Edward Newman, Ph.D.

 

The primary focus of my research program is the development of novel DNA (cytosine-5) methyltransferase (MT'ase) inhibitors for cancer therapy. An interest in both fluoropyrimidines and DNA methylation led to a collaboration with Steven Smith, Ph.D., and Lawrence Sowers, Ph.D., that demonstrated for the first time a covalent complex of human MT'ase with an oligonucleotide containing 5-fluoro-2'-deoxycytidine (FdCyd) and the methyl group from the cofactor AdoMet. We have continued to study the metabolism of FdCyd to FdCTP and the effects of its incorporation into cellular DNA on DNA methylation and gene expression.

Although FdCyd is rapidly degraded to FdUrd by cytidine/deoxycytidine deaminiase, this degradation can be inhibited by tetrahydrouridine (THU) without inhibiting its activation by deoxycytidine kinase. Thus, the effects of FdCyd on MT'ase and other potential intracellular targets can be examined in the presence of THU. Molecular studies of the gene activation profile of FdCyd have continued in my laboratory, and preclinical toxicology studies of the FdCyd/THU combination were performed utilizing the Animal Resources and Pathology core facilities. A detailed understanding of the mechanism by which FdCyd and other inhibitors of MT'ase result in a decrease in the methylation of cytosines in DNA is critical for the future development of this class of agents. The preclinical toxicology and other safety studies led to approval for the initial clinical studies of an Investigational New Drug (IND #54,223, 5-fluoro-2'-deoxycytidine) by the United States Food and Drug Administration.

In collaboration with James Doroshow, M.D., Robert Morgan Jr., M.D., and other clinical investigators, we conducted the first-in-human phase I trial of the combination of FdCyd, and THU, patients with advanced solid tumors. In addition to the clinical objectives, pharmacokinetic studies of FdCyd in plasma and laboratory correlative studies were included in the protocol. With funding from the National Cancer Institute and the Department of Defense Breast Cancer Research Program, we demonstrated the induction of fetal hemoglobin expression during treatment as surrogate marker for the biological activity of FdCyd.

 

 

In collaboration with Robert Chen, M.D., and Susan Kane, Ph.D., we are studying in vitro models of resistance to the antibody-drug conjugate brentuximab vedotin. Current studies focus on mechanistically based possible drug combinations which may overcome resistance.