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NEWS 950 VOLUME 19 | NUMBER 8 | AUGUST 2013 NATURE MEDICINE Uncommon ventures launch to tackle uncommon diseases CAMBRIDGE, MASSACHUSETTS — It’s been three days since Cristina Csimma moved into her company’s first office space, and already she is planning to relocate. The cofounder and chief executive of Cydan Development, the first drug accelerator focused on advancing therapies for rare diseases, points from a top floor conference room across the tree-lined courtyard outside to her company’s future home at 700 Technology Square. “The space is very long and thin,” Csimma says of what will become Cydan’s new headquarters toward the end of September. “I call it Chile.” For Csimma, the dimensions of the physical space the company will move into matter less than the location. “What’s important is being in a biotech and university hub in Tech Square,” she says. Her hope is to take advantage of the local drug-development know-how—as well as biomedical expertise from around the world—to rapidly generate a handful of promising start-ups in the orphan disease space, as well as to equip those nascent firms from the get-go with drug candidates with a high degree of clinical—and financial—success, all in an economically efficient manner. Recent advances in the understanding of the molecular underpinnings of rare diseases, including genetic targets, as well as a large unmet need in the patient population has made this area of medicine enticing for investors and researchers. The orphan drug market “is the new big thing,” says Christopher-Paul Milne, director of research at the Tufts Center for the Study of Drug Development in Boston. “It’s an area end result is the same, some RAS mutations can produce different patient outcomes and respond differently to therapies. “There are all kinds of totally unexpected, weird clinical observations that we don’t understand,” says McCormick. Misconceptions about this variation in Ras proteins have been the downfall of potential therapies in the past. White believes the field has learned its lessons: “We have come to a state of much more sophisticated ignorance.” Most experts agree that targeting Ras directly would be ideal, but it will require more creativity and focus on individual mutations. “Not all RAS genes are created equal, and, furthermore, not all Ras mutations are created equal,” says Der. “At the end of the day, it is possible that we may need not only isoform specific therapies but also mutation- targeted therapies.” New developments in the field suggest it is possible. At the Frontiers in Medicinal Chemistry meeting in San Francisco in June, UCSF chemist Kevan Shokat presented his discovery of a new small molecule that binds a specific K-Ras mutant present in melanomas. Meanwhile, chemist Greg Verdine, who last month took a leave of absence from Harvard University in Cambridge, Massachusetts, to lead a new startup company called Warp Drive Bio, has developed a technique called peptide stapling to bind mini-proteins to block K-Ras across the board. The NCI program aims to bring researchers like Shokat and Verdine to the same table and create a “Ras community,” McCormick says. That community will probably include industry players as well. Representatives from Genentech, Plexxikon and AstraZeneca, along with academic researchers, attended a workshop on the NCI project back in February. “There will certainly be interest in any new candidate drug targets that emerge from these projects,” says Jeff Settleman, senior director of discovery oncology at Genentech, which is based in South San Francisco. New pockets Within the past two years, many pharmaceutical companies, including Genentech, have restarted their Ras programs. Some researchers have even discovered potential pockets. The NCI hopes that a concerted effort that would bring researchers from disparate ends of the Ras field together will drive the innovation needed to produce a targeted drug, and many in the field agree. “We definitely have more tools, know much more, are smarter, than when a Ras- focused effort was made decades ago,” says Der. “I’m hoping...that we can potentially get some ideas from left field out there.” The Ras program will focus on five new projects. The first project will develop compounds that could target four common RAS mutants prominent in pancreatic, lung and colorectal cancers, although there’s some debate over whether these mutants behave the same way in different cancers. The second project will search for compounds that selectively target K-Ras—by far the most powerful driver of cancer among the Ras proteins. For example, a recent study from researchers in Germany showed that a small molecule called deltarasin prevents K-Ras from locking onto a protein called PDEδ that helps it interact with the cell membrane. In turn, the drug reduced tumor growth in mice (Nature 497, 638–642, 2013). McCormick’s own research suggests that K-Ras binds itself to make a dimer molecule—and blocking the formation of this self-binding and other K-Ras complexes will be the third goal of the NCI initiative. The fourth aim will be mapping the surface of K-Ras– mutated cancer cells to learn their protein composition and inform potential downstream targets using tools such as mass spectrometry and bioinformatics. The fifth and final project uses novel screening methods that prey on collateral damage in tumor cells in animal models and three- dimensional models of cells and tissues to test potential therapies. The projects address some of the major questions in the field of Ras research: whether to target Ras directly or indirectly, which arms of the Ras pathway are the most important, and whether to target specific mutants or isoforms. “I think if somebody’s going to make something happen, this is the way to do it—bring together diverse expertise at the right time,” says White. Many drugs that target Ras indirectly— particularly through the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways—have already made it to clinical testing. For example, MEK162, co-developed by Novartis and Array BioPharma, has shown activity in N-Ras– mutated melanoma. But, targeting one arm of the Ras monster alone has proven inefficient in fighting Ras-driven tumors, so combination trials may provide a short-term solution. MEK162 is in phase 1b/2 clinical trials by itself and with other agents. The NCI hopes to have the program up and running by the beginning of the next budget cycle in October. Meanwhile, the Ras community is cautiously optimistic. Channing Der compares tackling Ras to climbing Mount Everest: “We’ve got to climb it, even though it’s tough.” Helen Thompson npg © 2013 Nature America, Inc. All rights reserved.
