Professor Aimee Edinger and her lab’s researchers, while unpinning the fundamental mechanisms of tumor biology, are designing out-of-the-box therapies to fight cancer. In collaboration with medicinal chemist, Prof. Stephen Hanessian of UCI and University of Montréal, they are taking unprecedented steps in understanding and designing a treatment that targets a universal hallmark of all cancers, the high metabolic demand that sustains rapid, uncontrolled growth.
The “star” of Prof. Edinger’s newest studies, detailed in the October 2016 issue of the Journal of Clinical Investigation, is a class of molecules known as sphingolipids, which play crucial metabolic roles in yeast to man. Sphingolipids are waxy molecules that are naturally-produced in mammalian cells and reside in the cell membrane. They function to control nutrient access, and are important specifically in times of cellular stress (i.e. nutrient scarcity). In response to stress, sphingolipids, such as ceramide, are produced and trigger the down-regulation of nutrient transporters, thus limiting the flux of sugars and amino acids into the cell. This step is an important regulatory process that helps cells enter in quiescent states and conserve resources.
Considering the role that sphingolipids play in normal cell metabolism and stress responses, Prof. Edinger, a cancer biologist, sought to capitalize on their intended function and redirect them in a way to fight tumor growth. She explained that because tumor cells are constitutively in the “on” state and ever-growing, they are highly reliant upon, and therefore vulnerable to, an attack on their nutrient import pathways to sustain growth. Put simply: “normal cells act like bears in the winter, going into a hibernation-like state when nutrients are scarce; while cancer cells continue to try to grow regardless of the environmental conditions.” Targeting the “supply wagons” of tumor cells, therefore, is a strategic method of combatting cancer growth.
Microscope images of model tumor cells: untreated cells versus sphingolipid-treated cells. Cancer cells treated with no drug or with a normal sphingolipid, ceramide, appear unaffected; unlike those subjected to the novel compound 893, which develop large vacuoles, a sign of altered metabolic mechanisms.
General structure of sphingolipids
Inspired by naturally-occurring sphingolipids, Prof. Edinger and her collaborator, Prof. Hanessian, designed new sphingolipid-type molecules with improved pharmacological properties for use as anticancer drugs. These designer compounds are attractive pharmaceuticals to diminish tumor proliferation, as they are water-soluble, orally-bioavailable, and efficiently starve tumor cells, with nominal effects on healthy cells. Presented in the recently published article, lead author Seong Kim and her colleagues show that one of these compounds, referred to as “893”, is effective at disrupting nutrient access pathways in multiple preclinical cancer models. They found that their molecule not only causes the loss of nutrient transports, as predicted, but also affects other nutrient-uptake pathways that tumors rely on, including lysosomal fusion pathways involving endosomes, autophagosomes, and macropinosomes. It does so by mislocation of a key membrane molecule, PIKfyve. The effect of knocking out multiple nutrient pathways in parallel is profound cellular starvation. Cells treated in vitro and in vivo are observed to form large vacuoles, a striking visual that signifies starvation. Furthermore, the size of tumors in mice treated with the drug was significantly smaller, as much as 90%, than in untreated animals.
General structure of compound 893 (bottom).
The effects of sphingolipid 893 on model cancer cell lines and on tumors in animals were extremely promising to the researchers. Another extraordinary aspect of the drug is the lack of toxicity to healthy cells that were observed. Mice that were administered 893 over three months were found to have normal blood work and chemistry panels, and had no signs of liver or kidney damage. Prof. Edinger remarked that the animals “looked like mice on a diet, not mice on chemotherapy,” an unusual, but very welcome result of their studies. The rationale of why healthy cells are able to survive treatment is because, unlike tumor cells, they are able to tolerate fluctuations in nutrient availability by adapting their metabolic requirements. This distinguishing feature between healthy and cancerous cells is the key to this drug’s therapeutic index.
Prof. Edinger’s innovative research on cancer therapeutics is supported by many prominent agencies, including the National Institutes of Health (NIH), the American Chemical Society (ACS), and the DoD’s Congressionally-Directed Medical Research Program (CDMRP). Additionally, early in 2016, Prof. Edinger was awarded the Applied Innovation Commercialization Grant, aimed at developing the “proof of product” of this therapeutic by providing funds for additional animal studies.
Read Prof. Edinger’s recent article in the Journal of Clinical Investigations at http://www.jci.org/articles/view/87148. To learn about commercializing technologies, such as Prof. Edinger’s, visit innovation.uci.edu/itg
Aimee Edinger – Associate Professor, Francisco J. Ayala School of Biological Sciences, Department of Developmental and Cell Biology
Notable Achievements in Advancing Technology
Chancellor’s Award for Excellence in Undergraduate Research (2009)
UCI School of Biological Sciences Golden Apple teaching award (2014)
Applied Innovation Commercialization Grant Award (2016)