Drug resistance can be overcome by using a combination of several agents (quivers a-d) to attack both the original and resistant cancer cells.
The next generation
Even the remarkable successes of new, very selective cancer drugs like Gleevec, Iressa, and Erbitux have been plagued by resistance. These relatively new "targeted" drugs block overactive cell growth switches or other genetic weak points in cancer cells, causing them to self-destruct. Gleevec and drugs like it can shut down these switches and send many more patients into remission than can conventional cell-killing drugs. Cancer, however, always seems to find a way around such roadblocks. Case in point: A significant proportion of patients with diseases like chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST), effectively treated for a time with Gleevec, have relapsed.
Richard Stone, MD, a Dana-Farber oncologist who treats and studies blood cancers, explains the phenomenon this way: "Gleevec works by binding to a molecule and inhibiting an enzyme produced by the abnormal joining of two genes called BCR and ABL. When this target molecule mutates so that Gleevec can no longer bind to it, people stop responding to the drug." Another maneuver by resistant tumor cells is the activation of alternate growth-spurring genetic pathways that aren't susceptible to Gleevec's action.
Stone, along with James Griffin, MD, George Demetri, MD, and other Dana-Farber scientists, has been collaborating with drug companies to devise compounds—so-called "sons of Gleevec"—capable of out-flanking the resistance mechanisms within both CML and GIST cells.
One promising new drug, SU11248, blocks several overactive growth pathways in GIST cells. In clinical trials, this compound showed benefits in more than half of the GIST patients for whom Gleevec was no longer working. Demetri, who headed the trial, says that SU11248 not only shuts down growth-signaling pathways in the tumor, but also chokes off its blood supply by inhibiting the growth of small vessels that feed the cancer.
Another "son of Gleevec" has demonstrated exciting promise for drug-resistant CML. A collaboration between Dana-Farber scientists and the international drug company Novartis Pharma AG produced a compound called AMN107, whose molecules bind more tightly to the BCR-ABL protein than does Gleevec, hitting it with 20 times more effectiveness than the parent drug. AMN107 was designed to latch onto the binding site tenaciously, and Griffin hails the rapid journey it made from laboratory idea to early testing in patients.
"We're very encouraged by the results so far," remarks Griffin. "This is an elegant example of how rational drug design—developing drugs based on a molecular understanding of cell structures and processes—can be used to attack human diseases."
The seesaw battle with cancer drug resistance will be an ongoing challenge for oncology indefinitely, both with conventional chemotherapy agents and the new "targeted" drugs. Eder says the emphasis in resistance research has been shifting to the latter in recent years as these "smart" compounds don the mantle of cancer therapy promise.
"Why try to strengthen these same old toxic drugs," poses Eder, "when we now can design any drug we want to hit the growing list of targets in cancer cells that are being discovered today?"
