By altering gene activity, approach sensitizes cells to chemotherapy
CHICAGO —Traditional therapies go all out to kill cancer cells, but a new approach works by first persuading tumor and blood cancer cells to alter their rogue behavior — and then wiping the tumor cells out.
Drugs that alter some chemical tags on DNA make cancer cells behave more like normal cells, geneticist Stephen Baylin of Johns Hopkins University School of Medicine reported April 1 at the American Association for Cancer Research annual meeting. And the drugs seem to make cancer cells more susceptible to chemotherapy and attacks from the immune system.
Baylin and colleagues reported in the March 20 Cancer Cell that two drugs called azacitidine and decitabine, when used in low doses, change gene activity in leukemia and breast cancer cells in the lab. If DNA is a cell’s hard drive, then chemical tags attached to the DNA or DNA-packaging proteins called histones serve as software packages to tell the hard drive how to function. This type of chemical programming is called epigenetics.
Cancer researchers are tracking down glitches in epigenetic programming that turn cells cancerous and figuring out ways to reboot the system with drugs such as azacitidine.
Although the approach is new, the drugs aren’t. Azacitidine, a drug that helps strip chemical tags called methyl groups off of DNA, was developed decades ago, but it was too toxic to use in high doses. It and decitabine fell out of favor in the 1970s. “They were essentially sitting on the shelf gathering dust,” says Jean-Pierre Issa of Temple University School of Medicine in Philadelphia.
Issa, Baylin and a team of researchers dusted off the drugs and investigated how they and similar drugs work in cancer cells. In a clinical trial the team reported last year, azacitidine used in combination with a drug called entinostat helped stop or reverse tumor growth in some lung cancer patients whose cancer didn’t respond well to previous treatments. At the meeting, Baylin provided an update on the trial.
Baylin said that 28 of the 62 patients were given the drug combination and subsequent chemotherapies. Of them, eight responded to the chemotherapy, surviving an average of 20.75 months. The epigenetic treatment also improved therapies that stimulate the immune system to attack tumors.
Results from another clinical trial showed that low doses of a new drug called SGI-110, which also resets DNA methylation patterns, is most effective if given every day for five days compared with the usual single dose once every five days, Issa reported.
One patient who received SGI-110 was a 59-year-old man with acute myelogenous leukemia. The man’s leukemia had returned three months after a stem cell transplant. Usually patients die within a few weeks of a relapse, but after treatment with SGI-110 the man’s cancer went into remission. He is still alive, eight months later.
“What’s most exciting is that tumors that didn’t respond to therapy now will,” Phillip Sharp, a cell biologist at MIT, said of the new approach to cancer therapy. “If this works as it looks like it will, it could be used across a wide variety of cancers.”
H.-C. Tsai et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell. Vol. 21, March 20, 2012, p. 430. doi:10.1016/j.ccr.2011.12.029. [Go to]
S. Baylin. Bringing epigenetic therapy to the forefront of cancer management. American Association for Cancer Research meeting, Chicago, April 1, 2012.
J.-P. Issa. Interim results from a randomized Phase 1-2 first-in-human (FIH) study of PK/PD guided escalating doses of SGI-110, a novel subcutaneous (SQ) second generation hypomethylating agent (HMA) in relapsed/refractory MDS and AML. American Association for Cancer Research meeting, Chicago, April 2, 2012.
R.A. Juergens et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discovery. Vol. 1, December 2011, p. 598 doi:10.1158/2159-8290.CD-11-021. [Go to]