Anti-malaria Drug Quinine Heads the List of Breast Cancer Clinical Trials
Researchers at George Mason University are testing the ‘repurposing’ of a quinine derivative to determine if it will be successful in causing the death of breast cancer cells. The word ‘repurposing’ came into vogue about thirty years ago, mostly about how we take old stuff intended for one use and give it a new use, like a coffee can becoming a cookie tin. The word applies to many situations, including old pharmaceuticals. In fact, there’s a whole branch of research more or less dedicated to finding new uses for old proven drugs. Chloroquine is one of those drugs. Discovered in 1934, promptly forgotten, and then revived during World War II, chloroquine proved very effective as a treatment and preventative for malaria.
Among its many interesting properties, chloroquine – one of the family of quinine-derived drugs – has an affinity for fat cells (adipose tissue). It disburses quickly throughout the body and tends to reside primarily in the lysosomes, the so-called digestive organelles of cells. Lysosomes are involved with how cells dispose of waste material, including from the cell itself. In that role, they are important in the process of autophagy, where a cell under stress – in desperate need of nutrition – begins to feed upon itself. Autophagy is one way of killing cancer cells, which brings the story of chloroquine to the treatment of breast cancer.
Many forms of breast cancer begin with pre-cursor cells, anomalous cells among the normal fat and tissue cells of the breast. The most common location for these pre-cursor cells is in the milk ducts (they are technically ductal carcinoma in situ or DCIS). In an MRI they show up as white spots, tiny points of calcification, which eventually clump together to form lesions. That is usually the beginning of a tumor and an aggressive form of breast cancer.
One of the things that happen to the pre-cursor cells when they clump together is that they compete for resources – oxygen, nutrients. Because they are not (yet) connected to the main supply of those resources in the breast, they tend to be stressed, in effect, starved. In order to survive, they literally begin to use their own resources, the autophagy mentioned above.
A traditional chemotherapy for breast cancer works by speeding up the autophagy, so that the cancer cells literally consume themselves. Unfortunately, the chemicals involved also make nearby normal cells react the same way, making them collateral damage.
Chloroquine prevents the pre-cursor cells from using autophagy. This is a reversed strategy. By preventing the pre-cursor cells from surviving by consuming part of themselves, they simply die from starvation (lack of food and oxygen). Chloroquine in the cell’s lysosomes causes this effect.
An added benefit is that chloroquine has no effect on healthy cells because they do not use autophagy to stay alive.
That’s the theory behind chloroquine, but the proof is in the clinical trial. Researchers at George Mason University (Fairfax, Virginia USA), initiated the PINC (Preventing Invasive Neoplasia with Chloroquine) clinical trial, phase 1 and 2, to test the safety and preliminary effectiveness of chloroquine on treating DCIS.
Already diagnosed with DCIS by biopsy, women accepted into the trial take chloroquine once a week for four weeks, along with their normal course of treatment. The researchers are looking for a significant reduction in the size of lesions. It’s already known that chloroquine has few side effects (such knowledge being a benefit of repurposing an old drug), that it naturally concentrates in the fatty breast tissue, and impacts only cells engaged in autophagy. If it is effective, it should also be safe. In fact, the researchers believe that chloroquine stands a good chance as a routine drug taken by women on a yearly basis to prevent breast cancer. That, of course, will only happen after a long series of clinical trials.
The PINC trial joins two other clinical trials involving breast cancer led by George Mason researchers. One is developing a personalized treatment for women with metastatic breast cancer, where the tumors have spread to other organs. The current phase 1 trial involves 25 women failed by traditional chemotherapy. The new treatment draws upon the molecular profile of the cancer lesions. This genetic analysis will, hopefully, provide clues to effective treatments.
The other study, the I-SPY-2 trial, is also a personal genome analytic procedure designed for women with stage II/III breast cancer. The FDA earmarked this research for accelerated drug approval.