Anti-malarial drug chloroquine

Researchers at George Mason University's Center for Applied Proteomics and Molecular Medicine (CAPMM) and Inova Breast Care Institute (IBCI) are trying to prove, if a drug that has been used to treat malaria for years can possibly be used to treat pre-invasive breast cancer before it becomes invasive.

In January 2010, the IBCI and CAPMM launched the PINC Trial, short for Preventing Invasive Breast Neoplasia with Chloroquine. Chloroquine is a drug that prevents the development of malaria parasites in the blood. Doctors use it to both prevent and treat malaria. This drug was discovered in 1934 but it was ignored for a decade because it was considered too toxic for human use. During World War II United States government-sponsored clinical trials for anti-malarial drug development showed unequivocally that CQ has a significant therapeutic value as an anti-malarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.

To understand breast cancer, it helps to have some basic knowledge about the normal structure of the breasts. The female breast is made up mainly of lobules (milk-producing glands), ducts (tiny tubes that carry the milk from the lobules to the nipple), and stroma (fatty tissue and connective tissue surrounding the ducts and lobules, blood vessels, and lymphatic vessels).

Ductal carcinoma in situ (DCIS) is the most common type of non-invasive breast cancer. DCIS means that the cancer cells are inside the ducts but have not spread through the walls of the ducts into the surrounding breast tissue. Once the cancer cells start to spread in the breast and throughout the body, the condition is considered invasive and can often be fatal. About one in five new breast cancer cases will be DCIS. Nearly all women diagnosed at this early stage of breast cancer can be cured. A mammogram is often the best way to find DCIS early.

The three-year clinical trial PINC will test the effectiveness of the anti-malarial drug chloroquine in treating 90 women with DCIS. With an estimated 254,650 patients diagnosed in 2009 alone, breast cancer is the most common form of cancer in women according to statistics by the American Cancer Society.

According to Kirsten Edmiston, MD, the trial's principal investigator and medical director of cancer services at Inova Health System, the trial is designed to prevent breast cancer cells from becoming deadly by killing pre-invasive cancer cells using a novel therapy with chloroquine.

"We have identified a particular cellular process called autophagy that is very involved in the survival of DCIS. In pre-clinical 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," says Edmiston. "What this trial is proposing is to treat DCIS patients with chloroquine, an autophagy blocker before they receive standard of care surgery to treat their DCIS disease. We believe that the treatment will kill the DCIS cells before they become invasive and shrink the size of the DCIS. We may be able to prevent someone from needing a mastectomy and offer them breast conserving surgery."

According to Ginny Espina, a CAPMM research assistant professor, it works by starving the cancerous cells. "Pre-cancerous cells have adapted to survive inside the milk duct without a blood supply and with very few nutrients. They overcome starvation through a process called autophagy. It's a way for a cell to make its own food and store it in a 'cookie jar.' In the breast ducts, the DCIS cells use these 'cookies' to survive and potentially spread. 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," says Espina.

Once patients have consented and enrolled, the size of their breast tumor will be measured through a non-invasive imaging technique called magnetic resonance imaging (MRI). Tissue samples will be taken from patients by Inova's doctors and transported to CAPMM for analysis. The PINC trial will combine chloroquine with Tamoxifen (blocks the effect of estrogen on tissue and is used for the treatment of invasive breast cancer), depending on the patient's tumor profile. After treatment, the MRI will be repeated to see if the tumor has shrunk and the patient will then proceed with surgery and follow up therapy.

The treatment of DCIS is controversial because most DCIS lesions remain dormant. Physicians do not want to over treat DCIS and cause unnecessary side effects if the DCIS does not become aggressive. However, chloroquine is a relatively safe treatment that does not have the severe side effects of typical chemotherapy. Researchers are also using chloroquine in patients with unique types of brain tumors.

"I think the most exciting thing is that we are able to offer women a new clinical trial using a well tolerated therapy in a new way to help prevent the development of invasive breast cancer and hopefully, ultimately, it will keep them from needing any additional treatment or surgery," says Edmiston. "We look forward to a future where all breast cancer can be prevented or destroyed."

Author: Dagmar Smětalová