Biotech Firms On Quest For Apoptotic Therapies

DECOY RECEPTORS: Genentech's Avi Ashkenazi suspects that using ligands to bind to decoy receptors present in healthy cells, but not in cancer cells, could trigger apoptosis in tumors. Scientists studying signal transduction have spent the past several years piecing together the cell's apoptotic machinery-the complex signaling mechanisms that tell damaged cells to commit suicide. The discovery of more signaling proteins and their receptors has given biotechnology companies potential tools to fix this machinery when it goes awry. The investment community has followed this search for drugs with interest because successful apoptotic agents could treat diseases like cancer with more specificity and fewer side effects. The apoptotic engine acts as a regulatory mechanism by allowing healthy cells to proliferate while encouraging damaged cells to kill themselves (R. Lewis, The Scientist, 9[3]:15, Feb. 6, 1995). Tumor cells proliferate when that engine fails to operate. Potential methods of repair include finding chemicals that target receptors to restore the apoptotic function in tumor cells, inducing apoptosis in a tumor's developing blood vessel, and imitating apoptosis through the introduction of engineered bacteria. Avi Ashkenazi, senior scientist in the department of molecular oncology at South San Francisco, Calif.-based Genentech Inc., is targeting receptors. He notes that the apoptotic engine is present in cancer cells but has a faulty starter switch. His lab seeks to exploit the differences between healthy cells and cancerous cells, using the apoptosis-initiating ligand Apo2L (also known as TRAIL, for tumor necrosis factor-related apoptosis-inducing ligand) to jump-start the apoptotic engine in tumor cells. In vitro experiments have demonstrated how this process might work. In healthy cells, two "decoy" receptors, DcR1 and DcR2, divert the ligand from death-inducing receptors DR4 and DR5, preventing the healthy cells from committing suicide (J.P. Sheridan et al., Science, 277:818-21, 1997; S.A. Marsters et al., Current Biology, 7:1003-6, 1997). Because cancer cells lack the apoptotic brakes that the decoy receptors provide healthy cells, the ligand binds directly to the death-inducing receptors, selectively initiating apoptosis in the cancer tissues. "These decoy receptors seem to be preferentially expressed in normal tissues, as opposed to cancer tissues, for reasons we don't yet understand," Ashkenazi says. Apo2L may serve as a good ignition switch for apoptosis in tumor cells because, unlike some other ligands, it doesn't cause an inflammatory response, which can be lethal. It also seems capable of inducing suicide in many different types of cancer cells, he adds. Cell Pathways Inc., a privately owned molecular oncology firm based in Horsham, Pa., also seeks to interfere with the apoptotic pathway by using its lead compound, FGN-1 (Ixosulin). FGN-1 induces apoptosis in precancerous tumor cells while avoiding inf lammation. The compound is a metabolic byproduct of sulindac (Clinoril), an anti-inflammatory drug used to treat arthritis. Whitehouse Station, N.J.-based Merck & Co. Inc. manufactures sulindac. Rifat Pamukcu, Cell Pathways' chief science officer, thought sulindac could also be an anti-cancer agent when he heard anecdotal reports that the compound seemed to suppress tumors in some patients. Epidemiological evidence lent credence to those reports. Studies showed that a sulfone metabolite of sulindac caused apoptosis independently of the mechanism that made the drug an effective anti-inflammatory agent (G.A. Piazza et al., Cancer Research, 57:2452-9, 1997). Cell Pathways scientists then isolated the metabolite, turned it into an anti-cancer candidate, and began clinical trials, after noting that the drug resulted in low toxicity in animal models. Results from Phase III clinical trials look promising, attests Gary A. Piazza, Cell Pathways' senior director of cell biology, who notes that FGN-1 showed signs of causing precancerous polyp regression in earlier phases of the drug's testing. STRUCTURE KEY: Harvard Medical School's Donald Ingber thinks that apoptosis can be induced by interfering with a cell's structure, in addition to its biochemistry. TNP-470, a drug from Deerfield, Ill.-based TAP Holdings (a joint venture of Abbott Park, Ill.