ddn Cancer Research Portal Exclusive: Flying in the face of convention
NEW YORK—Some of the latest research from the Mount Sinai School of Medicine has resulted in the creation of a new avenue of approach in discovering cancer treatments. Based off of a cancer model built in Drosophila fruit flies, researchers developed an investigational compound, AD80, that can precisely target multiple cancer genes. The study, "Chemical genetic discovery of targets and anti-targets for cancer polypharmacology," was published in Nature.
Polypharmacology describes the emerging focus on multi-target drugs as a new model for drug discovery, a divergence from the current approach in which a drug targets a single gene or protein. Some drugs end up being polypharmacologic by happenstance, targeting more than one gene almost as a side effect, but according to Ross L. Cagan, Ph.D., professor and associate dean at Mount Sinai School of Medicine, drugs created through 'rational polypharmacology,' intentionally targeting multiple genes, have yet to hit the market.
"Many successful drugs now in the marketplace have, by chance, wound up hitting several tumor targets, which is probably why they work," Cagan, who is senior author on the study, said in a press release. "The intention of our research was to hit multiple targets purposefully. By using fruit fly genetics, we identified, step-by-step, the targets we needed. To my knowledge, this has never been done before. It's also a cost effective model and my prediction is there is going to be more emphasis on whole-animal polypharmacology approaches in cancer drug research in the future."
Rather than taking the typical tack of using human tumor cell lines to screen for a single-target anticancer drug, Cagan, along with co-authors Tirtha Das, Ph.D., from Mount Sinai and collaborators Arvin Dar, Ph.D., and Kevan Shokat, Ph.D., from the University of California, San Francisco, instead used fly cancer models to screen a large chemical library for novel drug leads that could shrink tumors. Following that, the team then combined classic fly genetic tools with chemical modeling to develop second-generation drugs with better specificity.
Fruit flies are useful for this work, Cagan notes, because "the basic core signaling pathways have been highly conserved between humans and flies," and flies offer the ability to "screen drugs in the whole-animal setting in a genetically complex model… cheaply and quickly."
The researchers began working with Ret, the kinase that drives growth in medullary thyroid tumors in people whose Ret has a cancer-activating mutation. A cancer form of Ret was engineered into the flies, which grew tumors wherever it was expressed, allowing the team to test drugs against the tumors for effectiveness. Specific targeting was necessary, since Ret has many normal cellular roles and a complete shut-down would lead to toxicity.
The team's lead drug, AD57, was found to suppress several of the cancer signals that emerge from Ret, signals that include well-known cancer proteins such as Raf, Src and Tor. In addition, AD57 did not shut down the kinase entirely. The researchers then worked to improve the compound by manipulating genes in the presence of the original drug hit, a completely new process that led them to discover that lowering the amount of Raf signaling in the presence of AD57 caused the drug to be even more effective. Raf was marked as a target, while Tor, which increased toxicity when reduced, was marked as an "anti-target," another new concept. Based on those discoveries, a derivative of AD57 was developed, AD80.
AD80 ended up performing 500 times better on human cell lines when tested in mice models, and markedly better in terms of toxicity, than a recent drug approved by the U.S. Food and Drug Administration for the same cancer type.
The approach has potential with a variety of other targets and diseases, Cagan notes, and other potential targets include inhibitors of metabolic pathways, proteasome inhibitors and inhibitors of chromatin remodeling.
"There are a number of receptor tyrosine kinases that have been pinned to cancer and other diseases … and in principle, this approach can be used for any of those," says Cagan. "And I'll broaden that out and say there's nothing special about kinases, it was just an easier set of things for us to look at…but in principle, and in fact in reality, since we're actually doing this, our approach can identify drugs outside those that attack the kinome. This approach of using fly genetics to look at a variety of pathways is really not pinned to any class of drugs or any class of targets. In principle, it could be used for anything that is conserved between flies and man."
The researchers will be doing a great deal more work with this approach, Cagan says. They are looking at other Ret-based tumors to determine whether AD80 still represents the best drug for those Ret isoforms, and the team is also examining the viability of utilizing this approach in targets such as EGF receptor. In addition, they will also look at using Drosophila to examine existing drugs and identify improved versions, an undertaking Cagan says he is very excited about. Cagan and his colleagues will also look at this approach in more major diseases, such as breast cancer, colorectal cancer and lung cancer, which represent more complicated diseases. The team will use Drosophila "to build really complex models of [the diseases], really multi-genic models, to complement our approach for polypharmacology drugs."
"We've come up with one drug that hits multiple targets through 'rational polypharmacology,' and our approach represents a new concept we believe will have great success in suppressing tumors," said Cagan in a press release. "Scientists are beginning to recognize that single-target drugs can be problematic. I believe that, within the next five years, we'll see more drugs entering clinical trials that use rational polypharmacology as the basis of drug discovery."