New study to prevent cervical cancer fuel supply stymies tumors

Drug combo shuts down tumor metabolism, a mouse study shows.

Radiation oncologist Julie Schwarz, MD, PhD, (right) and staff scientist Ramachandran Rashmi and their colleagues exploited cancer cell metabolism to kill cervical tumors that are resistant to standard chemotherapy and radiation
Radiation oncologist Julie Schwarz, MD, PhD, (right) and staff scientist Ramachandran Rashmi and their colleagues exploited cancer cell metabolism to kill cervical tumors that are resistant to standard chemotherapy and radiation. (Photo: Matt Miller/School of Medicine)

Recently researchers at Washington University School of Medicine in St. Louis have demonstrated that cervical tumors that don’t respond to radiation may be vulnerable to therapies that likewise strike cancer’s fuel supply.

Over the past two decades cancer treatments have ameliorated exceptionally in some cases but, treatment for cervical cancer has remained largely unaltered. All patients undergo radiation and chemotherapy, still, despite the aggressive approach, the regimen fails in about one-third of patients with cervical cancer that has to unfurl beyond the cervix but not outside the pelvis.

During the recent study mice implanted with human cervical cancer cells, the investigators wiped out many of the animals’ tumors with a combination of radiation and three drugs that target tumor metabolism. They select drugs that cut off cancer’s potential to burn glucose and shut down protective processes that help cancer cells survive.

Julie K. Schwarz, MD, Ph.D., an associate professor of radiation oncology said, “Cancer cell metabolism is a little bit peculiar. Tumor cells take up glucose faster and in higher amounts than normal tissues. In past imaging studies, my colleagues and I noticed that cervical tumors that took up a lot of glucose prior to radiation treatment tended to be more resistant to radiation therapy than other tumors. If consuming a lot of sugar makes them resistant, we wondered what happens if we inhibit their sugar uptake.”

Schwarz and her team utilized three distinct drugs, alone and in amalgamation to deprive cervical tumors of glucose and block downstream metabolic pathways that help protect cancer cells from building up toxic free radicals. Two of the drugs are investigational and approved by the Food and Drug Administration (FDA) for utilization in people as part of clinical trials whereas the third drug is FDA-approved to treat rheumatoid arthritis.

In addition to this, the researchers tested the drug combinations against four distinct human cervical cancer cell lines. One of the cell lines was vulnerable to being cut off from glucose alone, but the others required more interference.

All four cancer cell lines responded exceptionally to radiation plus the three-drug combination. One cell line was wiped out exhaustively. Schwarz and her team discovered that the mice did not show obvious unassertive side effects of this therapy, likely because healthy cells don’t rely on one fuel production pathway.

According to the researchers, when they cut off glucose, they force a cancer cell to scavenge for an alternative fuel. With the tumor in this vulnerable state, the researchers strike again by shutting down the cell’s ability to mitigate the toxic stew it forms from its own deranged metabolism. The treatment essentially forces the cell to drown in its own toxicity.

Ramachandran Rashmi, first author and a staff scientist in radiation oncology, said, “In many cases when you cut off glucose alone, the cancer cells find ways to compensate.”

“But if you then hit their metabolic pathways in two more ways at the same time, the cell can’t recover from that. The stress from the toxic free radicals will escalate, eventually overwhelming the cell.”

Schwarz said that historically, cervical cancer is arduous to study in the lab because most cases are caused by human papillomavirus (HPV), and there is no equivalent infection in mice.

Schwarz stated, “Ninety to 95 percent of cervical cancer cases are HPV-related, and there are very few studies of this type of cancer in mice because HPV is a human virus.”

“It’s very difficult to produce a mouse model of a solid tumor of the type we see in most women who are diagnosed with cervical cancer. Even though this is a relatively rare cancer, we know HPV is important in a number of other tumors, including those of the head and neck. We believe what we learn from studying cervical cancer will help improve treatments for any HPV-driven cancer.”

The study is published in the journal Cancer Research.