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Curing Cancer: An Investment in Basic Research
CHORI Scientist Helps Develop New Cure for Skin Cancer

June 2012 – A new study published in the New England Journal of Medicine by CHORI Senior Scientist Ervin H. Epstein Jr., MD, and University of Columbia's David Bickers, MD, heralds a new day in the treatment of the most common cancer in the United States: basal cell carcinomas (BCCs). In the three-year, randomized, double-blind, placebo-controlled study conducted at three different clinics, patients suffering from basal cell nevus syndrome (BCNS), a genetic condition in which patients develop hundreds to thousands of BCCs throughout their lives, were treated with a revolutionary new drug developed by Genentech, called vismodegib.

"Patients in our study showed a dramatic reduction in the growth of existing tumors and the development of new tumors," says Dr. Epstein. "Patients improved in just one month of treatment. Not only did all the BCC tumors respond to treatment, but some subjects achieved near complete clinical remission."

“Patients in our study showed a dramatic reduction in the growth of existing tumors and the development of new tumors.”



The groundbreaking results mark an incredible chapter in a story that began over three decades ago, with the dedication of a handful of scientists and an investment in basic science. "This all began with a pair of investigators in Germany doing fundamental basic research that focused on a very rare disease," says Dr. Epstein, whose own involvement in the story began 25 years ago, when he began collecting blood from a huge family suffering from BCNS.

"It starts there, with a patient, with a tumor you can see on their skin, and goes to a vial of blood, and the DNA that gets amplified from that blood, and the genetic testing that is done on the DNA that came from that blood, from that tumor, from that patient. You don't really know whether all these levels of abstraction are correct, even when you find a defective gene."

In this case, the gene defect that Dr. Epstein and his collaborators found was a mutation in what is called the PTCH1 gene. Under normal conditions, the PTCH1 gene codes for a protein that acts as a tumor suppressor by inhibiting a very common signaling pathway, called the hedgehog (HH) signaling pathway. In patients with BCNS, however, a mutation in the PTCH1 gene causes the protein it codes to be defective. As a result, the HH signaling pathway is upregulated, and tumor growth is rampant.

Patients with BCNS, like those from whom Dr. Epstein took his original blood samples, have uncontrolled BCC tumor growth. Their quality of life is marked by frequent and repetitive tumor removal surgeries that leave significant scar tissue behind, along with a significantly diminished quality of life. Since the discovery of the PTCH1 mutation, researchers have been trying to develop a drug that replaces the function of the mutated protein. Vismodegib is the first such inhibitor of HH signaling to be taken to trial.

As Dr. Epstein explains, "The protein the PTCH1 gene makes is still dysfunctional, but the drug provides a small molecule that inhibits the same target in the HH signaling pathway and substitutes for the defective protein."

In this trial, vismodegib significantly reduced the perpatient rate of new surgically eligible BCCs when compared to the placebo, as well as reducing the size of existing clinically significant BCCs by 65 percent, with some patients experiencing the disappearance of all BCCs.

The first treatment available to restore quality of life for patients with BCNS, vismodegib also provides new possibilities for treating other cancers in which tumor growth is linked to similar HH signaling pathway dysfunctions.

"There are currently three to four dozen trials of drugs produced by five other companies in patients with a variety of different cancers as well as other kinds of conditions, and none of this could have happened without the early support we all had in pursuing our basic research," says Dr. Epstein.

A landmark example of bench to bedside research, the vismodegib study was selected from about 5,000 other studies for presentation in the opening plenary session of the American Association for Cancer's 2011 Meeting in Orlando, Florida. Officially approved by the FDA as of January 30, 2012 for marketing by Genentech under the trade name Erivedge, vismodegib, and other drugs like it, have made treating a variety of different cancers not a hope, but a reality.

"Amazing moments like this are built on fundamental knowledge accumulated over years," says Dr. Epstein.

“It's often hard to understand that dramatic, groundbreaking treatments and cures of this kind don't come about without committed and substantial investment in basic research, but this is an example of fundamental and translational science at its best.”

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Sunday, July 29, 2012 12:38 PM

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