Combination of Traditional Chemotherapy, New Drug Kills Rare Cancer Cells in Mice

An experimental drug combined with the traditional chemotherapy drug cisplatin, when used in mice, destroyed a rare form of salivary gland tumor and prevented a recurrence within 300 days, a University of Michigan study found.

Called adenoid cystic carcinoma, or ACC, this rare cancer affects 3,000-4,000 people annually, and typically arises in the salivary glands. It’s usually diagnosed at an advanced stage, is very resistant to therapy, and there’s no cure. People may have read about ACC in the news lately, because elite professional runner Gabe Grunewald is currently undergoing her fourth round of treatment since her 2009 ACC diagnosis.

Typically, oncologists treat ACC tumors with surgery and radiation. They rarely use chemotherapy because ACC is extremely slow-growing, and chemotherapy works best on cancers where cells divide rapidly and tumors grow quickly, said Jacques Nör, a U-M professor of dentistry, otolaryngology and biomedical engineering, and principal investigator on the study.

The Nör lab treated ACC tumors with a novel drug called MI-773, and then combined MI-773 with traditional chemotherapy cisplatin. MI-773 prevents a molecular interaction that causes tumor cells to thrive by disarming the critical cancer fighting protein, p53.

Study co-author Shaomeng Wang, U-M professor of medicine, pharmacology and medicinal chemistry, discovered MI-773, which is currently licensed to Sanofi.

Researchers believe that blocking that interaction sensitized ACC cancer cells to cisplatin––a drug that under normal conditions, wouldn’t work. When administered to the mice with ACC tumors, the cisplatin targeted and killed the bulk cells that form the tumor mass, while MI-773 killed the more resistant cancer stem cells that cause tumor recurrence and metastasis.

“This drug MI-773 prevents that interaction, so p53 can induce cell death,” Nör said.  “In this study, when researchers activated p53 in mice with salivary gland cancer, the cancer stem cells died.”

The key is that in many other types of cancer, p53 is mutated so it can’t kill cancer cells, and this mutation renders the MI-773 largely ineffective. However, in most ACC tumors p53 is normal, and Nör said researchers believe this makes these tumors good candidates for this combined therapy.

Researchers performed two different types of experiments to test ACC tumor reduction and recurrence. First, they treated tumors in mice with a combination of MI-773 and cisplatin, and tumors shrank from about the size of an acorn to nearly zero.

In the second experiment, the acorn-sized tumors were surgically removed, and for one month the mice were treated with MI-773 only, with the hope of eliminating the cancer stem cells that fuel recurrence and metastasis.

“We did not observe any recurrence in the mice that were treated with this drug after 300 days (about half of mouse life expectancy), and we observed about 62 percent recurrence in the control group that had only the surgery,” Nör said. “It’s our belief that by combining conventional chemotherapy with MI-773, a drug that kills more cancer stem cells, we can have a more effective surgery or ablation.”

One limitation of the study is that it’s known that about half of all ACC tumors recur only after about 10 years, and this observational period was only 300 days.

In a typical metastasis, the cancer cells spread through the blood to other parts of the body. But ACC cancer cells like to move by “crawling” along nerves, and it’s common for ACC tumor cells to follow the prominent facial nerves to the brain––picture a mountain climber ascending a rope––where it’s often fatal.

Research is still too early-stage to know how humans will respond, and the drug will work primarily in tumors where p53 is normal. If p53 is mutated, which is fairly common in other tumor types, this drug won’t work as well, Nör said.

The work was funded by the Adenoid Cystic Carcinoma Research Foundation, U-M and the National Institutes of Health.

The study, “Therapeutic Inhibition of the MDM2-p53 interaction prevents recurrence of adenoid cystic carcinomas,” appeared earlier this year in the journal Clinical Cancer Research.

Spider peptides battle superbugs and cancer

As antibiotic resistance rises and fears over superbugs grow, scientists are looking for new treatment options. One area of focus is antimicrobial peptides (AMPs), which could someday be an alternative to currently prescribed antibiotics, many of which are becoming increasingly useless against some bacteria. Now, a team reports in ACS Chemical Biology that they have improved the antimicrobial — and anticancer — properties of an AMP from a spider.