-based Abbott Laboratories and Takeda Chemical Industries Ltd. of Osaka, Japan) is in late Phase II clinical trials. It seems to cause apoptosis through physio logical rather than biochemical means, according to Donald E. Ingber, an associate professor of pathology at Harvard Medical School and a research associate in surgery and pathology at Children's Hospital in Boston. The drug inhibits the growth of blood vessels, although its exact mechanism in humans remains unclear. But a group led by Ingber's colleague M. Judah Folkman, Julia Dyckman Andrus Professor of Pediatric Surgery at Harvard Medical School, showed that this drug causes the tumor cell's apoptotic rate to rise while not affecting the tumor cell growth rate in animal models. Ingber emphasizes that many researchers have overlooked physiological factors as triggers for apoptosis. He and colleagues have demonstrated in vitro that changing the shape of cultured endothelial cells-the flat, thin cells that line organs-can cause apoptosis (C.S. Chen et al., Science, 276:1425-8, 1997). Another anti-cancer drug also attacks blood vessels in tumors by inducing apoptosis in the endothelial cells, Ingber says. Ixsys Inc., a San Diego-based company, is wrapping up Phase I trials on Vitaxin (the humanized version of mouse antibody LM609). While Ingber suspects apoptosis is triggered because the antibody inhibits cellular adhesion, David A. Cheresh, a professor of immunology and vascular biology at the Scripps Research Institute in La Jolla, Calif., believes that the antibody acts biochemically by disrupting chemical signals between cells. Whatever the mechanism, the drug causes apoptosis in the tumor's growing network of blood vessels, while leaving existing blood vessels intact. "[This] therapeutic approach targets newly sprouting blood vessels and destroys tumors without actually binding to the tumor cells," Cheresh explains (S. Stromblad et al., Journal of Clinical Investigation, 98:426-33, 1996). In contrast to initiating apoptosis through signaling chemicals or by causing physical change in cells, the strategy of Onyx Pharmaceuticals Inc. in Richmond, Calif., relies on harnessing a virus to trigger a similar process, explains Allan Balmain, the company's vice president of research. Onyx scientists have engineered an adenovirus so that it will not bind to p53 protein, which is present in healthy cells. "Many tumor cells have no p53," Balmain says. The treatment, which involves a vaccine of the attenuated virus, is nearly through Phase II trials for head and neck tumors and is in Phase I trials for ovarian and pancreatic tumors and for colon tumors that have spread to the liver. "We inject the virus in very high concentrations into the tumor," Balmain says. He remarks that the tumor cell death caused by the vaccine resembles apoptosis: "Some of the same mechanisms are induced." However, the company's researchers have not pinpointed exactly which signaling pathways the virus triggers. LIMITING DAMAGE: LXR's L. David Tomei thinks that selectively inhibiting apoptosis can minimize heart damage from heart attacks and strokes as well as limit organ damage between removal and transplant. Another company, LXR Biotechnology Inc. in Richmond, Calif., seeks to harness those pathways to suppress apoptosis to treat heart disease, rather than to induce it to treat cancer, reports L. David Tomei, the company's chairman and chief executive officer. Selectively inhibiting apoptosis can minimize heart damage from heart attacks and strokes as well as limit organ damage between removal and transplant. One compound, Cardiosol (LXR029-1), entered Phase III trials this year for use in organ transplant. Cardiosol is a preservation solution based on a University of Wisconsin formulation with an additional anti-apoptotic polymer molecule related to polyethylene glycol. Cell Pathways, Inc. http://www.cellpathways.com Genentech Inc. http://www.gene.com/ LXR Biotechnology, Inc. http://www.lxr.com Idun Pharmaceuticals http://www.bio.org/memberprofile/welcome.dgw Onyx Pharmaceuticals, Inc. http://www.informagen.com/Sample7.html TAP Holdings http://www.tapholdings.com/angio/tnp470x.html Tomei adds that the process of devel-oping a related compound, Elirex (LXR015-2), differs from the more academic approach of isolating a pathway and targeting a receptor. Animal models show that Elirex limits coronary damage if injected after a heart attack. The compound contains both the anti-apoptotic polymer molecule in Cardiosol and an anti-apoptotic