverse cancers, which inactivate a limited number of tumor suppressor genes (driver-events) but frequently include many chromosomal neighbors as passengers, some of which play critical but redundant roles in normal cellular housekeeping. Our hypothesis is that collateral deletions of such “passenger” genes can be utilized as novel targets of synthetic lethality, an approach we term “collateral lethality” (See Muller et al, Trends Cancer 2015 1:161-173 for a review). We have provided in vitro proof-of-principal example of this general strategy, whereby a collateral homozygous deleted gene is a redundant member of a paralogous gene pair executing an essential function (Muller et al, Nature 2012 488:337-42)). As there are hundreds of passenger deleted genes in the cancer genome that were previously considered un-actionable for targeted therapies, collateral lethality promises to dramatically expand what may be considered actionable genetic alterations for the purposes of personalized cancer therapy.