Into the Future

One spring morning in the year 2025, Joe Smith might be tending the begonias when the computer on his wrist receives a message from the gene chip under his skin. The 78-year-old Smith's colorectal cancer is in remission, but its potential to genetically mutate is monitored by the biochip, which is spotted with thousands of molecular markers that bind to DNA fragments containing colon cancer's many known mutations. When blood carrying such DNA comes into contact with the chip, resultant binding sets off a signal sensed by the computer, which buzzes and glows a warning to its wearer. At the clinic, Smith's physician injects a functional imaging system directly into a small tumor on Smith's colon. In real time, this micro-machine monitors the biochemical effects of his drugs and his anatomical condition. The doctor then turns to her medicines, which reflect a stratification of colorectal malignancies into numerous distinct cancers, based on molecular lesions identified in biopsies of hundreds of tumor types. Her armamentarium is more necessary than ever in 2025, as aging global populations have precipitated an explosion in cancer compared to two decades earlier. But on the bright side, the physician can match the pattern of genes turned on and off in Smith's particular colon cancer with a drug specifically designed for such tumor profiles. Delivered in polymer nanoparticles, these small-molecule drugs bind to mutated receptors of proteins that regulate survival and proliferation of cancer cells. Also at the doctor's disposal are retooled biologics, including immunotherapeutic agents such as monoclonal antibodies, and vaccines that use tumor-specific antigens. Having determined that her patient's colon cancer has mutated into a new subcategory, she selects a medication that now matches his tumor profile, promising quick and painless results. Of course, the details of such treatments might change over the long journey from here to there, but this is the general thrust of the push toward personalized medicine. Even implanted gene chips may eventually be achievable, declares Karol Sikora, former chief of the World Health Organization's Cancer Program, who currently is adviser on cancer services for the London private hospital group HCA International. "It's all to do with the coming together of digital telephone technology, bioinformatics, and genetics," he says. "Everybody would be better off if we could tell which patients would benefit from different levels of therapy. That's the five- to 10-year goal. In the long term, based on knowing which drugs would be best, we could select from 100 different drugs on the shelves." Sikora, who headed global clinical programs in oncology for two major pharmaceutical companies in recent years, thinks that future achievements in cancer medicine will spring from yet-unknown technological breakthroughs, just as PCR opened the door to many advances, including the DNA microarray. He also believes that new developments--including the identification of biomarkers that accurately and reliably quantify the effects of drugs on their targets--will change the entire drug approval process. Phase I clinical trials will measure biomarker levels in healthy patients as pharmacodynamic endpoints of drug response, and Phase II studies will be much shortened through the use of these surrogates, Sikora thinks. He even postulates that the costly, randomized trials of Phase III could be eliminated when mechanisms of action are well-known and comparisons are made between old and new compounds of the same class, using biomarker endpoints. PROFILING BEGINS Tumor profiling already has begun to subcategorize cancers, says Charles Nicolette, director of antigen discovery at Genzyme Corp. in Cambridge, Mass. He believes that in the short term, gene expression patterns will be used to confirm diagnoses made with traditional markers such as proliferative index, morphology, and invasiveness. "One of the realizations coming out of the analyses being done now--and these are first-generation studies--is an appreciation that breast cancer, for example, is not one disease." Genzyme's efforts encompass both the identification of novel markers and the pursuit of new vaccines based on immune response. "We're generating quite a lot of data on a number of antigens not described before," says Nicolette. "These are targets of the immune system in a natural setting, we're not rigging anything." The method involves resecting tumors to clone immune cells found in them, including cytotoxic T cells. Through functional genomics, the researchers then can identify immunogenic antigens recognized by the T cell clones. Such antigens could be used to develop vaccines comprising a mixture of altered peptides that can activate T cells to lyse cancer cells much more effectively than the native epitopes could do. Nicolette says the potentially most useful antigens are proving to be broadly expressed across a range of independent tumors. In contrast to Nicolette's enthusiasm, University of Arizona medicinal chemistry professor Laurence Hurley doesn't hold great hope for vaccines in coming decades. "It's my prediction that small molecules will continue to play the major role in the treatment of cancer," says Hurley, who is also codirector of the National Foundation for Cancer Research (NFCR) Center for New Therapies Development. He thinks that most biologic approaches such as vaccines, antisense, and RNA interference will continue to pose delivery problems. Recent mishaps in Pennsylvania and France involving gene therapy demonstrate its continued hazards, he adds. Of biologics, only monoclonal antibody-based therapies such as Herceptin for breast cancer will complement small molecules and conventional treatments over the next 20 years, he predicts. LESS SPECIFICITY Hurley also forecasts a trend toward less-specifically targeted drugs. He says that while US Food and Drug Administration approval in 2001 of Gleevec to treat chronic myelogenous leukemia was an important milestone, because it was the first agent aimed at a specific cancer target (the Bcr/Abl tyrosine kinase), resistance nevertheless develops in many patients. Future drugs will avoid Gleevec's "high rigidity, or lack of floppiness." Lead compounds will be selected on the basis of conformational flexibility, enabling them to bind to more than one active site, which could counter selection for tumor cells bearing mutations that confer drug resistance. This less constrained binding would result in less potent but more sensitive drugs. "As we gain more insight into how a single drug will change expression