A new class of pharmacological agents may offer the best chance to prevent cancer from spreading.
"Things don't go from good to bad overnight," observes Michael Sporn. "There's a long period of time in which things gradually erode, going from good to not-so-good to getting bad, getting worse and, finally, you end up with a clinically manifested disease."
Sporn runs a laboratory at Dartmouth Medical School (DMS) dedicated to preventing that long-term cycle for individuals diagnosed with cancer. He believes the key to success may be a process called chemoprevention, a word he coined nearly thirty years ago when he was conducting research at the National Institutes of Health (NIH). Chemoprevention refers to the use of pharmacological agents to impede, arrest, or reverse carcinogenesis at its earliest stages.
Cancer, like high blood pressure and elevated cholesterol, can simmer in the body for years. Often individuals become aware they are at risk only when the disease becomes invasive or metastatic. But modern techniques now allow biochemical or genetic identification of things going wrong even in the absence of clinical symptoms. Prevention at this stage ultimately could decrease the number of people who die from cancer, just as drugs that control blood pressure and cholesterol have reduced the number of people who die from heart attacks and strokes. Already, some drugs, such as tamoxifen and raloxifene, have been successfully used clinically to treat breast cancer in its earliest stages.
Sporn, in collaboration with Gordon Gribble, Dartmouth professor of chemistry, and Tadashi Honda, research assistant professor of chemistry, has developed a new class of cancer-treatment drugs called triterpenoids. These synthetic chemical compounds are derived from materials which occur naturally in plants. The role of the chemistry department is to enhance the activity of the natural materials by adding new chemical groups multiplying their activity a million-fold.
There are around five thousand triterpenoids in nature. The program between Dartmouth's Burke chemistry lab and the DMS pharmacology group (which is coordinated by Nanjoo Suh, research assistant professor of pharmacology and toxicology) has tested nearly three hundred of them. The National Cancer Institute (NCI) has supported the triterpenoid research and has selected one of the compounds for treatment of leukemia for clinical trial this year. There are several different kinds of leukemia. Although some childhood leukemias are quite treatable, there is a need for new agents that could be more effective in treating the more difficult adult leukemias.
Sporn is working to develop similar compounds that could be used to treat other common forms of cancer, including colon cancer and lung cancer. And he hopes one day to take the treatment a step beyond. "I hope that we can use this research for the prevention of neurodegenerative disease, such as Alzheimer's or Parkinson's," he says. "We know now that somebody just doesn't become demented all of a sudden at age sixty. Bad things have been happening in the brain probably for ten or fifteen years before then, although they don't show up as symptoms in any way."
Similarly, there is no single event or breakthrough moment that produces a cure or an effective treatment. "Most fundamental research," Sporn says, "is incremental by nature and requires the concerted effort of a large group of people."
Getting a drug to the clinical test phase is much more difficult than it used to be in the current financial climate. And testing a drug clinically is a long and challenging process. It took his group seven years to achieve the success they've had to date. Much of their work was made possible by a grant from the National Institutes of Health (NIH) as well as support from members of Dartmouth's class of 1934, who helped purchase some of the most up-to-date lab equipment.
Although he was trained and licensed as a physician, Sporn has spent his career conducting basic research. He spent thirty-five years at NIH studying nucleic acids and investigating carcinogens. Some of the first studies on aloxifene were done in his lab there. He developed his interest in cancer prevention research earlier still, while caring for people with end-stage cancer during his internship at the University of Rochester.
Dr. Sporn believes that Dartmouth is a unique place for the kind of research he is able to do now. "The nature of our community and the close connection between colleagues across the campus spark tremendous innovation," he says. "That innovation is leading to powerful new treatments and approaches."