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Preclinically, Saridegib Shows Promise for Medulloblastoma

By Anette Breindl
Science Editor

The Sonic Hedgehog pathway is a critical developmental pathway that is reactivated in a number of cancers. Results with targeting the pathway to treat cancers have been mixed, as drug development is wont to be. But the successes have been enough to keep trying.

Roche AG unit Genentech Inc.'s and Curis Inc.'s hedgehog inhibitor Erivedge (vismodegib) was approved in January for advanced basal cell carcinoma, after previously failing in colorectal and ovarian cancer. (See BioWorld Today, Jan. 31, 2012.)

Infinity Pharmaceuticals Inc.'s saridegib (IPI-926) has also had some setbacks. The company halted the drug's development in pancreatic cancer following a recent Phase II failure in that indication. (See BioWorld Today, Jan. 30, 2012.)

But saridegib remains in Phase II trials for both chondrosarcoma, a cancer of the cartilage, and the bone marrow disorder myelofibrosis. And scientists at the Fred Hutchinson Cancer Research Center have tested saridegib in a mouse model of medulloblastoma.

In those experiments, they were pleased both with what they saw – and with what they didn't, namely, the rapid resistance via de novo mutations that bedevils many targeted therapies.

That's not to say that the drug was able to cure the mice. Ultimately, treated animals, too, succumbed to medulloblastoma.

But in the meantime, they lived five times as long as untreated controls did. And to the study's authors, their ultimate death is no reason to declare defeat.

"Eventually, cancers will escape almost any single agent," James Olson told BioWorld Today. And so the recurrences that his team did eventually see were "not surprising or disheartening – it's what you expect with single-agent therapy . . . Cancers are simply too evolutionary to think that we can eradicate them with a single agent – stated with appreciation for the few exceptions we've seen."

Olson is a researcher at the Fred Hutchinson Cancer Research Center and the senior author of the paper describing the findings, which were published in the April 30, 2012, online edition of the Proceedings of the National Academy of Sciences (PNAS).

Olson also is a clinical oncologist. "I take care of kids with brain tumors every week," he said. And that second hat affects the way he wears his first.

For one thing, his team is highly focused on getting to clinical trials as their ultimate goal. "We have a vested interest in not moving things forward just to get the next manuscript or the next grant." Unpromising studies are quickly abandoned.

Olson also places a high priority on "making sure that we do our studies in relevant animal models." The model his team used for the studies now published in PNAS, he said, is one such example. The mice lack the Patched gene, which "encodes the protein that puts the brakes on the Sonic Hedgehog pathway."

In the medulloblastoma mice, that lack of Patched translates into "very advanced, very aggressive tumors" to test Saridegib's mettle, Olson said. "The animals' skulls are bulging from the tumors' aggression."

Especially given those tumor characteristics, the team's results were encouraging – and in some cases, unprecedented.

After six weeks of treatment with saridegib, all of the treated animals survived, while none of their untreated brethren did. And when animals continued lower-dose maintenance treatment after those six weeks, their median survival was quintupled. Olson said that among the dozens of drugs his team has worked with, "we have never worked with a drug that extended survival fivefold."

To top it off, in many animals, treatment with saridegib beat back the tumor to an extent that allowed treated mice to recover functionally. Olson said that many treated animals "went from being neurologically damaged to being just about indistinguishable from their littermates that did not have cancer."

Infinity is not currently pursuing any additional preclinical work or pursuing a clinical trial in medulloblastoma. But to Olson, that fact is not at odds with his continuing to work on the compound.

"For our team, this is a pretty straightforward opportunity to do some key additional experiments and watch how things evolve in the clinical arena. For example, if the Novartis or Genentech drugs [LDE-225, LEQ-506, and Erivedge] provide long term event-free survival benefit, there may be little reason to move the Infinity agent forward in medulloblastoma," he said.

"If on the other hand, patients rapidly develop resistance to the currently studied agents, there may be an opportunity to help patients further by evaluating the Infinity drug, with their permission, through cooperative mechanisms."