In Remembrance: Robert C. Moschel, PhD

he CCR research community mourns the loss of Robert C. Moschel, PhD, who died April 20 due to complications from pancreatic cancer. Bob, who was both an outstanding chemist and a wonderful friend and colleague, is remembered as a kind and generous man whose work has led to the development of new drugs that enhance the effectiveness of chemotherapy for brain tumors and that could potentially help treat other cancers as well.

Dr. Moschel was born and raised in Cincinnati, Ohio. After receiving his PhD in biochemistry from Ohio State University in 1973, he conducted postdoctoral research in organic chemistry at the University of Illinois for three years and then settled in Frederick, Maryland. Dr. Moschel was promoted to staff scientist in 1987 in the ABL-Basic Research Program and then became head of the Carcinogen-Modified Nucleic Acid Chemistry Section in 1992. His section became part of the CCR at the NCI-Frederick in 1999.

Dr. Moschel and his colleagues developed compounds that can inactivate the human DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT). This protein is primarily responsible for the resistance to chemotherapy that tumor cells exhibit when treated with drugs that act through akylation of DNA at the O6 position of guanine. The inactivation of AGT can bring about a dramatic improvement in the effectiveness of these drugs. O6-benzylguanine, one of the alkyltransferase-inactivating drugs developed by Dr. Moschel’s lab, is currently in phase I and II clinical trials in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or temozolomide. His research team continues to develop new inactivators that are more potent, more water soluble, and more selective for tumor cells. These new drugs could prove to be very useful as chemotherapy adjuvants.

Dr. Gary Pauly, who worked with Dr. Moschel for more than 20 years, recalls that “Bob was unstoppable in his determination to bring his compounds from the bench to the bedside. He carried his drugs from discovery to proof of principle, through the pharmacology and toxicology, to the patients in the clinic.” Dr. Larry Keefer notes, “It was always inspirational to see the organ scans of patients whose tumors were regressing—indeed disappearing—after dosage with the combination drug therapy Bob developed. Second-generation therapeutic agents he ingeniously designed show promise for even greater clinical utility.”
 
In longstanding collaborations with Dr. Anthony E. Pegg of the Pennsylvania State University College of Medicine and Dr. Henry S. Friedman of the Duke University Medical Center, Dr. Moschel’s research led to significant improvements in chemotherapy for brain tumors. His collaborative studies with Dr. Eileen Dolan (University of Chicago) showed that pretreatment of several cell lines with O6-benzylguanine enhanced the cytotoxicity of the chemotherapeutic agent cisplatin. This pretreatment approach might improve the prognosis of patients with head and neck, ovarian, testicular, or lung cancer who are routinely treated with cisplatin.

Dr. Moschel’s team also used site-specific mutagenesis techniques to study the chemical and biological effects of carcinogen damage to DNA and the role played by DNA repair mechanisms in mediating these effects. In a collaboration with Dr. Lisa Peterson (University of Minnesota), they demonstrated that a pyridyloxobutylguanine adduct, which plays an important role in tobacco-induced lung carcinogenesis, is highly mutagenic in both Escherichia coli and human cells. Subsequent studies suggested that differences in the repair of this adduct by mammalian proteins may translate into differences in sensitivity that these cells exhibit to tobacco-specific nitrosamines.

In addition to conducting research, Dr. Moschel was a member of both the Chemistry and Structural Biology Faculty and the Molecular Targets Faculty. During his career, he published more than 100 scientific papers in prestigious journals, such as Cancer Research, Proceedings of the National Academy of Sciences USA, Cancer Chemotherapy and Pharmacology, Carcinogenesis, Chemical Research in Toxicology, and Journal of Organic Chemistry. In addition, Dr. Moschel also served on the editorial advisory board of Chemical Research in Toxicology and was a member of the American Cancer Society’s Peer Review Committee on Carcinogenesis, Nutrition, and the Environment.

Dr. Moschel will be remembered by his friends and colleagues as a kind and gentle man whose research has led to new treatments for brain tumor patients and renewed hope for their families.

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