Experimenting with cells in culture, researchers at the Johns Hopkins Kimmel Cancer Center have breathed possible new life into two drugs once considered too toxic for human cancer treatment. The drugs, azacitidine and decitabine, are epigenetic drugs and work to correct cancer-causing alterations that modify DNA.

The researchers also found that the drugs took aim at a small but dangerous subpopulation of self-renewing cells, sometimes referred to as cancer stem cells, which evade most cancer drugs and cause disease recurrence and spread.

In a report published in Cancer Cell, the Johns Hopkins team said their study provides evidence that low doses of the drugs cause antitumor responses in breast, lung and colon cancer cells.

Conventional chemotherapy agents indiscriminately poison and kill rapidly dividing cells, including cancer cells, by damaging cellular machinery and DNA.

“In contrast, low doses of azacitidine (AZA) and decitabine (DAC) may reactivate genes that stop cancer growth without causing immediate cell killing or DNA damage,” said Stephen Baylin, M.D., Ludwig professor of oncology and deputy director of the Johns Hopkins Kimmel Cancer Center in Baltimore, Md.

Many cancer experts had abandoned AZA and DAC in the treatment of common cancers, according to the researchers, because they are toxic to normal cells at standard high doses and there was little research showing how they might work for cancer in general.

Baylin and colleagues decided to reevaluate the drugs after low doses of each showed a benefit in patients with a preleukaemic disorder called myelodysplastic syndrome (MDS). Johns Hopkins investigators also found benefit with low doses of the drugs in tests with a small number of patients with advanced lung cancer.

“This is contrary to the way we usually do things in cancer research,” said Baylin. He noted, “Typically, we start in the laboratory and progress to clinical trials. In this case, we saw results in clinical trials that made us go back to the laboratory to figure out how to move the therapy forward.”

Baylin’s team worked with leukaemia, breast and other cancer cell lines and human tumour samples using the lowest possible doses that were effective against the cancers. In all, the investigators studied six leukaemia cell lines, seven leukemia patient samples, three breast cancer cell lines, seven breast tumour samples (including four samples of tumours that had spread to the lung), one lung cancer cell line and one colon cancer cell line.

Researchers treated cell lines and tumor cells with low-dose AZA and DAC in culture for three days and allowed the drug-treated cells to rest for a week. They then transplanted the treated cells and tumor samples into mice and observed continued antitumour responses for up to 20 weeks. This extended response was in line with observations in some patients with MDS who continued to have anticancer effects long after stopping the drug.

The low-dose therapy reversed cancer cell gene pathways, including those controlling cell cycle, cell repair, cell maturation, cell differentiation, immune cell interaction and cell death. Effects varied among individual tumor cells, but the scientists generally saw that cancer cells reverted to a more normal state and eventually died. These results were caused, in part, by alteration of the epigenetic, or chemical, environment of DNA. Epigenetic activities turn on certain genes and block others, according to Baylin.

The research team also tested AZA and DAC’s effect on a type of metastatic breast cancer cell thought to drive cancer growth and resist standard therapies. Metastatic cells are difficult to study in standard laboratory tumor models because they tend to break away from the original tumour and float around in blood and lymph fluids. The research team re-created the metastatic stem cells’ environment and allowed them to grow as floating spheres.

Baylin and his team are conducting ongoing studies that focus on the precise mechanism of how the drugs work. “Our findings match evidence from recent clinical trials suggesting that the drugs shrink tumours more slowly over time as they repair altered mechanisms in cells and genes return to normal function, and the cells may eventually die,” said Baylin.

The results of clinical trials in lung cancer, led by Johns Hopkins’ Charles Rudin, M.D., and published late last year in Cancer Discovery, a journal of the American Association for Cancer Research, also indicate that the drugs make tumours more responsive to standard anticancer drug treatment.

According to researchers, this means that the drugs could become part of a combined treatment approach rather than a standalone therapy and as part of personalised approaches in patients whose cancers fit specific epigenetic and genetic profiles.

Low doses of both drugs are approved by the U.S. Food and Drug Administration for the treatment of MDS and chronic myelomonocytic leukaemia. Clinical trials in breast and lung cancer have begun in patients with advanced disease, and trials in colon cancer are planned.

The research was funded by a Specialized Programs of Research Excellence grant for lung cancer from the National Institutes of Health, the Hodson Trust Foundation, the Entertainment Industry Foundation, Lee Jeans, the Samuel Waxman Cancer Research Foundation, the Department of Defense Breast Cancer Research Program, the Huntsman Cancer Foundation and the Cindy Rosencrans Fund for Triple-negative Breast Cancer Research.

All of the studies have been accelerated by funding from the Stand Up To Cancer project in partnership with the American Association for Cancer Research.

Source: AACR