A group of Yale researchers has identified a novel delivery method to suppress cancer-causing molecules and reduce tumors, with potential applications to other diseases.
In a study published on Nov. 17 in the journal Nature, the Yale team targeted tumors by utilizing their acidity. They developed a peptide structure (pHLIP) that could be bound to an anti-micro RNA molecule. An anti-micro RNA is the mirror image of a corresponding micro RNA, which it binds to using base pairing. That binding dynamic is similar to the lock and key dynamic of enzymes and substrates. But instead of the enzyme breaking down the substrate, the anti-micro RNA inactivates the micro RNA. Micro RNAs are key in gene regulation because they can silence the expression of genes. The researchers used a mouse model for cancer in which a particular micro RNA was the predominant driver of tumor formation.
“We have a viable strategy for delivering therapeutic agents with high specificity to the tumors themselves rather than the healthy tissue,” said study senior author and Yale genetics professor Peter Glazer MED ’87 GRD ’87. “And this specificity is based on the acidic environment that is found in tumors.”
That increased specificity allowed the researchers to bypass non-tumor cells, leading to fewer side effects than occur in other treatments like chemotherapy.
According to the study’s senior author and professor of chemical and biomedical engineering Mark Saltzman, the peptide pHLIP was also able to overcome many barriers to delivery into cells that previous micro RNA cancer treatments had faced.
“One problem with many delivery systems used in treating cancer is that they go to other places other than the tumor,” he said. “And we clearly showed that these constructs don’t go to the liver, spleen, bone marrow or other places that cause common side-effects to chemotherapy.”
Glazer said that most current cancer treatments have narrow therapeutic indices — the drug dosage that simultaneously achieves anti-cancer effects and tolerable side effects.
He explained that the anti-micro RNA the researchers use — anti-micro RNA 155 — works well because it has two levels of specificity. First, it only enters into cells that have low pH levels. Second, it silences a micro RNA that is only elevated in tumor cells and is not elevated in healthy tissues. The latter is important because, even if the treatment makes its way into healthy cells, there would be few adverse effects, as there are fewer of that specific micro RNA to bind with.
This work could be applied to many different types of cancer, not just lymphoma, Glazer said. He noted that pHLIP could be used to target other micro RNAs, depending on the type of cancer. Theoretically, researchers could develop many anti-micro RNAs to attach to pHLIP for delivery into tumors.
“One of the important biological lessons from the paper is that if you can deliver anti micro RNAs effectively to tumors, that this might be a new important therapy,” Saltzman said. “The power is that it is generalized. We’ve targeted a very general aspect of tumor physiology, the fact that they become slightly acidic because of how they grow, so the targeting part should work in any tumor that becomes acidic, and many do.”
This project was years in the making and involved a collaborative, multi-disciplinary effort. Four labs across four departments at Yale contributed to the paper.
“There was a lot of intellectual synergism in the group enterprise because people were coming at the problem from different directions, and we learned from each other and got this project accomplished in a way that none of our individual labs could have done on our own,” Glazer said.
Saltzman also credited the Yale Cancer Center for providing vital support on the project.
“Micro RNA is an extremely exciting topic. It’s basically a new field in the last ten years,” said Associate Director of the Yale Cancer Center and Professor of Pharmacology Roy Herbst ’84. He added that the Yale Cancer Center is currently working on applying micro RNA treatments to breast cancer and lung cancer. “The biggest problem with micro RNAs has been how to deliver them. Once you deliver them, the ability to turn off or on the critical processes that are driving a cancer cell are phenomenal.”
Saltzman’s lab specializes in nanoparticle drug delivery methods. The lab will be applying that approach to continue the project. He said his lab is currently working on putting pHLIP on the surface of nanoparticles that are loaded with anti-micro RNAs. This would allow each nano particle to deliver many anti-micro RNA compounds that could also be slowly released into the tumor site, possibly making the effect of the drug more durable.
Glazer said that his lab and Donald Engelmann GRD ’67 are working to improve pHLIP, in collaboration with Carnegie Mellon chemistry professor Danith Ly, before moving to testing in humans.
According to the Centers for Disease Control and Prevention, cancer is the second leading cause of death in the United States.