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Technology Developed by Liotta and Petricoin Used to Test Chloroquine to Treat Breast Cancer

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This story originally ran on March 3.

By Tony Fong

Using proteomics technology developed by Lance Liotta and Emanuel Petricoin, researchers are testing whether a drug used for malaria is also effective for treating pre-invasive breast cancer.

GU's Center for Applied Proteomics and Molecular Medicine and the Inova Breast Care Institute are collaborating on the project, which is aimed at investigating the effectiveness of chloroquine as a treatment for breast cancer before it becomes invasive. A three-year clinical has begun that will eventually include 90 women with ductal carcinoma in situ, or DCIS. The trial is called Preventing Invasive Breast Neoplasia with Chloroquine, or PINC.

In DCIS, cancer cells have formed in the milk ducts, but they have not yet become invasive and spread in the breast. Once the cancer reaches that stage, it can be fatal.

In an e-mail, Petricoin said that technology developed by him and Liotta, called reverse-phase protein microarray technology [See PM 03/29/07], was used by Virginia Espina, a senior research professor at CAPMM to discover protein alterations in a process called autophagy. Those changes then led Espina to " postulate that a drug, chloroquine, could be potentially effective in killing the premalignant cells — stopping everything before the cells turn invasive."

The technology, he added, will not be used in the trial to select patients for therapy "but will be critical in looking at the DCIS cells pre- and post-therapy, and then hopefully [Espina] can identify specific protein pathway markers to predict best responders to chloroquine."

Autophagy, is "very involved in the survival of DCIS," Kirsten Edmiston, the trial's principal investigator and medical director for cancer services at Inova Health System in Northern Virginia, said in a statement.

"In preclinical work, our team found that if we block autophagy in DCIS cells with chloroquine, that it kills the cells so that they're not able to become invasive," she said.

In the trial DCIS patients will be treated with chloroquine before they receive standard-of-care surgery. A patient's breast tumor will be measured by MRI, and tissue samples will be sent to CAPMM for analysis. Depending on the patient's profile, treatment will combine chloroquine with Tamoxifen.

After treatment, the tumor will be measured again to determine whether it has shrunk. The patient will then proceed with surgery and follow-up therapy, as necessary.

"We believe that the treatment will kill the DCIS cells before they become invasive and shrink the size of the DCIS," Edmiston said. "We may be able to prevent someone from needing a mastectomy and offer them breast-conserving surgery."

Espina said that chloroquine works by starving cancerous cells. Pre-cancerous cells survive inside the milk duct without a blood supply and with few nutrients through autophagy: In effect the cancerous cell makes its own food, then stores it in a "cookie jar," she said.

"In the breast ducts, the DCIS cells use these 'cookies' to survive and potentially spread," she added. "Simply put, chloroquine goes into the cell's 'cookie jars' and prevents the cells from using that food so that they eventually die from starvation."

The chloroquine trial is the second involving Liotta and Petricoin's reverse-phase protein microarray technology to investigate the efficacy of a drug for "off-label" purposes. Last summer, the two began a clinical trial to test whether Gleevec has therapeutic use for the treatment of metastatic colorectal cancer — one of the first instances of proteomics technology being used for personalized medicine [See PM 01/22/10].

That trial, which is still in progress, is being conducted in collaboration with Edmiston and Alexander Spira, director of the Fairfax Northern Virginia Hematology Oncology Research Program.

Gleevec, manufactured by Novartis, was approved in 2001 by the US Food and Drug Administration for treating chronic myelogenous leukemia. It also is used for treating gastrointestinal stromal tumors. Novartis is funding that trial.

The PINC trial is being funded by GU and Inova Health System.

According to Edmiston, the treatment of DCIS is controversial because most DCIS lesions remain dormant and do not become invasive — and so most physicians don't treat it unless it becomes aggressive. Nevertheless, she noted that chloroquine is relatively safe and does not have the typical side effects of chemotherapy.

Citing statistics from the American Cancer Society, the university and Inova Health said that breast cancer is the most prevalent form of cancer in women, with more than 254,000 estimated diagnoses in 2009 in the US. About 25 percent of the cases will have DCIS, they added.

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