Our research initially focused on mechanisms that restrict nuclear DNA replication during cell division to one complete copy of the genome during each of the trillions of cell divisions required for fertilized mammalian eggs to develop into adults. These studies led to discoveries in four areas. First, they elucidated the mechanisms by which trophoblast stem cells and megakaryoblasts are developmentally programmed to differentiate into nonproliferating polyploid cells via 'endoreplication', a process in which mitosis is bypassed and a second S-phase ensues. Second, they identified genes that are essential in non-malignant cells to prevent 'unscheduled endoreplication' from promoting cancer, as well as genes essential to prevent normal cells from re‑replicating their DNA more than once during a single S-phase. Third, these studies led to the discovery that induction of ‘DNA re-replication’ during the same cell cycle can selectively kill cancer cells with little or no harm to normal cells. Our efforts to identify small molecules that could selectively induce DNA re-replication in cancer cells resulted in the discovery of a family of PIKFYVE phosphoinositide kinase inhibitors that can selectively kill autophagy-dependent cancer cells. Current research focuses on distinguishing sensitive cells from insensitive cells, the mechanism by which PIKFYVE inhibitors kill cancer cells, and the therapeutic potential of PIKFYVE inhibitors.
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