Hopkins scientists test ability of low doses of drugs, once deemed too toxic for humans, to 'reprogram' cancer cells and restore normal gene function.
Stephen Baylin, M.D., deputy director of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, makes it easy even for someone who's never stepped foot inside a scientific laboratory to understand how his sophisticated research on epigenetic-targeted drugs show promise at extending the life of patients with advanced breast cancer.
"The hard drive of our body and cells is the DNA. Every piece of information that allows us to do things right and wrong is in the hard drive. The hard drive needs a software package; that's what epigenetics are like," Baylin says. "Lots of genes have the software package abnormality. These drugs [Azacitidine (AZA) and Decitabline (DAC)], in the laboratory, can reverse the abnormalities of the software package. We’re trying to bring that to the clinic, to restore normal gene function. For the first time, we're bringing that potential to breast cancer."
Financial support from Stand Up 2 Cancer—an initiative that generously funds collaborative cancer research by world-class scientists dedicated to bringing rapid, innovative and targeted therapies to patients—is making possible this bold attempt at reprogramming breast cancer stem cells. Without support from the progressive program, Baylin believes he'd be talking about these drugs' potential only in hypothetical terms. "It probably would have taken us years to get these trials approved," he says.
While Stand Up 2 Cancer allows select scientists to fast track their research, it asks a lot of researchers in return. "In active trials you've got to show you're going to make a major change in the management of cancer," Baylin says. That's precisely what his research team is poised to do.
A second look at drugs once considered too toxic for humans
Once considered too toxic for human treatment, epigenetic-targeted drugs had been all but abandoned by most scientists. But Baylin and associates took a second look at the drugs after low doses of AZA and DAC proved beneficial in patients with a preleukemic disorder, myelodysplastic syndrome. Since then, Baylin's research team has seen positive results in lung cancer patients using low doses of the drugs. Now, their effects are being tested in patients with advanced breast cancer.
"The drugs being tested target the most stubborn of cancer stem cells—those which continue to renew, thereby dodging most cancer drugs and resulting in reoccurrence and spread of cancer," Baylin says. "We're trying to change gene memory. A dead cell can't remember anything.”
But it takes time for cancer cells to die.
Subsequently, the research requires a delicate balancing act. The scientists need to give the drugs sufficient time to work at attempting to change the pattern of gene expression among certain stubborn cancer cells. Patients who harbor these cells have advanced cancer, but the disease can't be too far along. “You have to have someone with advanced disease who is still doing okay; who has at least a month or two to live,” Baylin says.
Baylin and his associates have reason to believe the epigenetic-targeted drugs AZA and DAC are worth the wait. In the laboratory, they have treated breast cancer cell lines and human tumor samples with low doses of AZA and DAC for a few days before transplanting them into mice, in which antitumor responses have been observed for as long as 20 weeks.
Now the scientists running the trials, Roisin Maritxell Connelly, MBBS and Vered Stearns, MD, are seeing how patients with advanced breast cancer that has metastasized and is resistant to standard therapies respond to low doses of AZA and DAC. Thus far, the small cohort of 25 subjects has reported few adverse side effects aside from fatigue and the time commitment (drugs must be administered on-site). Overall toxicity is low, and the drugs do not cause hair loss. But the most exciting result of the study thus far has been the positive response to common cancer therapies among study subjects who, prior to receiving the epigenetic-targeted drugs, showed no benefit.
"We're getting our first evidence as to why these drugs may sensitize patients to tamoxifen, making it work better," Baylin says.