Epigenetics and Stand Up To Cancer
Co-leading the Epigenetic Dream Team
Few would dispute the amount of epigenetic research talent amassed at the Johns Hopkins Kimmel Cancer Center. Laboratory findings in leukemia and lung cancer paved the way for clinical trials of a drug that appeared to have the ability to fix some of the epigenetic initiated changes to genetic code that helped cancers grow and thrive.
The world was beginning to take notice, and Dr. Stephen Baylin’s laboratory model was becoming a clinical model. Crucial to these advances was a type of drug called a demethylating agent. Too much methylation in the active regions of tumor suppressor genes was found to shut the genes down, giving advantage to one of the cancer cell’s iconic behaviors – uncontrolled growth. Blocking the methylation of the gene turned it back on.
In 1980, another leading epigenetics expert, Peter Jones of the University of Southern California, provided some of the first evidence that demethylating agents might have unique and unexpected anticancer properties. He was studying the drug 5-azacytidine as a potential chemotherapy agent, when he observed that in low doses the drug didn’t brutally destroy cancer cells as most chemotherapy drugs did, but rather gently nudged the cell into behaving differently.
Years later, Dr. Baylin and team decided to take another look at the drug, which had largely been abandoned because of its toxicity. Laboratory studies in lung cancer and leukemia led to a clinical trial for patients with a pre-leukemia condition called myelodysplastic syndrome (MDS). It worked so well, with some patients disease-free for 10 years and counting, that the drug received FDA approval for treatment of MDS. Dr. Baylin wondered if the drug might also work against other cancers.
Then in 2008, the Entertainment Industry Foundation and Major League Baseball formed Stand Up To Cancer (SU2C) to mobilize the public to donate money for cancer research and to motivate the scientific community to collaborate on promising areas of research that could quickly be moved to clinical trials.
“Dream Teams” made up of clinicians and scientists from around the country—the best in their fields were formed—selected after rigorous review by another panel of esteemed cancer experts and directed to take on specific cancer research projects. When the Epigenetics Dream Team was announced, Drs. Baylin and Jones were the natural choices to lead it.
Dr. Baylin’s research of the role of DNA methylation in cancer had led him to a molecular co-conspirator. He observed that it wasn’t just DNA methylation that affected gene expression but also how the DNA was packaged in the cell. If the DNA contained within one cell was extracted and stretched out, end-to-end it would extend six feet. Yet all of that molecular material is compacted and packed inside the nucleus of a human cell. The nucleus is a structure so tiny that more than 50,000 of them can fit on the head of a pin.
Steve Baylin and Cynthia Zahnow
Chromatin, a complex combination of proteins, mainly histones, is responsible for compressing the DNA to fit inside a cell. This packaging also plays a role in gene expression and the copying of DNA as cells divide. A loose chromatin results in normal gene expression, but add methylation to the mix, and histones hold the DNA together tightly and interfere with the gene expression.
This tightened chromatin, Dr. Baylin and team found, can keep genes, including tumor suppressor genes, in a constant state of non-expression. It can cause cancer cells to behave in a primitive, embryonic-like manner. Unlike normal embryonic cells, which receive and respond to signals that tell them to stop making new cells, epigenetically altered cancer cells seem to maintain their ability to replicate, renew and divide.
Scientists do not know what prompts the cancer-promoting changes in chromatin structure. They suspect it may be a repair mechanism engaged in response to cell injury, such as chronic inflammation. While the cause is uncertain, Dr. Baylin’s research has identified a way that may fix it. In the laboratory, when he and his team combined a demethylating drug with a histone-blocking drug (HDAC inhibitor) in human cancer cell lines, the chromatin structure loosened and some gene expression was restored. This discovery became the focus of the first SU2C Epigenetic Dream Team patient study.