Breast Cancer Lab Discoveries Quickly Lead to New Clinical Trial

A new strategy for treating a common form of breast cancer has emerged from lab studies by UCSF oncologist Mark Moasser, MD. Clinical trials to evaluate the treatment approach already are underway at the UCSF Helen Diller Family Comprehensive Cancer Center. The protocol being evaluated calls for giving women intermittent, higher-than-standard dosages of a newer biological agent used to fight breast cancer. The strategy derives from new discoveries by Moasser’s lab team related to a major target in breast cancer that drives tumor growth in about one-in-four women with the disease. Moasser’s enthusiasm for new treatment ideas that are emerging from scientists’ success in probing cancer cells was on display recently when he presented new research results to scientists and breast cancer advocates at an annual symposium organized by the Cancer Center’s Breast Oncology Program. The approach of using larger drug dosages with breaks in between is based on what Moasser has learned about a protein called HER2 and its associates. HER2 and its protein partner HER3 make up a biochemical team that functions to regulate growth signals. Due to genetic mutations, the cells of “HER2-positive” breast tumors make abnormally high amounts of HER2. This abnormality helps stimulate the growth of these breast cancers. The first drug developed to target HER2 was Herceptin, which was approved by the US Food and Drug Administration in 1998. It has become a standard treatment for HER2-positive breast cancer. Herceptin was the first approved biological treatment developed to target a specific abnormality in breast cancer. By attaching to HER2, Herceptin inhibits HER2’s effectiveness in relaying growth signals. Research advances in the decade since FDA approval of Herceptin have provided much greater insight into how HER2 functions. These insights have paved the way for the development of drugs that are much more effective than Herceptin, Moasser says. In particular, Moasser and his team have discovered that HER2 is protected by its partner HER3. The key to treatment of this disease is the inactivation of the HER2-HER3 team, according to Moasser. In a study published in the January 27 issue of Science Translational Medicine, Moasser and colleagues found that the HER2-HER3 complex can be effectively inactivated, but to do so requires high doses of drugs which may produce toxicities. But they also found that toxicity from high doses can be avoided if there are breaks in drug therapy. This novel treatment design proved to be highly effective in mouse models of HER2-positive breast cancer. A drug that targets HER2, called Tykerb, now is being used to test this new dosing strategy. In the clinical trial, women with advanced breast cancer are being treated with large, intermittent dosages of the drug instead of with daily, lower-dosage treatment. The larger dosage should more effectively kill tumor cells, Moasser, says. Breaks in treatment are intended to limit side effects. The Phase 1 clinical trial is open to women with HER2-positive breast cancers that continue to grow after prior treatment with standard therapies.

Sorting out the HER2 signaling pathway

The idea for using higher dosages emerged from lab findings. A compensatory biochemical response permits HER2-driven tumor cells to survive all but complete inhibition of HER2, a team led by Moasser and UCSF colleague Kevan Shokat, PhD, reported in a 2007 study. HER2 signals must be relayed through other proteins downstream along the biochemical signaling pathway. The downstream signaling network creates a buffer, so that signaling can withstand drug treatment, Moasser says. If the dosage is increased, signaling revs up to compensate -- up to a point. Dosages that are higher still can stop signaling, but are toxic when given continually. A minimum of three days without HER2 signaling is needed to kill HER2-positive breast cancer cells, Moasser says. HER2 is able to transmit signals despite treatment thanks to its partner HER3. This is because HER3 is connected to a complex network that functions like an amplifier volume knob. If signaling decreases due to drug therapy, the network can increase signaling volume to compensate. Understanding the network is a principle challenge for Moasser. “There’s a complex network in which HER2 and HER3 operate,” Moasser says. “We want to reduce its complexity. We want to know how big it is. We want to know where it is susceptible to attack.” Some of the most important proteins in HER2’s signaling pathway are downstream from HER3, Moasser says. He says resistance to current treatments for HER2-driven breast cancer might one day be overcome by combining current HER2 inhibitors with other targeted drugs that separately attack either HER3 or proteins downstream in the signaling pathway. In collaboration with Joe Gray, PhD, head of UCSF’s Breast Oncology Program and director of the Life Sciences Division at Lawrence Berkeley National Laboratory, Moasser is taking a systems biology approach. The researchers are trying to unravel the complexities of the network and to model it with mathematical formulas. These models would then allow computational methods to predict how cells will respond to specific drug treatments. Moasser also continues to work with Shokat, a chemist who is innovative at making inhibitors that specifically target individual proteins. “Step by step we march down the pathway and interrogate the signaling circuitry with these inhibitors,” Moasser says. “At every step we measure how the cell responds.” Although complexities of HER2-driven breast cancers have not yet been completely elucidated, these tumors may be less complex and resilient than many other cancers, Moasser says. “In most solid tumors there are many signaling pathways that go wrong, and many genes that are mutated,” he says. “I think that this cancer is more simplistic, and that HER2 is the critical driver. I think we should be able to cure this cancer if we can shut down HER2, even in advanced cases.” There is a precedent for using targeted drugs to vanquish cancers driven primarily by a single signaling pathway in the treatment of non-Hodgkin’s lymphoma and chronic myelogenous leukemia.

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