lipid derived from soy extract. Tomei and colleagues knew that soy extracts could suppress apoptotic death after gamma radiation in animal models and in cell cultures. They spent two years finding the molecule responsible, lysophosphatidic acid. They then identified and cloned the gene encoding the receptor for it. Finally, they identified likely signaling pathways and the genes regulated by them. "This is similar to 'reverse engineering' because a strictly molecular approach does little to tell the scientist whether the pathways and mechanisms will actually turn out to be important for therapeutics," Tomei states. "The process is so complicated, it's difficult to start at the molecular level and develop a useful therapeutic." However, Lawrence C. Fritz, executive vice president of research at Idun Pharmaceuticals of La Jolla, says there are advantages to starting at the molecular level. "We are doing a lot of rational designs of molecules rather than random screenings," he notes. The company doesn't have any compounds in trials yet, but it is focusing on small molecules that both inhibit and induce apoptosis selectively. Idun scientists are using genetics to identify specific targets. Right now, Fritz says, the researchers are focusing on caspases, because these cysteine proteases are essential executioners of the apoptotic pathway. He notes that they are good targets because of their key death functions. He adds that the fact that there are at least 10 different members of the family suggests that different enzymes play a role in different diseases. "There's opportunity for specificity-if you can figure out which one is important to a particular disease." Fritz also thinks the growth regulator Bcl-2 protein is an important target because its presence in tumors seems to prohibit apoptosis. "It's an Achilles heel of the tumor," he says. Even without a compound in trials, his company can stay competitive through this rational design strategy and its approach to intellectual property, Fritz maintains. Early in the company's history, Idun secured patent applications for some genes and gene targets. "We made some bets that certain targets would be important," he explains. IMPROVEMENTS WELCOME: Paine Webber's Stelios Papadopoulos reasons that apoptotic cancer therapy has a chance in the marketplace because many existing cancer treatments are relatively crude. TOUGH SELL: Burrill & Co.'s G. Steven Burrill notes that soliciting investment in apoptotic therapies can be difficult, since a marketable product still remains years away. The biotechnology industry's search for more specific, less toxic therapeutic approaches to cancer and other diseases has piqued cautious interest in the investment community, notes Stelios Papadopoulos, managing director and head of the health care investment banking group at Paine Webber Inc. in New York. From an investment standpoint, one factor affecting the fortunes of companies that are developing apoptotic cancer therapies is the relatively crude cancer treatments now in use, he comments. "From a business point of view, you don't need an incredibly potent, thoroughly nontoxic drug," he notes. "All you need is something that is a little better than what's out there today." By way of example, Papadopoulos observes that the breast cancer drug taxol-not an apoptotic agent-is "not a perfect drug." Yet taxol approached worldwide sales of $1 billion last year. While Papadopoulos remarks that therapies to induce apoptosis in tumor cells won't be "a magic cure," he does think the approach is worth pursuing. "I think it's progress, and I think there will be some good drugs out of it." G. Steven Burrill of Burrill & Co. Inc., a private merchant bank in San Francisco, notes that because clinical apoptosis research is still young, soliciting investment can be "a tough sell." Still, he adds, "I think there's a lot of investor interest." Ashkenazi, too, cautions against too much optimism in the field, since no therapy has yet completed Phase III trials. "The idea of en-gaging cell death receptors as a means of inducing apoptosis has yet to be demonstrated in the clinic," he says. Fortunately, he points out, multiple pathways to apoptosis mean that different approaches exist. And a stream of findings reporting new receptors means there may be many viable targets.

Biotech Firms On Quest For Apoptotic Therapies

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