A multi-disciplinary team of Yale Cancer Center researchers has discovered a promising new method for delivering drugs into aggressive tumors by exploiting a unique feature of tumors themselves. The novel delivery system, described in MicroRNA silencing for cancer therapy targeted to the tumour microenvironment,was published November 17th in the journal Nature.
The project, involving four Yale labs, a dozen scientists, and pilot funding from Yale Cancer Center, built upon ten years of research at Yale and elsewhere into the role microRNAs play in the development and spread of cancer. Leading the project were Frank J. Slack, PhD; Chris Cheng, PhD; W. Mark Saltzman, PhD; Donald M. Engelman, PhD; and Peter M. Glazer, MD, PhD.
The foundation of the work was an earlier nanoparticle delivery system developed by Saltzman, Slack, and Cheng to treat lymphomas in mice genetically engineered in Slack’s lab. That early work showed that novel delivery systems could slow down the progress of aggressive lymphoma. The next step was to improve the delivery system by incorporating discoveries from Engleman’s lab in pHLIP peptides delivering biological agents to aggressive disseminated tumors, and work by Raman Bahal, PhD, in Glazer’s lab in designing and synthesizing DNA analogs for gene and cancer therapy.
“This opens up a new pathway to gene therapy, not just for treatment of cancer but for a host of other diseases as well,” said Yale’s Donald Engelman, a co-author of the paper.
MicroRNAs may be tiny – as few as 20 genetic letters compared to 3 billion in the DNA of a human – but they play a major role in biology, helping determine which genes are expressed or silenced. However, their potential as a cancer therapy has not been realized because of a daunting problem that has held back clinical applications of gene therapy: How can you target a minute piece of genetic material locked safely in nuclear membranes of billions of cells? The team may have solved the problem by designing an even better therapeutic molecule that both penetrates cells and targets the acidic microenvironments of tumors. The new delivery system effectively killed advanced tumors in mice.
“This project is a demonstration of the highly collaborative and interdisciplinary environment at Yale. Faculty members from four Yale departments contributed their expertise and laboratory resources to make it happen,” said Saltzman, a co-author. “The project could not have succeeded without the active participation of all four groups, and the success is a great indicator of the strength of the collaborative environment at Yale.”
The project was supported by a Yale Cancer Center award for collaborative research with a significant translational or clinical component, with the express purpose of developing multi-investigator grant submissions.
Slack, the paper’s senior author is director for the Institute for RNA Medicine in the Cancer Center at Beth Israel Deaconess Medical Center. First author Cheng is with Alexion Pharmaceuticals.
At Yale, Saltzman is the Goizueta Foundation Professor of Biomedical Engineering, Chemical & Environmental Engineering & Physiology; chair of the Department of Biomedical Engineering.
Engelman is the Eugene Higgins Professor of Molecular Biophysics and Biochemistry; and Glazer is Robert E. Hunter Professor of Therapeutic Radiology and Professor of Genetics, and chair of the Department of Therapeutic Radiology.
Yale Cancer Center (YCC) is one of only 41 National Cancer Institute (NCI)-designated comprehensive cancer centers in the nation and the only such center in Connecticut. Comprehensive cancer centers play a vital role in the advancement of the NCI’s goal of reducing morbidity and mortality from cancer through scientific research, cancer prevention, and innovative cancer treatment. www.yalecancercenter.org