It's difficult to imagine where cancer research would be without the National Cancer Institute (NCI). Since its founding in 1937, the NCI has had a profound impact on the understanding, diagnosis, prevention, and treatment of diseases from leukemia to HIV-AIDS. According to a 1996 analysis, two-thirds of the anti-cancer drugs approved by the Food and Drug Administration (FDA) began as NCI-sponsored Investigational New Drugs.
Over the years, research at the NCI has expanded along with its scientific discoveries. Today, some of the most advanced work is coming from Frank J. Gonzalez and his team in the Laboratory of Metabolism at the NCI's Center for Cancer Research (CCR).
“One of our key areas of study is the use of metabolomics to find early biomarkers for cancer, and we are beginning to see success in mouse models and in human studies,” said Gonzalez. “We also want to determine the mechanisms of carcinogenesis, and metabolomics nicely fits into that goal, as well. For example, some of the metabolites we find could point to novel pathways of cell proliferation and areas for therapeutic intervention.”
Gonzalez and his group are primarily focused on developing an understanding of the mechanisms of chemical carcinogenesis. Using a multi-faceted approach involving mouse models, molecular biology, and analytical chemistry, they are pursuing a number of projects centered on the roles of xenobiotic receptors (proteins in organisms that sense the presence of foreign substances) and drug/carcinogen-metabolizing enzymes in carcinogenesis.
For example, by studying mice that lack cytochromes P450 (CYPs), a family of enzymes involved in the metabolism of most therapeutically-used drugs, toxicants and carcinogens, the Gonzalez team discovered that CYPs mediate the toxicity and carcinogenicity of chemicals in vivo, and thus have a role in cancer susceptibility.
“We’ve had a couple of recent papers on cancer biomarker discovery using mouse models, and we have manuscripts in the pipeline on early biomarkers for lung and colon cancer,” said Gonzalez.
The search for biomarkers has intensified in recent years, largely due to their potential to improve early disease detection.
“Many labs are now focused on the discovery of disease biomarkers that can be detected in readily available fluids, such as urine or blood,” explained Gonzalez. “We focus on urine, although we do complementary studies with serum, normal tissues and cancer cells. A rapid, non-invasive urine test would allow the routine screening of more people for the presence of early stage cancers. A positive urine biomarker test could then be confirmed by use of MRI, CT, and PET scanning. Thus, patients could be triaged by use of a urine test. Cancer biomarkers could also be used to monitor response to chemotherapy.”
Diagnostic biomarkers are also being investigated for other diseases associated with increased cancer risk such as liver diseases including steatosis, steatohepatitis, viral infections with HBV and HCV, and metabolic diseases such as type 2 diabetes and inflammatory bowel disease.
The search for biomarkers is being driven by advances in metabolomics, the systematic study of the unique chemical fingerprints left behind by cellular processes.
“While proteomics has been around for a while, and has led to some valuable advances in diagnosis, metabolomics has been a little slower to be recognized,” said Gonzalez. “But I think that it will become even more important than proteomics in biomarker discovery.”
Over the past ten years, advances in UPLC/MS technologies have driven the increased interest and use of metabolomics in academic labs. “Readily available instrumentation suitable for high throughput analysis is absolutely critical,” said Gonzalez. “When we first started doing metabolomics, we tried NMR, and didn’t get very far. We found that it was expensive, suffered from very low throughput and poor specificity, and lacked the sensitivity required for the detection of low abundance biomarkers, at least with the NMR instruments that were available at the time.”
Now the Center for Cancer Research uses several Waters mass spectrometers, including the original QTof Premier™, a SYNAPT® HDMS, a Xevo G2 QTof, and a Xevo® TQ MS, and will soon deploy a SYNAPT G2-Si HDMS and Xevo TQ-S MS mass spectrometers.
Had his life taken another route, Frank Gonzalez might be spending more time working with a different kind of equipment.
“My father owned a construction company in Tampa, Florida” he said. “And I worked as a laborer on building sites during the summers when I was in high school and college.”
Things changed during his undergraduate years at the University of South Florida, where he majored in Biology.
“I got an unpaid job in the laboratory of an assistant professor in the Biology department studying Trypanosome kinetoplast DNA,” said Gonzalez. “I thought it was interesting and fun to work in the laboratory, and it was certainly more enjoyable than digging ditches and carrying lumber on construction sites.”
That first experience in the lab led Gonzalez to another opportunity working on cancer research as a Master's degree candidate at the University of South Florida School of Medicine. That spurred an interest in pursuing a career in science, and soon he was working on a Ph.D. in Oncology at the University of Wisconsin, Madison.
Gonzalez is clearly happiest in the laboratory, where he enjoys “interacting with the post-docs (the NIH does not have a graduate school).” That interaction is important to his efforts to help train the next generation of cancer and metabolomics researchers.
“My number one priority is getting promising young scientists in the lab, training them, and making sure they have productive projects conducive to their interest and skills.” He noted, “We’ve had several post-docs leave our lab to start metabolomics programs at major universities.”
In his own work, Gonzalez remains focused on making a major impact on the detection and treatment of cancer.
“The trend now is toward translational research, showing that we can turn some of this work into information that’s of value in the diagnosis and treatment of human disease,” said Gonzalez. “We hope to continue to publish high-impact papers on biomarker discovery for the early diagnosis of human cancer, and ultimately launch some clinical trials with a partner in industry.”
Dr. Gonzalez emphasized that the credit for his laboratory’s accomplishments to date goes to everyone who has served on the team. “I’m very proud of all that the metabolomics program in the CCR has achieved over the last 10 years, he said. “And I’m especially thankful for the collaboration and input of colleagues Jeff Idle and Kris Krausz, and the work of many talented post-docs”.