Most aspirin users don’t know what aspirin does to make you feel better. Most doctors and scientists didn’t know, either, until recently. In fact, scientists know how only a handful of drugs really work and they know that drugs can have different effects on different people. That’s why Tudor Oprea, MD, PhD, wished for database that could tell him a drug’s chemical structure, its molecular biology activity and the diseases it is used to treat. Now, after a 20-year effort, Oprea and his collaborators from the UK-based European Bioinformatics Institute in Hinxton and from the Institute for Cancer Research in London have created the beginnings of that archive. They recently published their work in the journal Nature Reviews Drug Discovery.
“This is a landmark paper,” says David Schade, MD, a Distinguished Professor at The University of New Mexico School of Medicine, who oversees clinical research in the Department of Internal Medicine. “Diseases that were not treatable 10 years ago are now treatable,” he says. “That’s because of new medications that have been developed and approved by the Food and Drug Administration.”
But while new drugs have saved lives, they can also complicate treatment. Schade explains that doctors often use more than one drug to treat diabetes, for example. They must make sure those drugs work together and that no dangerous side effects result they’re when combined. “What we want to do,” says Schade, “is hit multiple targets that are causing the disease.” And Oprea’s archive will help doctors to do just that, he says.
Olivier Rixe, MD, PhD, agrees. Rixe oversees all clinical research at the UNM Comprehensive Cancer Center. “At the end of the day,” he says, “it’s for the benefit of the patients because we will be better able to tailor the way we treat their cancer.” Rixe also plans to use Oprea’s archive to speed the process of drug discovery and development at UNM Cancer Center. “We can use this type of data to better align drug development with the characteristics of the patients.”
Oprea, now a Professor at the UNM Cancer Center, started the drug database 20 years ago when he was a drug developer. He archived drug targets, which are molecules that drugs act on to make the cell change its behavior. He later expanded his list to include properties of the drugs themselves and any information about how they acted on their targets. While it sounds simple, creating this type of repository proved far from easy. “It was pretty hard to get here,” Oprea says.
To develop the information, Oprea and his international collaborators had to mine data from all over the world. They correctly mapped the drugs’ molecular structures. They searched for data on the diseases the drugs helped to treat. They collected data on the drugs’ effects on humans and animals. They also listed what scientists had learned about how the drugs reacted with the proteins in cells.
In all, they cataloged 893 drug targets linked to Mode of Action, which is how drugs exert their therapeutic effect at the molecular level, and 1,578 drugs approved by the United States Food and Drug Administration. The information, which has gaps, is now publicly available through a system that Oprea’s research team at UNM developed, called DrugCentral. DrugCentral resides at UNM and Oprea is building his team to be experts in drug discovery. “This type of expertise is rare,” he says. “We are one of the teams that has it.”
Creating the drug targets database unearthed some interesting details. The collaborators used the database to compare drug targets with the Sanger Institute’s list of genes shown to be important in developing cancer. They found that only 38 molecular targets for cancer overlapped with the important cancer genes. “That’s not a lot,” Oprea says, “but the question is, can we treat cancers by blocking the cancer gene drivers? We don’t know that yet.” This effort will help in finding the answer. Oprea hopes that others will contribute their information to grow the drug knowledge for everyone to use.
Tudor Oprea, MD, PhD, is a Professor of Medicine and Chief of the Translational Informatics Division in the Department of Internal Medicine at The University of New Mexico School of Medicine. He completed his medical and doctoral degrees at the University of Medicine and Pharmacy in Timisoara, Romania. Dr. Oprea completed post-doctoral training at the Center for Molecular Design, Washington University, with Garland Marshall and then at Los Alamos National Laboratory in Theoretical Biology, with Angel García. Dr. Oprea’s in silico evaluations at UNM Cancer Center have resulted in two drugs, raltgravir and ketorolac, now in clinical evaluation; eight granted US patents; and several funded proposals, including a U54 and an R01 funded through the National Cancer Institute.
David Schade, MD, is a Distinguished Professor and Chief of the Division of Endocrinology in the Department of Internal Medicine at the UNM School of Medicine. He serves as Vice Chair of the Office of Research at the Department of Internal Medicine.
Olivier Rixe, MD, PhD, is a Professor in the Department of Internal Medicine, Division of Hematology/Oncology, at the UNM School of Medicine. He serves as Associate Director of Clinical Research and holds the The Dana C. Wood Endowed Chair in Cancer Therapeutics and Early Phase Clinical Research at the UNM Comprehensive Cancer Center.
“A comprehensive map of molecular drug targets” was published in the January, 2017, print edition of Nature Reviews (www.nature.com/nrd/). It was published online in December, 2016. Authors are: Rita Santos, Oleg Ursu, Anna Gaulton, A. Patrícia Bento, Ramesh S. Donadi, Cristian G. Bologa, Anneli Karlsson, Bissan Al-Lazikani, Anne Hersey, Tudor I. Oprea & John P. Overington.
The University of New Mexico Comprehensive Cancer Center is the Official Cancer Center of New Mexico and the only National Cancer Institute-designated Cancer Center in a 500-mile radius. Its 125 board-certified oncology specialty physicians include cancer surgeons in every specialty (abdominal, thoracic, bone and soft tissue, neurosurgery, genitourinary, gynecology, and head and neck cancers), adult and pediatric hematologists/medical oncologists, gynecologic oncologists, and radiation oncologists. They, along with more than 500 other cancer healthcare professionals (nurses, pharmacists, nutritionists, navigators, psychologists and social workers), provided cancer care for nearly 60 percent of the adults and children in New Mexico affected by cancer. They treated 11,249 patients in 84,875 ambulatory clinic visits in addition to in-patient hospitalizations at UNM Hospital. These patients came from every county in the State. More than 12 percent of these patients participated in cancer clinical trials testing new cancer treatments and 35 percent of patients participated in other clinical research studies, including tests of novel cancer prevention strategies and cancer genome sequencing. The 130 cancer research scientists affiliated with the UNMCCC were awarded almost $60 million in federal and private grants and contracts for cancer research projects and published 301 high quality publications. Promoting economic development, they filed more than 30 new patents in FY16, and since 2010, have launched 11 new biotechnology start-up companies. Scientists associated with the UNMCCC Cancer Control & Disparities have conducted more than 60 statewide community-based cancer education, prevention, screening, and behavioral intervention studies involving more than 10,000 New Mexicans. Finally, the physicians, scientists and staff have provided education and training experiences to more than 230 high school, undergraduate, graduate, and postdoctoral fellowship students in cancer research and cancer health care delivery. Learn more at www.cancer.unm.edu.
Dorothy Hornbeck, JKPR, 505-340-5929, email@example.com
Michele Sequeira, UNM Cancer Center, 505-925-0486, firstname.lastname@example.org