According to the U.S. Centers for Disease Control and Prevention, 2 million people become infected with antibiotic-resistant bacteria in the U.S. each year. Because no known antibiotics work against these bacteria, patients simply have to hope that their natural defenses eventually overcome the infection. But some patients experience severe symptoms, landing them in a hospital, and in extreme cases, they could die. Researchers are trying to find alternatives to traditional antibiotics, and one such possibility is a group of peptides called AMPs. These peptides are found in all plants and animals as a type of immune response and have been shown to be potent antibiotics in the laboratory. Gomesin, an AMP from the Brazilian spider Acanthoscurria gomesiana can function as an antibiotic, but it also has anticancer activity. When gomesin was synthesized as a circle instead of as a linear structure, these characteristics were enhanced. Sónia Troeira Henriques and colleagues wanted to further boost the peptide’s traits.

The team made several variations of the cyclic gomesin peptide and found that some of these were 10 times better at killing most bacteria than the previously reported cyclic form. In other experiments, the new AMPs specifically killed melanoma and leukemia cells, but not breast, gastric, cervical or epithelial cancer cells. The researchers determined that the modified peptides killed bacteria and cancer cells in a similar way — by disrupting the cells’ membranes. The group also notes that the modified AMPs were non-toxic to healthy blood cells.

Brain Scans Show Dopamine Levels Fall During Migraine Attacks

Using PET scans of the brain, University of Michigan researchers showed that dopamine falls and fluctuates at different times during a migraine headache.

This could help scientists better understand dopamine-based therapies for migraines as well as a patient’s behavior during an attack.

The connection between dopamine and migraines has long been a poorly understood therapeutic and research area, says Alex DaSilva, assistant professor at the U-M School of Dentistry and Center for Human Growth and Development at the University of Michigan.

Dopamine—sometimes called the brain’s feel-good neurotransmitter—helps regulate emotion, motivation and sensory perception.

Physicians and emergency rooms often give migraine patients dopamine antagonists, drugs that block overactive dopamine receptors, to level off wild dopamine fluctuations and ease migraine attacks.

DaSilva and colleagues took various measurements of brain activity and dopamine levels of eight migraine sufferers and eight healthy patients during migraine attacks and between headaches. They compared study participants to each other with and without headaches, and also migraineurs to healthy patients.

When migraine patients were between headaches, their dopamine levels were as stable and even as the healthy patients, DaSilva said. But during an attack, the migraine patients’ dopamine levels fell significantly.

“Dopamine is one of the main neurotransmitters controlling sensory sensitivity,” said study co-author Kenneth Casey, U-M professor emeritus of neurology. “Therefore, a drop in dopamine could produce increased sensory sensitivity so that normally painless or imperceptible sensory signals from skin, muscle and blood vessels could become painful.”

This supports the hypothesis held by some researchers that migraines are a periodic disorder characterized by sensory hypersensitivity during which light, sound and odors may become abnormally intense, Casey says.

DaSilva says he was surprised when patients who were resting during their migraine attacks experienced a small dopamine spike and worsening symptoms when researchers applied warmth to their foreheads.

This condition in chronic pain patients is called allodynia—when a stimulus that normally wouldn’t cause pain does. DaSilva says the sudden small spike in dopamine was probably an aversive reaction to environmental stimulation.

This small fluctuation was only a partial recovery of dopamine, but it made the suffering worse because the dopamine receptors were highly sensitive by then, and even a small recovery would induce more nausea, vomiting and other symptoms related to migraine, he says.

In addition to the pain of migraines, DaSilva says the fall in dopamine in general could also explain some of the isolation and withdrawal that migraineurs exhibit during an attack.

“This dopamine reduction and fluctuation during the migraine attack is your brain telling you that something is not going well internally, and that you need time to heal by forcing you to slow down, go to a dark room and avoid any kind of stimulation,” he said.