Rapamycin study is first stage in development of new treatment

Rapamycin isn't your ordinary potential anti-cancer drug…It had a long and somewhat exotic history before undergoing preclinical (laboratory-based) studies at St. Jude as part of a national Pediatric Preclinical Testing Program (PPTP) investigation of its anticancer activity.

Scientists originally discovered that bacteria in a soil sample from the isolated triangle of volcanic rock in the South Pacific known as Easter Island produced rapamycin, and that it was a good anti-fungal agent.

But when drug makers discovered it also could prevent rejection of transplanted organs by suppressing the immune system, rapamycin’s career took a significant turn. And still later, scientists discovered it had anti-cancer activity as well.

Rapamycin is a highly specific inhibitor of the molecule mTOR, an enzyme the cell needs to turn genetic blueprints into specific proteins required for cell growth.

When used to treat cancer, such highly specific drugs are called molecularly targeted therapy; they are designed to inhibit specific molecules rather than “poison” the cell as a whole. This strategy, which depends on discovering precise protein targets, is likely to reduce the level of toxic side effects common with standard chemotherapy, according to Peter Houghton, PhD, Molecular Pharmacology chair.

In a report appearing in the online edition of Pediatric Blood Cancer, an international team of PPTP investigators led by Houghton describes results of a series of laboratory tests that put rapamycin through its anti-cancer paces.

PPTP is a consortium of institutions in the United States and Australia that tests agents or combinations of agents in laboratory cultures and mouse models of common childhood cancers. The program is supported through a National Cancer Institute research contract, with Houghton as the principal St. Jude investigator.

The current study was a stage I (preclinical) PPTP investigation of rapamycin’s ability to inhibit growth of specific cancers, either in culture dishes or in mouse models of the cancers. The team reported that rapamycin is effective in tumor cultures and mouse models of diseases such as the solid tumors rhabdomyosarcoma and osteosarcoma, as well as in acute lymphoblastic leukemia.

In the culture dish studies, rapamycin reduced cancer growth by at least 50 percent among 10 of 23 cell lines (populations of cells originally obtained from specific cancer patients). These included five out of seven cell lines that represented lymphoid cancers (cancers of white blood cells or tissues in which they develop), as well as osteosarcomas (bone cancer) and Rhabdomyosarcoma (muscle cell cancer). In two lymphomas, a non-Hodgkin lymphoma and an ALL cell line, rapamycin reduced growth by 85 percent and 77 percent, respectively.

In mouse models, rapamycin was especially effective against a total of four cell lines: rhabdoid tumor (kidney cancer), rhabdomyosarcoma, osteosarcoma and ALL. Rapamycin significantly increased event-free survival in 75 percent of the 36 tumor lines examined. Although the overall response rate was 16 percent, drugs like rapamycin will not be most useful when used alone to target mTOR, according to Houghton, the paper’s first author.

“During the next stage of testing we will combine rapamycin with standard chemotherapy drugs to see if there are combinations that work particularly well against specific cancers,” he said. “But the greatest potential for improving treatment might be combining rapamycin and other molecularly targeted drugs in specific ways according to the genetic characteristics of the cancer and of the child.”

Other St. Jude authors of the paper include Christopher Morton, Molecular Pharmacology; and Catherine Billups, Biostatistics.