G. Andrés Cisneros and his team at UNT's Center for Advanced Scientific Computing and Modeling (CASCaM) are using computers to look at how mutations of certain proteins may be related to cancer.
The Cisneros research group focuses on reactions in biological systems, but there are not any beakers or cell cultures in their computational chemistry laboratory. Instead, they develop programs that simulate reactions in biological systems and use them for cancer research.
"My research has two main objectives. One is to develop tools that could be useful for the scientific community for computational modeling," says Cisneros, professor of chemistry. "The other is to investigate DNA repair and modification proteins and how or if these enzymes have cancer mutations and if so, how these mutations affect how the proteins function. This knowledge could result in the development of new cancer treatments and helping to improve human health."
Cisneros has received an R01 grant for $1.25 million over four years from the National Institutes of Health (NIH) and a $250,000 from the National Science Foundation (NSF) over the next three years for his research that has both fundamental and applied applications.
The NIH grant is a continuation of funding for developing simulation programs and investigating how mutations related to cancer affect specific proteins that are related to DNA repair. In 2017, the Cisneros group published a paper related to the previous research grant linking a specific mutation to prostate cancer.
Cisneros collaborates with groups across the U.S. and in Europe in his research.
"The collaborations are very broad, everything from environmental to organic chemistry," Cisneros says. "Sometimes they come to us saying 'We saw this cool method you are using. We have this problem. Would you be interested in helping us solve it?' Other times we initiate collaborations."
Investigations using their computer programs have led to multiple publications, including a recent paper published in the Journal of the American Chemical Society. The study, a collaboration with researchers at the University of Houston, presents the analysis of the enzyme Uracil DNA Glycosylase using their computational chemistry methods. The research was funded by prior grants from the NSF and NIH.
"This NIH renewal is a continuation of this research. We will build on the tools we have developed," Cisneros says. "We are expanding the characterization of cancer mutations to three different enzymes."
His team first mined cancer databases to identify specific DNA repair enzymes with mutations linked to leukemia and lung, prostate and other cancers. They found 24 mutations at the DNA-level, which they will now examine to find the role they play in these cancers.
"We're asking, do you get this particular cancer because of this mutation, or do you get this mutation because of this cancer?" Cisneros explains. "There are passenger mutations and driver mutations. Cancer driver mutations are the important ones. Those are the ones that give rise to cancer."
Identifying the driver mutations could lead to important applications in the medical field. Cisneros hopes the research could be used in the development of diagnostic tools that look for biomarkers for certain cancers. These would be similar to tools used to test for mutations of BRCA genes, the ones associated with breast cancer. Another application could be gene therapy as a treatment for cancer related to these mutations.
Cisneros' new NSF grant also is using computational models to look at proteins, but on a more fundamental level, looking at the solutions around proteins in certain bacteria and the role they play in reactions. The research, a collaboration with researchers at UT Austin, although more basic science, could one day have biomedical applications.
"One possible application is in bioengineering," Cisneros says. "When you have bioreactors, you have to keep your enzymes at the optimal conditions, but sometimes the optimal conditions for the system are not the optimal condition for the process."
The findings in Cisneros' lab are being validated by researchers in clinical settings. Some of their publications are joint publications with researchers at medical schools.
"We are collaborating with Professor Linda Chelico at the University of Saskatchewan. She is conducting experiments, including in a cellular context. Every single thing we've predicted, her work actually confirms experimentally," says Cisneros.
Cisneros is a 2019 recipient of UNT's Early Career Award for Research and Creativity, and he credits the productivity of his research group - more than 90 publications - to his graduate students and postdoctoral research assistants. The recent Journal of the American Chemical Society paper was coauthored by his senior doctoral student, Erik Vázquez-Montelongo, who will soon be defending his dissertation related to the research, and postdoctoral student, Sehr Naseem-Khan, who just returned from the American Chemical Society National Conference where she presented three posters on their work. These grants will continue supporting students and postdocs involved in this project and allow the Cisneros research group to expand the impact of their work.