patterns, we will find that agents with multiple targets will produce protein changes with signatures that are more apoptotic, if you like, than more selective ones," Hurley says. "It's completely opposite to our dogma as medicinal chemists," he admits, but the movement has already begun. Avastin, which targets vascular endothelial growth factor and is poised for FDA approval as the first antiangiogenic cancer drug, is "sloppy" in this respect, he says. The concern that sloppy drugs could endanger normal cells in which proto-oncogenes are expressed has not become a problem so far, says Hurley. One explanation is that oncogenes are so heavily overexpressed in cancer cells that they become "addicted" to these proliferative signals, and their downregulation sends the cells into apoptosis. Normal cells, in contrast, seek alternate survival pathways. Hurley says the best examples of the potential to hit multiple targets are kinase inhibitors in development to follow Gleevec, which blocks tyrosine kinases. But the trickiest part of designing a small-molecule drug as a "key" capable of fitting numerous mutational "locks" is anticipating how a tumor cell DNA might mutate. Identifying gene expression patterns are critical to this effort, he says, because they can provide information about multiple disease pathways. That allows the medicinal chemist to select the lead compound with the most appropriate conformational flexibility. In May, oncology associate professor Victor Velculescu of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University boosted the prospects for new kinase inhibitors by sequencing all exons that encode kinase domains in the entire tyrosine kinase family.1 His team identified 14 genes with 46 mutations specific to colorectal tumors; they currently are evaluating them as a prelude to drug development. "The biggest challenge is to develop drugs in a rational way," he says, "based on mutated genes." DESIGN BY NUMBERS Another way to generate new drug leads in the future could be the still-theoretical process of computational design, although Oxford University chemistry chairman Graham Richards acknowledges that computer-aided design of small-molecule drugs is an elusive Holy Grail. "One clear feature would be to have more and more drug targets," says Richards, who directs NFCR's Center for Computational Drug Discovery. Unfortunately, the structures of only a few thousand of the perhaps 200,000 proteins encoded in the human genome are yet known. Richards expects that this Herculean task will be completed over the next two decades, and his group is working on computational methods to determine structures. He thinks the goal is achievable, because a denatured protein will refold: "It clearly doesn't happen in a random way, so there must be some physics there." The other side of the problem, to find computationally substances that can interfere with protein activities, involves a search among billions of molecules, perhaps 1014, says Richards. His team has marshaled the equivalent of 100 teraflops of computing power through a screensaver program that enlists computers worldwide to screen 3.5 billion small molecules against a few known cancer proteins. "We now have more computing power than all the pharmaceutical companies in the world put together." Whatever avenues new drug discovery and development take, many researchers feel that the future of cancer treatment lies in combination therapy. In the near term, traditional chemotherapy and radiotherapy will be employed with small-molecule drugs, Hurley says. Small molecules will be used in tandem and in succession, as tumors change. Tyrosine kinases, angiogenic and lymphangiogenic growth factors, antiapoptotic proteins such as Bcl-2, and cell cycle checkpoint regulators like p53 are among likely targets of future small-molecule drugs. Among biologic agents, oncolytic potential resides in monoclonal antibodies, immunostimulatory cytokines, antigen-specific vaccines that stimulate T-cell immune response, some bacteria, and conditionally replicative viruses that target tumors.2 Whatever treatments the long term may hold, Nicolette speaks for many researchers in foreseeing that cancer will not be vanquished over the short term. "Certainly, there will be no slowdown in efforts to effect cures, but I think the way we're heading is toward cancer as a manageable, chronic disease." Steve Bunk (steve@home.com) is a freelance writer References 1. A. Bardelli et al., "Mutational analysis of the tyrosine kinome in colorectal cancers," Science, 300:949, 2003. 2. R.J. Arceci, T.P. Cripe, "Emerging cancer-targeted therapies," Pediatr Clin N Am, 49:1339-68, vii-viii, 2002. IN CANCER MEDICINE'S FUTURE, TIME IS MONEY Ask a few scientists what might cloud the future of biomedicine's asymmetrical struggle with cancer and you're likely to get different answers that boil down to the same bottom line. "This is not going to be a cheap solution to a problem," warns the University of Arizona's Laurence Hurley. He concurs with Genzyme's Charles Nicolette that the costs will outweigh the benefits in prolonged survival, but he says the difficulty lies in getting governments to invest far ahead of anticipated returns. Karol Sikora of HCA International offers a care-oriented assessment of the money issue: "All you're doing is keeping elderly people going for a few months longer, when you could be spending those dollars on making other lives significantly better." Other monetary considerations that could accompany the achievement of personalized medicine are an elevated threat of lawsuits and more stringent regulatory demands. "It would be very, very difficult to do something not tested because it's so individualized," says Oxford University's Graham Richards. "The metabolite being chewed up by the body and becoming ineffective, or some other metabolites being toxic, are serious problems that always must be borne in mind." Victor Velculescu of Johns Hopkins proffers yet another concern related to the consumer culture. "Although there's a lot of promise in these technologies, we don't want to oversell them to patients as cures, or make them more than what they are." And Hurley adds a similar "buyer beware" twist to his worries about insufficient funding. "The second fear I have is that as we become more and more successful at this type of targeted therapy, people will become more lax in their attitudes toward smoking, diet, and general lifestyle choices." Pointing to this problem among AIDS patients, he admonishes, "It's far better to prevent than to treat."

Into the Future

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