Helping Oncologists Choose a Medicine That Will Work

Maria Burnatowska-Hledin, Ph.D.
The Frederich Garrett and Helen Floor Dekker
Professor of Biomedicine and Chemistry

When mixing a drug cocktail to treat cancer, the more information an oncologist has, the better. As part of an army of cancer researchers inching toward a cure one complicated detail at a time, Dr. Maria Burnatowska-Hledin has zeroed in on a gene that she hopes can help doctors assess whether a particular drug will work for a specific patient.

That drug is thalidomide. Introduced in the 1950s to control pregnant women’s morning sickness, it was pulled off the market because it caused birth defects. Since then, research has shown that derivatives of thalidomide work well in other ways. In 2006, the FDA approved a derivative for treatment of multiple myeloma (cancer of the white blood cells).

While this drug can’t cure multiple myeloma, it can extend patients’ lives by slowing cancer’s growth and spread — but only for those who respond to thalidomide. Previous research by other scientists indicates that’s less than one-third of patients.

Why does thalidomide work in some patients’ bodies, but not others? Burnatowska-Hledin and her students sought to answer that critical question.

For 20 years, Burnatowska-Hledin’s research group has focused on the gene CUL-5, which is part of a system that “cleans” cells on a daily basis. It’s one of many genes that control cell growth and, consequently, cancer. The group’s long-term research goal is to identify the chemical compounds that regulate expression of CUL-5 — that is, that use information from the gene to synthesize the protein CUL5 (no dash!), which does the actual work of regulating cell function.

The gene is present in every human’s DNA. However, the protein is not expressed in every individual — and when it is, its properties can vary.

In grant-supported experiments over several years, Burnatowska-Hledin’s research group found that CUL-5 appears to be key to thalidomide’s cancer-fighting mechanism, specifically in the cells that comprise blood vessels.

A quick briefing on how cancer cells work may be helpful here. Cancer cells can stimulate the growth of new capillaries, which is bad news in two ways; first, additional blood vessels increase the flow of blood to tumors, which helps them grow, and second, they also extend the pathways through which cancer can spread. Thalidomide fights back by inhibiting the growth of endothelial cells, those that line the inside walls of blood vessels. Without them, blood vessels can’t function.

Burnatowska-Hledin and her students used the gene-silencing technique known as siRNA to remove CUL-5 from cells that can form capillaries. Then they treated edited and unedited capillary cells with thalidomide. They discovered that thalidomide didn’t kill the cells from which they’d stripped CUL-5.

Doctors can put this new knowledge to work. Through a biopsy, a doctor can establish whether the protein CUL5 is expressed in a particular patient. If it is, thalidomide may be a good choice for treatment — and if it’s absent, just the opposite.

This research was supported by a grant from the National Cancer Institute, and by grants to specific student researchers from the Arnold and Mabel Beckman Foundation, Schaap Endowed Fund for Undergraduate Research, and American Society of Biochemistry and Molecular Biology. Burnatowska-Hledin and her students reported their findings in 2018 in the journal PLOS-ONE.

Hope’s Department of Chemistry and Biochemistry has generous support for long-term research that advances scientific inquiry and engages Hope students in authentic research as undergraduates. One example of this support is the Schaap Research Fellows Program endowed by A. Paul Schaap ’67 and Carol Schaap, which provides supplemental funding to Dr. Burnatowska-Hledin and six other professors whose work also is supported by major grants from foundations and other agencies.

Below, read about the other Schaap Fellows’ research. For more detail, follow links from the Chem/Biochem research webpage.

Dr. Kenneth Brown’s work contributes to development and improvement of glucose biosensor test strips for diabetics and (in collaboration with Dr. Leah Chase) methods to study compounds implicated in mental disorders. Instrumentation to train Dr. Brown’s student assistants has been purchased through the Schaap Fellows program.

Dr. Jason Gillmore makes and studies organic dyes for photoresponsive materials (such as ophthalmic lenses that darken in sunlight, or plastic actuators that reversibly bend in response to a laser beam). One way he uses Schaap funds is to travel with student researchers to national and international meetings, such as the 2018 Reaction Mechanisms Conference in Vancouver, Canada.

Bonds between carbon atoms are the framework of all organic molecules. Dr. Jeff Johnson develops new chemical reactions to advance understanding of the
reactions that break those bonds — and develops new methods for synthesizing complex molecules.

Dr. Brent Krueger applies the tools of physics — lasers, microscopes and computer models — to a variety of problems in biology, including nerve regeneration, the interplay between microbes in bodies of water, and the improvement of a scientific technique for studying the structure of DNA, RNA and protein.

Dr. Will Polik and his students use lasers, mathematics and computers to study chemical reactions. Lasers energize molecules in different ways; math models how the energy flows within the molecules; and computers predict how other chemical systems will respond when energized.

Dr. Joanne Stewart is assessing how the international inorganic chemistry organization IONiC enables faculty to teach more effectively — and the impact of such shifts on students’ learning, self-confidence, interest and effort. She serves on IONiC’s leadership council.