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Princeton scientists discover mechanism involved in breast cancer's spread to bone
Date:2/3/2011

further stimulate the expression in Jagged1 in tumor cells," Sethi said. "The link between the Jagged1/Notch and TGF-beta pathways establishes a vicious cycle, essentially driving the unstoppable expansion of tumor and the destruction of skeletal tissues."

As a medical student, Sethi said he is acutely aware of the consequence of bone metastasis. "These patients suffer a lot. They have fractures, severe bone pain and debilitating nerve compression," he said. In addition, as the bone breaks down, calcium builds up in the blood, causing other life-threatening complications.

BLOCKING DESTRUCTIVE PATHWAY A POTENTIAL TREATMENT PATH

The key to stopping the process appears to be finding a way to neutralize the Jagged1 signaling molecule or its receptor Notch.

Kang has several ideas on how scientists may learn how to do just that. One way to interrupt the destructive process is to put a roadblock in the Notch pathway. There is a way to do that by halting the activity of gamma secretase -- an enzyme that plays a key role when the Notch pathway is activated --because without it the delivery of instructions to bone cells cannot be completed. The pharmaceutical firm Merck & Co. has developed one such experimental drug that stops gamma secretase, known as a gamma secretase inhibitor or GSI, and the company has provided it to Kang's lab to support his team's work.

The drug has already shown promise treating metastatic bone cancer, Kang said. In animal experiments, the inhibitors have been proven to block the disease-causing signaling between tumor cells and bone cells, communication mediated by Jagged1 and Notch. Kang said GSI can reduce bone metastasis significantly, along with a dramatic reduction of bone destruction.

He hopes his team's new data showing that GSIs appear to work to halt the spread of cancer to the bone will result in clinicians starting a clinical trial of GSI to fight breast cancer metastases in
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Contact: Emily Aronson
earonson@princeton.edu
609-258-5733
Princeton University
Source:Eurekalert  

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