Stephen Wozniak of Easthampton, Mass., was diagnosed with small-cell lung cancer in 2004, when his daughter, Heather, was only 13. At the time, he was devastated to think that he might not be around to coach his only child's softball teams or help her through adolescence.
Over the next couple of years, the now 51-year-old endured numerous chemotherapy regimens and a course of radiation to treat tumors that eventually spread from his back and chest to his spine and the lymph nodes in his abdomen.
By December 2005, his doctor told him that he had used up his options and his time was limited.
At that point, Wozniak made a critical decision: he enrolled in a trial of an experimental drug combination at Dana-Farber's Early Drug Development Center (EDDC). He was hoping for a cure, but if one didn't materialize, at least he'd know he had played an important role in research that might, one day, result in better treatments for other cancer patients.
The EDDC, directed by Geoffrey Shapiro, MD, PhD, specializes in conducting phase I clinical trials. These are small, carefully designed safety studies of investigational drugs that determine the side effects and highest safe dose of each drug and allow physician-scientists to observe whether the treatment produces benefits.
Wozniak's trial tested the safety of combining an approved chemotherapy drug called irinotecan – which he had previously taken as a standalone treatment, without success – with E7070, an experimental agent designed to improve, or reverse resistance to, chemotherapy.
Within six months, Wozniak's tumors stopped their activity, until eventually they disappeared completely. Remarkably, for the past two-and-a-half years, he has had no evidence of disease while remaining on the protocol. He's continued pursuing his passions for travel, golf, a good steak and beer, and the Red Sox.
Most important, however, he's been there for Heather. He's coached her softball teams, taken her on family trips to Aruba, and watched proudly as she graduated from high school and entered nursing school.
"I wake up every day and feel fortunate," he says.
The road from scientific discovery to approved treatment for patients like Wozniak can be lengthy and arduous.
Discoveries in the laboratory lead to optimization of chemical compounds that are then subjected to pre-clinical studies in test tubes (in vitro) and in animals (in vivo) that test for biological activity and safety. Only then can researchers at a pharmaceutical company or an academic medical center such as Dana-Farber apply to the U.S. Food and Drug Administration (FDA) for approval to test the therapy with people.
These clinical trials provide information the FDA uses to determine whether the new treatment shows enough evidence of safety and effectiveness to be approved for its intended use. In general, it can take more than eight years and $800 million to bring a single drug to market.
Sometimes, already approved treatments can be used in new ways, or – as in the case of Wozniak's trial – they can be combined with experimental agents to increase their effectiveness. Many of the trials under way at Dana-Farber's center are testing such combinations.
Several classes of drugs can be used in conjunction with standard chemotherapy agents to bolster their efficacy, explains Shapiro. After exposure to DNA-damaging chemotherapy, cancer cells attempt to repair themselves by pausing in their cell cycle at specific stages called "checkpoints." Checkpoint inhibitors or cell-cycle inhibitors can disrupt the cells' ability to reinvigorate themselves. Other drugs can directly inhibit the DNA repair process. These DNA-repair blockers may also increase the number of cancer cells killed by chemotherapy.
Another class of drugs under development in the center is a group known as signal-transduction inhibitors. Signal transduction refers to the many protein pathways by which cells divide and grow. These pathways are frequently overactive in cancer cells, helping them survive chemotherapy treatments designed to damage them. Combining signal-transduction inhibitors with standard chemotherapy agents may prevent such evasive maneuvers.
Signal-transduction inhibitors are also being developed for use on their own. Over the past several years, the center has tested many of them in patients, with successes against a variety of cancers. In the most dramatic cases, the inhibitor drug directly targets an altered (or mutated) protein in a transduction pathway, short-circuiting the cell's growth signals.
Unfortunately, however, the blockade of one growth pathway often leads to the activation of another, so that the cancer cell ultimately develops resistance to the single-drug therapy. Different signal-transduction inhibitors are now being combined to block multiple growth pathways at once.
One example of such work has beginnings deep in Dana-Farber's history. In the 1980s, Thomas Roberts, PhD, now co-chair of the Department of Cancer Biology, co-discovered a cancer-driving protein called PI3K. In a set of landmark studies, Roberts and his Dana-Farber colleague Jean Zhao, PhD, identified individual components of PI3K that could be programmed with pinpoint precision to shut down unrestrained cell growth of PI3K-driven tumors.
Their research was published in 2008 and 2011 in the journals Nature and Nature Medicine. News of their findings helped spark a flurry of development activity among drug companies, resulting in a range of PI3K inhibitors, many of which are undergoing their initial testing in the EDDC. To date, investigators have learned that, while a PI3K inhibitor used alone can help some patients, many have not benefited. This discovery has prompted researchers to combine PI3K inhibitors with other signal-transduction inhibitors capable of extinguishing additional cancer cell growth pathways.
Shapiro and his team, as well as other groups at Dana-Farber, have been playing a leadership role in pairing PI3K inhibitors with other promising agents. One particularly compelling combination has been studied by Kwok-Kin Wong, MD, PhD, of Dana-Farber's Medical Oncology department. Using mice genetically engineered to develop lung cancer from a mutation of a gene known as K-RAS, Wong and his colleagues found that a combination of a PI3K inhibitor and a MEK inhibitor successfully shrank the tumors.
Their research, published in 2008 in the journal Nature Medicine, generated great excitement, because K-RAS-driven cancers can be among the most difficult to treat. Motivated by these findings, Shapiro's group launched a phase I clinical trial in 2009 combining drugs that block PI3K and MEK. The trial is a collaboration of Dana-Farber, other Harvard-affiliated hospitals, and two additional major cancer centers.
By early 2011, more than 40 participants had been enrolled, with encouraging preliminary results. Many patients have shown decreased metabolic activity in their tumors, and several have had some degree of tumor shrinkage.
Most important, the trial found that the P13K-MEK drug combination is safe. By summer, many participants had been on the study for more than four months, and some were nearing the six-month mark. Furthermore, approximately 10 patients with tumors harboring the K-RAS mutation were doing well on the study. Most found that their tumors were stabilizing or shrinking. Some, however, are experiencing unpleasant side effects such as nausea, diarrhea, and acne, leading the clinical investigators to evaluate various doses and schedules.
"The need to adjust dose and schedule demonstrates the critical importance of carefully performed phase I studies," explains Shapiro.
If the treatment continues to show promise, once investigators determine the optimal dose of the PI3K and MEK inhibitors, the EDDC will pilot the combination in K-RAS-driven tumors of the lung, colon, pancreas, and endometrium, prior to the launch of phase II studies. Additionally, Dana-Farber/Harvard Cancer Center will initiate four similar studies combining other novel agents that target PI3K and MEK.
As for Wozniak, six years after being given only a short time to live, he remains cancer-free and active. He has even held three fundraisers for the center; the last one, attended by around 200 people, raised more than $14,000.
Shapiro is delighted, but not unfamiliar, with outcomes like Wozniak's. "It is an exciting time in drug development," he says. "There are new drugs coming all the time. If one doesn't work, or the cancer develops resistance, there's hope that there will be something else. We don't develop definitive diagnostic timelines here, because people surprise us all the time."
People like Wozniak, who is now focusing on May 2013 – when his daughter is slated to graduate from nursing school.
Learn more about clinical trials at Dana-Farber
Paths of Progress Fall/Winter 2011 Table of Contents
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