Courtesy of Biocarta
In addition to cell-cycle regulation, mTOR plays a role in muscle hypertrophy following increased use through the growth factor IGF-1 and tumor suppressor PTEN. Blocking mTOR with drugs like rapamycin prevents muscle growth.
Rapamycin could have been an anti- than tumor contender. Indeed, for more than 30 years, researchers have sized up this immunosuppressant's potential in treating a variety of cancers, including prostate, brain, and lung. Currently, however, the drug is approved only for treating transplant patients. Initial struggles with formulation and the 1982 closure of the original Ayerst laboratory that produced it has kept rapamycin in the background as a cancer therapeutic.
Now, new findings are revealing the details of rapamycin's antitumor abilities through its aptly named therapeutic target, the mammalian target of rapamycin (mTOR). Moreover, the molecular pathways affected by mTOR, a key kinase in regulating cell-cycle progression, have grown to include some...
TEMPTING TARGETS
Both results suggested that rapamycin, in combination with mutations of these genes in the mTOR pathway, could stop tumor growth. "There you have events that have lead to a synthetic lethal interaction between mTOR inhibitors and the cells," says Houghton, who calls the potential to identify these sensitive cancers, very tempting.
Sawyers' work provided a rationale for using a rapamycin analog, CCI-779, on human cancers known to contain PTEN mutations.1 More work that year emerged from Ramon Parsons and colleagues at Columbia University, who used the same compound to reduce neoplasia in
Today, researchers are filling out the mTOR pathway's upstream and downstream components and finding proteins previously linked to cancer. Alan Lichtenstein and others at UCLA recently combined polysome isolation with microarray analysis to uncover mRNAs whose downregulation was required for cellular sensitivity to mTOR inhibition.4 It revealed c-Myc and cyclin D1 as important downstream mRNA targets of how CCI-779 blocks tumor growth. Such research points to the components that signal through mTOR as potentially new therapeutic targets.
Particularly enticing, says University of Texas professor Gordon Mills, is that two widespread cancer mutations render cells sensitive to mTOR inhibition. "The PI3K pathway is more frequently aberrant than any other pathway in cancer, with the possible exception of the p53 pathway." Mills cautions, however, that rapamycin analogs have shown only "modest single agent activity" and that long-term use may be required.
Bill Sellers, assistant professor at Harvard Medical School, agrees that the findings are generating excitement, and he predicts that studies combining mTOR inhibition with other cancer therapeutics will soon pop up. "The main side effect that people think about is immuno-suppression," says Sellers. He and Mills both suggest that chronic use could be a problem, "but you can probably handle that with prophylactic antibiotics," says Sellers.
Wyeth Pharmaceuticals, which merged with Ayerst Laboratories in the 1980s, has CCI-779 in clinical trials for renal and breast cancer. The full understanding of how mTOR inhibition and resistance work at the molecular level will open new opportunities, says Houghton: "mTOR seems to play this watershed role in the cell cycle and cell signaling," and as a result, finding the tumors controlled by mTOR will point the way to fighting those cancers.
David Secko
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