Exploiting cancer cells' weaknesses

Mar 08, 2011 by Anne Trafton
Professor of Biology Angelika Amon. Photo: Donna Coveney

When designing new cancer drugs, biologists often target specific gene mutations found only in cancer cells, or in a subset of cancer cells. A team of MIT biologists is now taking a slightly different approach, targeting a trait shared by nearly all cancer cells -- they have too many chromosomes.

MIT biology professor Angelika Amon has been studying this peculiarity, known as aneuploidy, for several years. In developing fetuses, aneuploidy causes death or . However, in cancer cells, aneuploidy appears to confer a survival advantage.

“We’re interested in this because the vast majority of human cancers are aneuploid,” says Amon, a member of the David H. Koch Institute for Integrative Cancer Research. “The question arises, can we exploit the fact that all tumor cells are aneuploid for treatment? Compounds that selectively kill aneuploid cells would be effective against a broad spectrum of human tumors.”

In a study published Feb. 18 in the journal Cell, Amon and her colleagues identified three such compounds, and they are now running a large-scale screen of thousands of compounds, with researchers from Harvard, to identify even more drug candidates. Lead author of the paper is Yun-Chi Tang, a postdoctoral fellow at the Koch Institute.

Cell stress

Amon has previously shown that aneuploid cells divide very slowly and grow too large. Aneuploidy also puts significant stress on cells: It takes a lot of energy to replicate all of that extra genetic material, and to produce the proteins encoded by those extra genes. Furthermore, the cells then have to break down all those proteins, since they’re not needed. “Cells have a limited number of tools available to deal with extra proteins,” Amon says. “These pathways get stressed and they can’t keep up.”

In the Cell study, Amon selected about 20 potential drug compounds that might exploit those weaknesses. “We said, maybe we can enhance those stresses and induce lethality. The hope is to enhance it to a level that does not affect normal cells but would affect aneuploid cells more,” she says.

The researchers tested the compounds in mouse embryonic fibroblasts that have an extra chromosome, and then in human cancer cells. They identified three compounds that preferentially targeted the aneuploid cells (both human and mouse): chloroquine, a drug commonly used to treat malaria, and two other compounds called AICAR and 17-AAG.

AICAR stresses cells by activating an enzyme called AMPK, which cranks up cellular metabolism. 17-AAG inhibits the production of a protein involved in stabilizing other proteins that cancer cells need to grow. Chloroquine acts by blocking a cancer cell’s ability to rid itself of damaged proteins and cell structures.

Amon says she believes the drugs are exaggerating the stresses of , but more experiments are needed to show that.

All three compounds induce human cancer cells to kill themselves, but they work much better when two are used together. 17-AAG is already in clinical trials for leukemia, but these new data suggest that it would be better used in combination with other drugs, Amon says.

AICAR is not approved for human use, but a similar drug called metformin is used to treat diabetes. However, metformin did not perform as well in this study as AICAR.

Pumin Zhang, professor of molecular physiology at Baylor College of Medicine, says the results represent a significant step toward finding drugs that specifically target cancer cells, unlike most of the chemotherapy drugs now available. “It shows there is a clear difference between normal cells and aneuploid , and we can exploit that difference,” says Zhang, who was not involved in this research.


This story is republished courtesy of MIT News (web.mit.edu/newsoffice/), a popular site that covers news about MIT research, innovation and teaching.

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yobosangria
not rated yet Mar 08, 2011
The fantastic diabetes drug Metformin also upregulates AMPK and is effective at preventing cancer. It has also been shown to increase apoptosis in pancreatic cancer cells. AMPK is an energy sensor and by upregulating it, the body responds as if it is a famine state, exerting its energies in repair rather than growth. This research fits within that general framework and I hope to see the day when metformin or another Caloric Restriction mimetic is prescribed to all persons middle-aged and older. Google metformin and aging, metformin and cancer, metformin, even metformin and Alzheimer's. Metformin has well over a billion man-years of use, and is safe except for those with renal failure. I'm proud of my alma mater for this research effort and the out-of-the-box thinking it represents.

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