At the interface of chemistry and cancer

There was a time when chemists, and other physical scientists, might not have felt very welcome in the cancer research community. Today, innovative approaches to cancer detection, prevention and treatment are front and center, and chemists are transforming the field through transdisciplinary science.

At the University of Chicago, the physical sciences are impacting basic, translational and clinical cancer research like never before. An influx of investigators – both senior and junior faculty – recruited to UChicago in recent years have been enthusiastic to contribute their expertise and collaborate with cancer biologists and clinicians.

In addition to several biochemists and molecular engineers, the University of Chicago Medicine Comprehensive Cancer Center now has four members from the Department of Chemistry: Chuan He, PhD, John T. Wilson Distinguished Service Professor of Chemistry; Wenbin Lin, PhD, James Frank Professor of Chemistry; Ray Moellering, PhD, assistant professor of chemistry; and Bryan Dickinson, PhD, assistant professor of chemistry.

Genetic modifications and gene expression

And the science being conducted is paying big dividends. He, for example, is developing novel tools to detect nucleic acid (both DNA and RNA) modifications - chemical tags that alter their structure and biological function - and is a leader in studying how RNA modifications control gene expression. His team is collaborating with cancer experts, including leukemia, endometrial, neuroblastoma, lymphoma, breast and colorectal cancer, to understand how these tags differ in cancer and whether targeting them might provide a therapeutic opportunity. He and fellow Comprehensive Cancer Center member Tao Pan, professor of biochemistry and molecular biology, are leading a new Center of Excellence in Genomic Science to spur technology development for diagnostics and therapeutics that target RNA modification pathways.

Fluorescent probes

Dickinson's laboratory is developing small molecule, fluorescent probes to study enzymes in cells responsible for removing a class of protein modifications called palmitoylation. Hundreds of proteins in human cells are tagged by this modification, including some known to play an important role in cancer. In a recent paper published in Nature Chemical Biology, Dickinson and colleagues showed that they could detect these eraser enzymes in live cells, and the activity of the erasers changed in cancer cells depending on their growth state. Dickinson was recently awarded a five-year, $1.25 million grant from the National Institutes of Health to develop similar fluorescent tools to track the activity of another type of eraser protein, one that removes lysine acetylation, in living cells.

Approaches that marry chemistry, biology and physics to study and manipulate biological systems are able to provide resolution in living cells in both space and time.

"Chemical biology can answer questions that genetics can't," Dickinson said.

Exploring the proteome

Also employing synthetic chemistry approaches, Moellering's team is developing chemical tools to better understand the proteome – the entire complement of proteins in cells, tissues or an organism – and to manipulate target proteins and pathways for cancer treatment. For example, his lab has discovered several novel post-translational modifications on proteins that bridge metabolism and cell signaling in cancer cells. This work, which is supported by a Pathways to Independence Award from the National Cancer Institute, has resulted in the discovery of new signaling pathways and small molecule probes that regulate metabolism in cancer cells. Additionally, the Mary Kay Foundation recently funded Moellering's project on developing precision imaging diagnostics to detect and treat the metastatic spread of breast and ovarian cancer.

Finally, to address newly discovered cancer pathways, Moellering's lab is developing novel protein-based drugs to block the activity of cancer proteins that have proven challenging to disrupt through more conventional means. In 2015, Moellering was awarded the V Foundation for Cancer Research V Scholar Award and Cancer Research Foundation Young Investigator Award for his work on targeting oncogenic transcription with synthetic biologics.

Nanoparticles for drug delivery

Lin is a leader in designing novel nanoparticle platforms for targeted delivery of chemotherapeutics and biologics for cancer therapy and for enhancing radiotherapy and immunotherapy. Recently, his laboratory has developed two types of nanoparticles (nanoscale coordination polymers and nanoscale metal organic frameworks) that have shown to be effective in tumor models and can serve as carriers for anticancer drugs such as chemotherapy and as sensitizers for radiotherapy. Nanoparticles like these have the advantage of prolonged stability in circulation, capacity to carry large therapeutic payloads, and ability to directly target cancer cells and circumvent drug resistance mechanisms.

Lin's research is funded by an innovative Research in Cancer Nanotechnology grant from the National Cancer Institute, the Cancer Research Foundation and University of Chicago Ludwig Center for Metastasis Research. To translate these discoveries into the clinic, he recently founded two startup companies, RiMO Therapeutics and Coordination Pharmaceuticals. The first phase I trial of RiMO-1 for treating recurrent head and neck cancer is expected to open in early 2017.

Beyond just bricks and mortar, the facilities at UChicago have also helped to foster interactions and propel scientific discovery. The Gordon Center for Integrative Science, built in 2005 and home to the Ben May Department of Cancer Research and Department of Chemistry, is one of the few research facilities in the nation that bring the physical and biomedical sciences under one roof. Moreover, UChicago is one of only a handful of academic centers that has a strong chemistry program on the same campus as a medical school or hospital.

"Interdisciplinary approaches often open new directions for basic research and translational opportunities," He said.