Gaining an Edge Against Cancer
Cancer research pushes forward as scientists find creative ways to attack cancer.
Four decades later an overly optimistic comment by fellow scientist and co-discoverer of the DNA double helix, James Watson, PhD, landed angiogenesis on the front page of The New York Times, claiming, “
It hasn’t proven that simple.
Although Folkman’s observations laid the foundation for the successful development of antiangiogenic therapies—several of which have been approved—the more researchers learn about cancer, the more they understand the complex interaction between patient and tumor, genes and treatment, and the adaptability of cancer cells to survive and multiply.
The dream of finding a single cure for cancer has been replaced with hitting cancer cells with combination therapies affecting growth pathways, DNA, environment, and other dependencies. Researchers could potentially cure specific types of cancer, prolong patients’ lives, and prevent recurrence.
The challenge scientists face today is the same that they have grappled with in the past—finding the best drug to kill the cancer, while allowing as little harm to the patient as possible. The increasing number not only of drugs but also entirely new classes of drugs to test in the laboratory and in human trials also means increases in research funds, the number of patients for clinical trial participation, and time to test new drugs and combinations.
Clinical trials must be designed to show sufficient safety and efficacy for an agent or it may be set aside and forgotten. Finding which patients respond, knowing when to treat them, and determining what combination of drugs to give are only some of the goals scientists are working toward, as well as tackling drug resistance and cancer cell adaptation.
When Gleevec (imatinib) was approved in 2001 for chronic myeloid leukemia, it was considered the proverbial “magic bullet”—a drug designed to target the bcr-abl gene located on an abnormal chromosome called the
Soon after Gleevec’s approval, researchers started working on two second-generation bcr-abl inhibitors, Sprycel (dasatinib) and Tasigna (nilotinib), to target the mutations. These more potent drugs provided promising second-line treatment for Gleevec-resistant and Gleevec-intolerant CML. Still, some cancers failed to respond. Currently, researchers are developing and testing agents that target another mutation called T315I, the only known mutation that is not responsive to the three approved bcr-abl inhibitors.
Neil Shah, MD, PhD, assistant professor of hematology/oncology at the University of California, San Francisco, helped develop Sprycel and says it’s encouraging that the first effective therapy for Gleevec-resistant or intolerant patients was approved five years after Gleevec.
“[Sprycel] is an excellent example of not being complacent with the exciting initial responses of any particular therapy, but to really ask focused questions about why certain patients either don’t respond or lose their response.”
Scientists are also working to overcome drug resistance by blocking two or more targets with drugs like Tykerb (lapatinib), the breast cancer drug that inhibits both HER2 and the epidermal growth factor receptor (EGFR). Scientists are learning that cancer cells evolve and adapt, perhaps switching from one growth factor to another to spur proliferation, which may be why using drug combinations and targeting multiple mutations and pathways—what researchers call total receptor blockade—is often successful.
Oncologists have been using chemotherapy for more than 60 years, and while it carries a bad reputation for side effects, newer chemotherapies are more effective and cause less damage to healthy tissue. Reformulations of older agents have reduced life-threatening allergic reactions, and research challenging conventional treatment combinations is gaining ground. Indeed, breast cancer trials comparing the standard combination of the heart-toxic Adriamycin (doxorubicin) and Cytoxan (cyclophosphamide) versus Taxotere (docetaxel) and Cytoxan show the TC combination works as well or better than the AC combination, and is easier on the heart.