The recognition that cancer is more like an organ than just a clump of cells with DNA mutations in cell nuclei may also explain why some of the previous approaches to chemotherapy have met with limited success. “People have taken cells and then transformed them in culture and stuck them into animals,” Pollard says. “They grow as little balls. They do certain things there. But they are not complex tissues, whereas a naturally occurring tumor is a very complex tissue.”
Instead of just killing cancer cells—the goal of current drug therapies and radiation—new approaches may supplement existing drugs by slowing inflammation. Without the involvement of macrophages and other innate cells, the premalignant tissue would remain in check.
Cancer could, in essence, become a chronic disease akin to rheumatoid arthritis, another inflammatory condition. “Keep in mind almost no one dies of primary cancer,” says Raymond DuBois, provost of the University of Texas M. D. Anderson Cancer Center and a researcher of anti-inflammatory agents for cancer. “A patient almost always dies from a metastasis.”
A pharmaceutical against chronic inflammation represents a more alluring proposition than massacring malignant cells (and, unavoidably, healthy ones), a consequence of existing chemotherapies. Taken alone, such an agent might be benign enough to use every day as a preventive for high-risk patients. Epidemiological and clinical studies have shown some promise for the use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin to stave off the onset of some solid tumors. Investigations continue on more selective blocking of the production of prostaglandins, the regulatory molecules that are curtailed by NSAIDs. In particular, drugs that inhibit production of prostaglandin E2 may curb inflammation and tumor growth, while avoiding the cardiovascular side effects of drugs such as Vioxx and the gastrointestinal problems of the earlier class of NSAIDs [see “Better Ways to Target Pain,” by Gary Stix; Scientific American, January 2007]. The anti-inflammatory effects of the ubiquitous statins used to lower cholesterol are also being contemplated.
Some treatment options already exist. The drug Avastin inhibits production of the angiogenesis- promoting VEGF, although oncologists must contend with other molecules in the tumor microenvironment that promote blood vessel growth. Drugs developed for more familiar inflammatory diseases may also fight cancer—and these medicines might be combined into HIV-like drug cocktails, that also include angiogenesis inhibitors and cell-killing agents.
Inhibitors of TNF have received approval for treatment of rheumatoid arthritis, Crohn’s disease and other disorders and are now in clinical trials for both solid tumors and blood cancers. The drug Rituxan, a monoclonal antibody that represses B cells in rheumatoid arthritis and B cell lymphoma, might prevent the inflammatory response that fuels formation of solid tumors. Other cytokines and related molecules (IL-6, IL-8 and CCL2, among others) are also potential targets, as is NF-KB.
Some existing compounds, including NSAIDs and even one found in the spice turmeric, exert at least some of their effects by inhibiting NF-KB. But major pharmaceutical laboratories are investigating highly selective inhibitors of this molecular linchpin, many of them targeted at the enzymes (such as I-KB kinase) that regulate NF-KB activity.
A Chemical Trojan
One group is contemplating a radically ambitious treatment, a molecular Trojan horse of sorts. Claire Lewis and Munitta Muthana of the University of Sheffield in England and their colleagues have designed a drug delivery scheme that takes advantage of the natural attraction of macrophages to the oxygen-starved areas in tumors. They have engineered macrophages to deliver a therapeutic virus to hypoxic tumor regions, which respond poorly to conventional treatments such as chemotherapy and radiation because of an insufficient blood supply. Once the macrophages arrive in a tumor (grown in culture so far), each one releases thousands of copies of the virus, which then infect the cancer cells, after which a protein in those cells activates the therapeutic gene in each virus. This action then directs synthesis of a cell-killing toxin. “The macrophage is migrating into a site and doing what we want it to do rather than driving tumor development in a normal way,” Lewis says.