Aveo’s Better Mousetraps for Cancer Drugs

Oncology researchers are fond of saying that if you’re a mouse with cancer, they’ve found drugs that can cure you. Scientists at Cambridge-based Aveo Pharmaceuticals have even better news: They’ve developed mice with tumors that don’t always respond well to anticancer drugs. That heralds an important advance because it means that cancers in Aveo’s bioengineered rodents act much as they do in people. As more realistic models for testing new drugs, the mice promise to speed the quest for potent, precision-targeted weapons against specific kinds of tumors.

One of the biggest problems in cancer research is that standard “xenograft” models of the disease, in which human tumors are implanted in mice, usually lead drug developers astray. The cultured cells used for xenografts typically have evolved while in storage, losing their close likeness to real human cancers. What’s more, tumor cells normally draw strength from their surroundings, milking growth factors and nutrients from nearby cells to abet their runaway growth. Parted from these helpers and placed in such alien surroundings as skin-implanted xenografts, the cells develop traits that are radically different from those seen in human cancers. No wonder fewer than one in ten drugs that work wonders in mouse studies ultimately reach the market.

Closely-held Aveo has gathered some of the biggest names in cancer research to solve this problem: its scientific advisers include Ronald DePinho and Lynda Chin at Boston’s Dana-Farber Cancer Institute, Raju Kucherlapati at Harvard Medical School, Douglas Hanahan at the University of California at San Francisco, and Tyler Jacks, who directs MIT’s Center for Cancer Research. Under CEO Tuan Ha-Ngoc, an industry veteran who earned his biotech stripes as an executive vice president at Genetics Institute, it has raised over $100 million since its formation in 2002—a hefty sum for an early-stage biotech these days—and cut deals with the likes of Merck and Schering-Plough. Its Series D financing round last May, which raised $53 million, included a who’s who of backers.

To build its better mousetraps for cancer drugs, Aveo begins by planting tumor-initiating gene glitches in cells of embryonic mice—an example is a mutated form of a gene called EGFR that’s known to trigger various kinds of cancer. Further genetic trickery renders these genetic time bombs inactive during the rodents’ early development. To recapitulate what happens in human cancers, the deadly genes are switched on in later life in desired organs. When activated, they spawn human-like tumors that spontaneously evolve the same kinds of additional mutations human cancers do as they progress. Thus, Aveo’s models can mimic different subtypes of cancer emerging at different stages of the disease—an invaluable aid in developing drugs that work like precisely timed smart bombs instead of randomly fired nukes.

For its breast-cancer model, Aveo also employs a trick pioneered by Charlotte Kuperwasser at Tufts University School of Medicine in Boston: Implanting human “stromal” cells—which tumor cells normally harness to supply nutrients and other growth aids—along with tumor-generating cells. Under the microscope, says Kuperwasser, an Aveo adviser, the resulting rodent cancers “beautifully” mimic the appearance of breast tumors in human patients.

Ha-Ngoc cautions that proving the value of Aveo’s mouse models will require showing that they can lead to useful predictions about the way novel anticancer drugs will work in people. The proof may come soon: Aveo is pressing its models into use to guide in-house drug development. One of its new medicines blocks hepatocyte growth factor, a signaling molecule that helps drive the growth of various cancers. Aveo, co-developing the drug with Schering-Plough, plans to use its mouse models to pinpoint sets of cancer patients mostly likely to respond to the drug before testing it in people. If successful, that would represent a major first, potentially saving hundreds of millions of dollars that would otherwise be spent on clinical trials that go nowhere.

Aveo also hopes to accelerate the discovery of new drug combinations. A test case involves its development of a novel “anti-angiogenesis” drug, which blocks formation of new blood vessels that feed tumor growth. Aveo has licensed rights to the drug outside Asia from Japan’s Kirin Brewery, which despite its name has long been a major player in pharmaceuticals, agribusiness, and other sectors. The drug promises to work well when combined with existing chemotherapy drugs; Aveo’s models promise to show which combinations are likely to yield good results, as well as which tumor types to attack with them.

“Everyone in cancer research is going after smart bombs,” says Ha-Ngoc. “But you really need guidance systems to do that. That’s what we’re creating.”

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