“Lipids, or fats, are essential building blocks of cell membranes and are involved in many chemical functions in the body,” explains Timothy F. Osborne, Ph.D., director of the Johns Hopkins All Children’s Institute for Fundamental Biomedical Research in St. Petersburg, Florida. “However, an over-accumulation of fats carries the risk for obesity — a serious problem in America today — and also contributes to certain kinds of cancer.”
In potentially revolutionary research, Osborne and his colleagues may have found a way to interfere with certain biological pathways to deprive some cancer tumors of the fats upon which they thrive.
In their recent study, published in the Feb. 18, 2021 issue of the prestigious peer-reviewed scientific journal Cell Chemical Biology, Osborne and colleagues describe how the drug dipyridamole, a previously developed drug aimed at thinning the blood to prevent blood clots after some types of heart surgery, can be “repurposed” to inhibit an unrelated specific biological pathway to “starve” certain cancers, such as pancreatic cancer, prostate cancer, colorectal cancer, breast cancer and liver cancer, by denying them the fats on which they depend for growth.
Although in its early stages, their work could have a profound impact on treating certain cancers and other serious conditions where there is an imbalance in cell lipid metabolism, such as fatty liver disease.
A biochemist and molecular biologist, Osborne, who is also a Professor of Medicine and Biological Chemistry and member of the Division of Endocrinology, Diabetes and Metabolism of the Johns Hopkins University School of Medicine, focuses his research on the molecular aspects of genes and how they are expressed and regulated to maintain homeostasis in the body. One of his missions has been to unravel the biochemical, molecular and genetic secrets of metabolism — the process by which the body converts the foods we eat into energy and building blocks for storage and growth. One aspect of his research has been to gain a better understanding of metabolism to be able to develop more insight into metabolic disorders and, he hopes, find ways to prevent them.
What are SREBPs?
For several decades, Osborne has investigated “sterol regulatory element-binding proteins,” or SREBPs. “SREBPs regulate cellular metabolism to adapt to fluctuations in lipid availability and environmental challenges,” Osborne explains. “They are activated when cells need new lipid, and they regulate genes that encode for proteins needed to synthesize, utilize, and store fats and cholesterol in the cell.”
Over the last few years, studies have shown that lipid metabolism disorders can play an important role in cancer development and SREBPs can drive production of various fats (including cholesterol), which are growth limiting for many tumors.
Osborne and his co-researchers found that adding dipyridamole to cells worked to inhibit SREBPs and this starves the lipid-addicted tumor cells. Osborne noted that dipyridamole was already known to inhibit phosphodiesterases, enzymes also called PDEs but the inhibition of SREBP did not depend on the PDE inhibiting capacity of dipyridamole. They found that by modifying the chemical structure of dipyridamole they could remove its PDE-inhibiting activity without altering its ability to decrease SREBP activity.
“Prior to our work, the mechanism for how dipyridamole inhibits SREBP maturation and lipid synthesis was unclear,” Osborne explains.
The SREBP-SCAP pathway
SREBP cleavage activating protein, called “SCAP,” is a cellular escort protein for SREBPs, and it helps convert an inactive SREBP to its biologically active form. Dipyridamole targets SCAP to limit the activation of SREBP, which decreases production of cellular lipids.
“Compounds like dipyridamole that decrease SREBPs through altering SCAP present a potential therapeutic targeting strategy and an alternate chemotherapy for cancers that rely on lipids to accelerate tumor growth,” Osborne explains. “Unfortunately, long-term treatment with PDE inhibitors can result in significant weight loss and other side effects, but we were able to separate the effects of dipyridamole on PDE and SREBP by modifying its structure. This provides a starting point for a focused effort to discover derivatives of dipyridamole that inhibit the SREBP-SCAP pathway.”
Taken together, all of these biological interactive aspects, and the use of dipyridamole, add up to the potential for treating certain cancers, but without the side effects of other chemotherapies. The eventual therapeutic compound may also help those with other diseases where lipid metabolism is out of balance such as diabetes and non-alcoholic fatty liver disease.
“I’m very excited about the potential for improving this compound,” says study co-author Peter Espenshade, Ph.D., a professor in the Departments of Cell Biology and Oncology at the Johns Hopkins University School of Medicine in Baltimore. “It’s the first compound specific to the SCAP pathway, but much more chemistry needs to be done before it can make its way into the clinic.”
Collaboration and the future
Espenshade hopes that in not too many years their research will lead to clinical trials and eventually start making a big difference, not only in cancer treatment but also preventing conditions such as fatty liver disease that can accompany obesity, diabetes and cardiovascular disease.
Early in their careers, both Osborne and Espenshade worked in a laboratory at the University of Texas Southwest Medical Center under 1985 Nobel Prize winning researchers Michael Brown, M.D., and Joseph Goldstein, M.D., who continue to carry out ground-breaking research on the regulation of cholesterol metabolism.
They began working closely together when Osborne joined the Johns Hopkins faculty in 2018 and, in addition to publishing the current scientific paper, they jointly direct two research grants and one contract with a major pharmaceutical company. Despite the distance between the campuses, researchers at Johns Hopkins All Children’s Hospital in St. Petersburg, and their colleagues on the Baltimore-based Johns Hopkins campuses have a close working relationship.
“We are part of the same faculty, and it is vitally important to our research and the success of the St. Petersburg campus that we have strong interactions,” Osborne says.
Osborne and Espenshade and their colleagues are continuing their work with the objective of further developing a drug that can deprive cancers the fats they hunger for. That reality may be several years away and there is more work to be done before this “bench science” knowledge can be translated to the “bedside.” But the future looks bright.