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Personalized Chemotherapy Devised from Patients’ Tumors

Chemotherapy (National Institutes of Health)

(National Institutes of Health)

Researchers at Johns Hopkins University in Baltimore developed a new lab technique to personalize the selection of chemotherapy drugs, with cell lines based on patients’ own tumors and genetically engineered mice. The findings of the team led by Johns Hopkins professor James Eshleman appear online in a recent issue of the journal Clinical Cancer Research (paid subscription required).

Current techniques for customizing chemotherapy drugs, say the researchers — which include team members from Colorado, Germany, and Spain — are technically challenging, of limited use, and slow. Commercial tests are available that analyze tissue samples against some cancer drugs. But Johns Hopkins professor and co-author Anirban Maitra says tissue samples used in these tests can be harmed by anesthetic drugs or by shipping to a remote lab, compromising the results.

The method devised and tested in the study takes human pancreatic and ovarian tumor cells and injects them into mice genetically engineered to quickly produce tumors. When the tumors grow to one centimeter in diameter, the scientists transfer the tumors from the mice to culture flasks in the lab, for testing with potential anticancer drugs.

The mice in this study were further engineered and bred to overcome a nagging problem facing attempts to grow human tumor cell lines in the lab: the tendency of noncancerous cells in a tumor to overgrow cancerous cells. This problem, say the authors, prevents growing cell lines for some cancers, or reflecting the full scope of the disease.

To get clear this hurdle, the mice were engineered and bred to replace the noncancerous cells with mouse cells that chemicals can destroy, leaving pure human tumor cells for testing against potential drugs. “Our technique allows us to produce cell lines where they don’t now exist,” says Eshleman, “where more lines are needed, or where there is a particularly rare or biologically distinctive patient we want to study.”

In a proof-of-concept study, the researchers created three cell lines for pancreatic cancer and one cell line for ovarian cancer. The team tested one of the pancreatic cancer cell lines against the Johns Hopkins library of 3,131 drugs, which returned 77 candidates approved by the FDA with potential activity against the tumors, including digitoxin and nogalamycin to which the tumor cells in this one line appeared most sensitive.

The researchers then tested the two drugs on mice grafted with the tumor cells from that pancreatic cancer cell line, compared against tumor cells from another pancreatic cancer cell line, as well as against a control medication. After 30 days, the digitoxin and nogalamycin treatments reduced the size and appearance of tumors more in the cell line predicted to be more sensitive to these drugs, than in the comparison pancreatic cell line.

Maitra notes that “our cell lines better and more accurately represent the tumors, and can be tested against any drug library in the world to see if the cancer is responsive.” Johns Hopkins is partnering with The Jackson Laboratory, a mouse genetics research facility in Maine, to breed and distribute one type of engineered mice from this study, and is seeking collaborators for two other types.

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