Associate Member/Professor
Moffitt Cancer Center
Mark G. Alexandrow, Ph.D. (PI), has more than 16 years experience as a Principal Investigator in cancer research. My research group studies the molecular machinery that governs progress through the cell cycle, specifically DNA-replicative events. Our long term goal is to take advantage of tumor-associated weaknesses in these processes in order to develop innovative therapeutics to treat cancer. My graduate training with Harold Moses, M.D., in the TGFß1 inhibitory pathways was instrumental in developing an overall hypothesis that TGFß1 targets and inhibits unique druggable enzymes that regulate entry into S-phase. Following postdoctoral training with Joyce Hamlin, Ph.D., in mammalian DNA replication mechanisms, my own research group indeed identified the replicative CMG helicase as one such TGFß1 target and then demonstrated that Rb and Myc regulate the CMG (MCB, 2010 and 2016; Communications Biol, Nature press, 2019; BioEssays, 2020). My group additionally demonstrated that the CMG helicase represents a tumor-specific weakness and effective anti-cancer target for chemotherapeutic development (Mol. Canc. Res., 2015). Toward this goal, our group has recently identified the first human CMG helicase small molecule chemical inhibitors (CMGi), in a collaboration between our group and Celgene/BMS. We are now investigating the mechanisms by which CMGi inhibit the CMG and DNA replication, elicit DNA damage, and induce apoptosis in tumor cells. Multiple mechanistic and pre-clinical studies have thius far indicated that CMGi represent a new class of anti-cancer compounds with unique characteristics that interfere with DNA replication, DNA repair and recovery, and sensitize tumor cells in a selective manner to standard of care chemotherapy drugs. The CMGi also display effective anti-tumor capacity in xenograft studies in vivo, at low concentrations used as monotherapy that elicit no side effects on bone marrow or liver. Further studies are underway to advance these CMGi and derivatives into the clinic.