Developing therapy-resistant cancers for research

A cancer cell line that is resistant to one of the newest classes of cancer treatments has been developed by researchers who already are using it to determine treatment alternatives for when it starts appearing in patients.

"The ultimate goal is to be able to understand how cancer cells develop resistance and to have forward-thinking strategies about how to combat that resistance," said Dr Warren Fiskus, postdoctoral fellow at the Medical College of Georgia (MCG) Cancer Center.

The scientists developed the cancer by treating human leukemic cells with regular, increasing doses of histone deacetylase (HDAC), inhibitors similar to what patients would receive.

Fiskus presented the findings during the American Society of Hematology's 49th Annual Meeting and Exposition in Atlanta this December.

"At each dose level, there were some cells that did die," said Fiskus.

"Ultimately, we isolated a population of cells that were resistant to very high concentrations of these agents and other agents in the same class."

They found the HDAC inhibitor-resistant cell line resistant to many therapies, including more standard treatment such as chemotherapy, but highly sensitive to heat shock protein 90 (hsp90) inhibitors, another emerging cancer treatment.

"As part of their resistance mechanisms, they acquired greater sensitivity to hsp90 inhibitors," said Dr Kapil Bhalla, director of the MCG Cancer Center.

"This particular cell line can be used to really look at newer agents and new combinations in vitro and in vivo and see if they are safe and effective together," said Fiskus.

Heat shock proteins are protein caretakers, activating genes that ultimately make proteins, move them around cells and fold them into shape for proper function. Misfolded proteins can cause cancer.

MCG is participating in an early-phase clinical trial of the oral HDAC inhibitor, LBH589, developed by Novartis. Studies are also underway for some innovative uses of hsp90 inhibitors, including its potential as an anti-angiogenesis agent and an anti-inflammatory agent for sickle cell disease.