ddn Cancer Research Portal Exclusive: Flying in the face of convention

Mount Sinai Drosophila research leads to multi-target cancer treatment

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NEW YORK—Some of the latest research from the Mount SinaiSchool of Medicine has resulted in the creation of a new avenue of approach indiscovering cancer treatments. Based off of a cancer model built in Drosophilafruit flies, researchers developed an investigational compound, AD80, that canprecisely target multiple cancer genes. The study, "Chemical genetic discoveryof targets and anti-targets for cancer polypharmacology," was published in Nature.
Polypharmacology describes the emerging focus onmulti-target drugs as a new model for drug discovery, a divergence from thecurrent approach in which a drug targets a single gene or protein. Some drugsend up being polypharmacologic by happenstance, targeting more than one genealmost as a side effect, but according to Ross L. Cagan, Ph.D., professor andassociate dean at Mount Sinai School of Medicine, drugs created through 'rationalpolypharmacology,' intentionally targeting multiple genes, have yet to hit themarket.
"Many successful drugs now in the marketplace have, bychance, wound up hitting several tumor targets, which is probably why theywork," Cagan, who is senior author on the study, said in a press release. "Theintention of our research was to hit multiple targets purposefully. By usingfruit fly genetics, we identified, step-by-step, the targets we needed. To myknowledge, this has never been done before. It's also a cost effective modeland my prediction is there is going to be more emphasis on whole-animalpolypharmacology approaches in cancer drug research in the future."
Rather than taking the typical tack of using human tumorcell lines to screen for a single-target anticancer drug, Cagan, along withco-authors Tirtha Das, Ph.D., from Mount Sinai and collaborators Arvin Dar,Ph.D., and Kevan Shokat, Ph.D., from the University of California, SanFrancisco, instead used fly cancer models to screen a large chemical libraryfor novel drug leads that could shrink tumors. Following that, the team thencombined classic fly genetic tools with chemical modeling to developsecond-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 humansand flies," and flies offer the ability to "screen drugs in the whole-animalsetting in a genetically complex model…cheaply and quickly."
The researchers began working with Ret, the kinase thatdrives growth in medullary thyroid tumors in people whose Ret has acancer-activating mutation. A cancer form of Ret was engineered into the flies,which grew tumors wherever it was expressed, allowing the team to test drugsagainst the tumors for effectiveness. Specific targeting was necessary, sinceRet has many normal cellular roles and a complete shut-down would lead totoxicity.
The team's lead drug, AD57, was found to suppress several ofthe cancer signals that emerge from Ret, signals that include well-known cancerproteins such as Raf, Src and Tor. In addition, AD57 did not shut down thekinase entirely. The researchers then worked to improve the compound bymanipulating genes in the presence of the original drug hit, a completely newprocess that led them to discover that lowering the amount of Raf signaling inthe presence of AD57 caused the drug to be even more effective. Raf was markedas a target, while Tor, which increased toxicity when reduced, was marked as an"anti-target," another new concept. Based on those discoveries, a derivative ofAD57 was developed, AD80.
AD80 ended up performing 500 times better on human celllines 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 thesame cancer type.
The approach has potential with a variety of other targetsand diseases, Cagan notes, and other potential targets include inhibitors ofmetabolic pathways, proteasome inhibitors and inhibitors of chromatinremodeling.
"There are a number of receptor tyrosine kinases that havebeen pinned to cancer and other diseases … and in principle, this approach canbe used for any of those," says Cagan. "And I'll broaden that out and saythere's nothing special about kinases, it was just an easier set of things forus to look at…but in principle, and in fact in reality, since we're actuallydoing this, our approach can identify drugs outside those that attack thekinome. This approach of using fly genetics to look at a variety of pathways isreally 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 withthis approach, Cagan says. They are looking at other Ret-based tumors todetermine whether AD80 still represents the best drug for those Ret isoforms,and the team is also examining the viability of utilizing this approach intargets such as EGF receptor. In addition, they will also look at usingDrosophila to examine existing drugs and identify improved versions, anundertaking Cagan says he is very excited about. Cagan and his colleagues willalso 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 polypharmacologydrugs."
"We've come up with one drug that hits multiple targetsthrough 'rational polypharmacology,' and our approach represents a new conceptwe believe will have great success in suppressing tumors," said Cagan in apress release. "Scientists are beginning to recognize that single-target drugscan be problematic. I believe that, within the next five years, we'll see moredrugs entering clinical trials that use rational polypharmacology as the basisof drug discovery."

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