Edward Newman, Ph.D.
- Associate Professor, Department of Cancer Biology
Edward Newman, Ph.D.
- The Mechanism of Reactivation of Tumor Suppressor Genes by Inhibitors of DNA (Cytosine-5) Methyltransferase
- Mechanisms of Drug Resistance
- Cancer Biology
- Developmental Cancer Therapeutics Program
- Comprehensive Cancer Center Co-leaders
- Early Therapeutic Disease Team
- Leukemia Disease Team
- Lymphoma Disease Team
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 (FDA).
In collaboration with Dr. James Doroshow, Dr. Robert Morgan, Jr., 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 NCI 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.
Somlo, G., Frankel, P.H., Arun, B.K., Ma, C.X., Garcia, A.A., Cigler, T., Cream, L.V., Harvey, H.A., Sparano, J.A., Nanda, R., Chew, H.K., Moynihan, T.J., Vahdat, L.T., Goetz, M.P., Beumer, J.H., Hurria, A., Mortimer, J., Piekarz, R., Sand, S., Herzog, J., Van Tongeren, L.R., Ferry-Galow, K.V., Chen, A.P., Ruel, C., Newman, E.M., Gandara, D.R., and Weitzel, J.N. Efficacy of the Poly (ADP-ribose) Polymerase Inhibitor (PARPi) ABT-888 (veliparib) Alone or in Combination with Carboplatin in Germline BRCA1- or BRCA2-Associated Metastatic Breast Cancer California Cancer Consortium Trial NCT01149083. Clin. Cancer Res. 23, 4066-4076, 2017. PMID: 28356425. PMCID: PMC5540749