Noncancerous Cells of the Tumor Microenvironment Skew Drug Effectiveness Assays

Cancer researchers have developed a system for screening drug candidate compounds that is based on cancer cells that are "co-cultured” with noncancerous cells in a format that mimics the natural tumor microenvironment.

Conventional anticancer drug screening is typically performed in the absence of noncancerous cells of the tumor microenvironment, which can profoundly alter antitumor drug activity. To address this limitation, investigators at the Dana-Farber Cancer Institute (Cambridge, MA, USA) developed a tumor cell-specific in vitro bioluminescence imaging (CS-BLI) assay. In this assay system tumor cells (for example, myeloma, leukemia, and solid tumors) that stably express the gene for the enzyme luciferase are cultured with nonmalignant accessory cells (for example, stromal cells) for the selective quantification of tumor cell viability following drug treatment. The test is carried out in parallel on cultures of the tumor cells lacking the presence of stromal cells. CS-BLI is a high-throughput assay system that is able to identify stroma-induced chemo-resistance in various types of cancer.

The assay measures the amount of light emitted by living cancer cells. After treatment with a drug candidate, reduction in the amount of light being emitted indicates how proficient the drug was at killing tumor cells, and whether this effectiveness changes when normal cells are around the tumor. To determine whether the candidate compound is also toxic to normal cells, a "counter-screen,” is conducted to measure the effect of the compound on normal cells.

Results published in the March 14, 2010, online edition of the journal Nature Medicine revealed that in general drug candidates that acted powerfully against isolated samples of tumor cells were significantly less effective against the same types of tumor cells co-cultured with nonmalignant cells. However, in an exception to this trend, they found that the drug candidate reversine was more active against myeloma tumor cells when the cells were in contact with healthy cells of the bone marrow.

"Despite their often impressive results in the laboratory, for every 100 potential anticancer therapies administered in patients in clinical trials, only about eight prove safe and effective enough to receive Food and Drug Administration approval,” said senior author Dr. Constantine Mitsiades, professor of medical oncology at the Dana-Farber Cancer Institute. "This success rate is clearly not as high as we would like it to be, and one reason may be that so far we have not had a good way to account, at the earliest stages of laboratory testing, for the impact of the tumor microenvironment on these drugs.”

"The technique also provides a powerful tool for determining which biological mechanisms allow cancers to become resistant to certain treatments and which new therapies can neutralize those mechanisms,” said Dr. Mitsiades. "It will be of use in prioritizing candidate drugs for further rigorous study of their properties before embarking on clinical trials. This technique may show that the classical methods of studying candidate cancer drugs in laboratory conditions have overestimated the effectiveness of some agents, and underestimated others.

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Dana-Farber Cancer Institute