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In this PET scan, dense black spots in the chest and abdomen represent melanoma metastases before treatment (top) and after treatment with experimental “tailored” drug PLX4032 (bottom). Images courtesy of Jeffrey Sosman, M.D.

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The drug is effective in the overwhelming majority of CML patients with the Philadelphia chromosome, Pao notes.

“Gleevec is really the poster child of personalized cancer medicine,” he says. “There’s a genetic change that leads to an aberrant signaling protein and causes CML. You give the patients a pill that inhibits the activity of that protein, and the tumor cells go away.”

At about the time that Gleevec was starting to work in patients with CML, Pao was a research fellow in the laboratory
of Harold Varmus, M.D., at Memorial Sloan-Kettering Cancer Center. (Varmus and J. Michael Bishop, M.D., won the 1989 Nobel prize for their discoveries that oncogenes are actually cellular genes involved in normal cell growth and division, and that disturbances in these genes can lead to cancer.)

Pao and colleagues were exploring the same question that was being tested with Gleevec in CML – can tumors become so dependent on a single mutant growth-enhancing signaling protein that disrupting that signal kills the tumors? Their model was lung cancer. They had shown in mice that turning on a mutant oncogene in the lung caused lung tumors, and turning the oncogene off caused the tumors to die. The studies supported the concept of “oncogene addiction” – a phrase coined by the late Bernard Weinstein, M.D., to describe an apparent dependency of some cancers on one or just a few mutant genes.

As they worked to understand the molecular signaling in the mouse lung tumors, Pao and colleagues (and other investigators around the country) were also testing two targeted therapies – Iressa and Tarceva – in patients with lung cancer, the leading cause of cancer-related death in the United States.

The timing was fortuitous.

Most of the patients had no response to the drugs, but about 10 percent of the patients had a rapid and sometimes dramatic clinical response.

“In some patients, within five days we could see evidence of tumor shrinkage,” Pao recalls. “It looked just like this phenomenon of oncogene addiction that we were studying in the mice, and it said to us that these pills must be turning off something that’s critical for the tumor. We just had to figure out what that was.”

The Varmus group and others, including David Carbone, M.D., Ph.D., and colleagues at Vanderbilt-Ingram, focused on Iressa and Tarceva’s molecular target, the epidermal growth factor receptor (EGFR). They found activating mutations in the EGFR gene in lung tumor tissue from patients who responded to Iressa
or Tarceva.

Subsequent trials have shown that patients whose tumors have certain EGFR gene mutations have a 75 percent chance of having their tumors shrink when they are treated with EGFR-targeted medicines – oral pills with relatively mild side effects compared to chemotherapy. (These medicines are effective in only about 10 percent of “unselected” lung cancer patients.) By contrast, patients treated with standard chemotherapy have a 20 percent to 30 percent chance of tumor shrinkage, Pao says.

Pao and others have also identified genetic changes that predict that a patient will not respond to Iressa or Tarceva. And they have discovered changes that occur in tumors that are initially responsive but then become resistant to therapy.

Now the race is on, Pao says, to catalog the genetic defects in all kinds of cancers, discover which mutations are critical to tumor survival, and link those mutations to specific targeted therapies.

In the fitting room
In 2002, investigators reported that about 60 percent of melanomas contained a single mutation in a gene called BRAF. The BRAF protein functions in a cell growth signaling pathway, and the mutation activated the pathway and caused cells in culture to behave like tumor cells.

“Everyone who read that paper said, this is a target for melanoma – if we can target BRAF, we’re going to see Gleevec-like responses in melanoma,” Sosman recalls.

A drug called Nexavar targeted a related RAF protein and was already in clinical trials (and has since been approved) for kidney cancer. As a single agent in patients with melanoma that had resisted other therapies, it “didn’t do much of anything.” Another few drugs that worked in the same pathway, but not on BRAF, showed some activity, but the overall results were discouraging, Sosman says.

And then along came PLX4032, a BRAF inhibitor produced by Plexxikon and Roche Pharmaceuticals that in cultured cells specifically blocked the BRAF mutant most commonly found in melanoma. Puzanov led Vanderbilt’s participation in the Phase I trial (which has ultimately included six centers).

Initial results were not stellar, Sosman recalls, but a reformulation of the drug allowed the investigators to achieve higher doses and “all of a sudden, everybody started seeing responses.” He remembers the striking images that investigators at the various centers shared electronically.

“It was really stunning. Some of the patients were responding incredibly quickly, and we even saw symptomatic improvement – patients who were sick when they started, got the drug, and felt much better. That’s something I’ve never seen in treating patients with melanoma,” Sosman says.

Rita Quigley started taking PLX4032 in August 2008. Her tumors have shrunk, and she continues to take the pills daily, with minimal side effects. She felt well enough to return to work as a part-time nurse in a pediatrics practice, after seeing her second of three daughters off to college.

She has the highest praise for Sosman and his colleagues and finds it “amazing that it’s a possibility” to have a medicine selected to fit her tumor.

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