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Surely cancer care has always been personalized, you might be thinking. And to the extent possible, it has been. Oncologists take into account the patient’s characteristics and the cancer’s characteristics (tissue type, stage) to plan therapy.
But it’s not an exact science. Chemotherapy treatments are often a one-size-fits-all approach – sometimes they work, and sometimes they don’t. In general, patients receive a course of chemotherapy and then wait – up to six weeks or longer – to find out if the drug is having an effect. If it doesn’t appear to be killing the cancer cells, the doctor and patient will decide on another treatment option. In the meantime, the patient may have suffered the unpleasant side effects of chemotherapy, without any benefit.
Rita Quigley knows this approach first-hand.
In the summer of 2007, she noticed a small bump, the size of a mosquito bite, under the skin on her upper arm. She mentioned it to the dermatologist she was routinely seeing because of a malignant melanoma (skin cancer) that had been removed from her back 17 years earlier. There was nothing visible on the skin, and the dermatologist had trouble even feeling the bump, Quigley recalls. Her family physician suggested it might be a sebaceous cyst.
Quigley requested that the mass be removed. The pathology report came back with ominous news: melanoma.
CT and PET imaging scans revealed that she had tumors
in her lungs, and Quigley’s Huntsville, Ala., oncologist referred
her to Jeffrey Sosman, M.D., director of Vanderbilt-Ingram’s Melanoma Program.
Malignant melanoma that has metastasized to distant sites in the body is notoriously difficult to treat.
“Melanoma has been the most frustrating of solid tumors,” Sosman says. “There have been some positive results with various therapies in a small minority of patients, but the great majority of patients do not respond to the chemotherapy or immunotherapy treatments that we have.”
Sosman opted to treat Quigley with the chemotherapy
drug dacarbazine. She came to the clinic for an intravenous
infusion once every three weeks for three months, but the tumors in her lung didn’t shrink. She says she was fortunate to only
suffer mild discomfort – achiness and flu-like symptoms – during the chemotherapy.
At the end of October 2007, thoracic surgeon Eric Lambright, M.D., at Vanderbilt-Ingram removed her lung tumors. The surgery was successful, and she recovered from it.
But a follow-up scan several months later showed new tumors in Quigley’s pelvic area, and Sosman decided to treat her with interleukin-2, an immunotherapy aimed at stimulating the patient’s immune system to kill the cancer. For the interleukin-2 treatment, Quigley was hospitalized for five days while the medicine was administered every eight hours around-the-clock through a central venous catheter. After one week of rest at home, the treatment was repeated. Hospitalization is required because the side effects of interleukin-2 treatment can be severe.
“Interleukin-2 is a different ballgame. It was several weeks after the second treatment before I felt like myself again,” Quigley says.
Six weeks after the treatment, imaging scans showed no tumor shrinkage.
It had now been a year since Quigley had noticed the bump on her arm. She had been through two surgeries, two grueling treatments, and still the cancer persisted.
But at this point a door opened for her – Sosman and his Vanderbilt-Ingram colleague Igor Puzanov, M.D., were studying a new drug in patients with metastatic melanoma. The study was a Phase I clinical trial, meaning that the drug had passed through pre-clinical (cell and animal) testing, but was just beginning to be tested in patients. The drug was not “off-the-rack” – instead it was tailored to a particular genetic change in tumor cells, and Quigley’s cancer had the genetic change. She enrolled in the trial.
Measuring cancer genes
To understand the experimental drug being offered to Quigley – and others like it – we need to back up.
For more than 30 years, cancer has been linked to genetic mutations that give cancer cells a growth and survival advantage. As the thinking goes, tumor formation involves multiple genetic mutations in a single cell – some that activate growth-enhancing genes (oncogenes) and others that inactivate growth-inhibitory genes (tumor suppressor genes).
Recently, investigators and the pharmaceutical industry have aimed drug development efforts at these mutant gene products that contribute to cancer cell growth, with the hope that medicines “targeted” at these molecules will kill cancer cells without harming normal cells. But how likely is it that blocking just one target – when tumor cells often have many mutated genes – will kill the cancer?
Consider Gleevec. The drug bounded onto the world stage
in 2001, with accelerated approval from the Food and Drug Administration for the treatment of chronic myelogenous
The genetic abnormality that causes CML – the so-called Philadelphia chromosome (named for the city in which it was discovered) – results from a translocation, a rearrangement that fuses two genes from different chromosomes together. One of the genes encodes a cellular signaling protein (ABL, a tyrosine kinase), which is usually turned “on” and “off” in a well-controlled manner. The rearrangement produces an abnormal protein (BCR-ABL), which is stuck in the “on” position and drives cells to become leukemic. Gleevec blocks the activity of the aberrant receptor, and kills the cancer cells.