Sirtris Finds Anti-Cancer Effect, Teams with NIH

Cambridge’s Sirtris Pharmaceuticals is known mainly for studying compounds like resveratrol that affect how the body uses insulin and may therefore have a role in treating metabolic disorders such as diabetes and obesity. But the company has always maintained that resveratrol-like compounds, which apparently work by boosting the activity of a gene called SIRT1, may also help to fight cancer. And this week the company has two pieces of news on the cancer front.

Firstly, John Lacey, Sirtris’s associate director of corporate communications, says that the company will present data next week in San Francisco showing that pushing SIRT1 to greater-than-normal activation levels can suppress tumor formation in an animal model that researchers use to study colon cancer. The as-yet-unpublished data was collected by David Sinclair, a Harvard Medical School pathologist and the company’s co-founder, and MIT biologist Leonard Guarente, the co-chair (and newest member) of Sirtris’s scientific advisory board.

Lacey, citing the Ingelfinger rule, declined to be more specific about which animal model Sinclair and Guarente studied, which compound they used to boost SIRT1 activation, or how great the anti-tumor effect was. (The Ingelfinger rule, named after Franz Ingelfinger, the editor of the New England Journal of Medicine from 1967 to 1977, says that researchers are disqualified from publishing their research in NEJM if the substance of it has already been reported elsewhere. Many other peer-reviewed journals have adopted the same stance, to the eternal frustration of journalists.)

But Lacey did say that the Sirtris study, which Sinclair will discuss on February 28 in a talk at the Gladstone Insitute at the University of California, San Francisco, is the first in which SIRT1 activation has been shown to deter cancer in vivo, that is, outside of a petri dish. And he said the effect was significant enough that Sirtris plans to launch a Phase Ib oncology trial of its SIRT1-activating compound or compounds in humans in the second half of 2008.

The study also represents the first time Sinclair and Guarente have collaborated since Guarente joined Sirtris’s scientific advisory board. As I recounted last November, the two researchers have a convoluted history together. Sinclair was a doctoral student in Guarente’s lab at MIT in the 1990s. He declined to join his mentor when Guarente launched Elixir Pharmaceuticals in 1999 to pursue drugs that might modulate SIRT1 and similar genes. Sinclair then co-founded Sirtris in 2004 to do the same thing. Elixir has since drifted away from its focus on SIRT1 activation and recently postponed its planned IPO; Guarente left the company and, after the expiration of a year-long non-compete agreement, joined the Sirtris advisory board.

Sirtris’s second piece of news is about an agreement to collaborate with the National Institute of Health’s National Cancer Institute (NCI) to study the anti-cancer effects of SRT501, the company’s proprietary formulation of resveratrol, and other unrelated compounds or “new chemical entities” that are reportedly much more powerful activators of SIRT1. Under a recently signed cooperative research and development agreement (CRADA), Peter Elliott, Sirtris’s senior vice president and head of development, will work with Thomas Sayers, a principal investigator at the NCI, to test Sirtris’s compounds on cell lines commonly used to study tumor development, as well as mouse models.

Under the agreement, NCI will foot the bill for the studies. Lacey says it’s not clear how long it will take for the collaboration to produce results. “The NCI is providing the financial resources for the study and the human resources, and we will be providing the new chemical entities and SRT501 as well as guidance in the study,” Lacey says. “In terms of the length of the study, there is no endpoint at this time. It is a study with multiple variables, so it could take some time.”

Elliott and Sayers have their own history together. A similar CRADA between Sayers’ lab at NCI and Cambridge’s Millennium Pharmaceuticals, where Elliott was vice president of pharmacology and development, led to the development of Velcade, a treatment for multiple myeloma and mantle cell lymphoma that is now Millennium’s premier drug product.

“I am proud to be teaming again with Tom Sayers,” Elliott said in a Sirtris press release announcing the agreement. “Several years ago Tom and I worked successfully together on the development of the anti-cancer drug Velcade, and now we are exploring an exciting new opportunity for targeting cancers using SIRT1 activators.”

NCI is interested in SRT501 and Sirtris’s other compounds because of the dearth of novel treatments for cancer, and because Sirtris’s early studies have shown that activating SIRT1 is a safe and promising approach, according to Lacey. “What we’ve seen from the Phase Ia and Ib studies that we’ve reported is that SRT501 is safe, and that it lowers insulin, which is proof of principle that the benefits of SIRT1 activation seem to be carried over to humans,” Lacey says. “And one of the things about the overexpression of SIRT1 in long-lived mouse models is that you do not see cancer in these animals. So that makes it an interesting potential therapy.”

Wade Roush is a contributing editor at Xconomy. Follow @wroush

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