New Cancer Therapies Aim Above & Beyond the Genome

Cancer researcher Christopher Vakoc, PhD, goes “above the genome” in search for leukemia drug targets.

New Cancer Therapies Aim Above & Beyond the Genome

If cells in the human body contain identical DNA, why are skin cells so different from lung cells? If identical twins have the same genome, what accounts for differences in their physical characteristics? Enter epigenetics-a term literally meaning "above the genome"- to refer to biological processes that impact gene expression, without altering the underlying DNA sequence. The idea behind epigenetics is that if researchers can first identify the proteins that play a crucial role in tumor cell survival, they may then be able to find means to inhibit these proteins and cut cancer pathways off at the pass.

Epigenetics is particularly appealing to cancer researchers because it could give insight into why some patients experience significant side effects, do not respond to conventional cancer treatments, or have recurrent cancer. The emerging field of epigenomics has led to the critical identification of pathways that are not only disrupted in cancer, but are also selective enough to leave the 'normal' cells behind, unharmed, while also contributing to treatment response.

Cold Spring Harbor Laboratory's Christopher Vakoc, PhD, and his research team have been studying the epigenome and acute myeloid leukemia (AML); in 2011, they discovered that a protein called BRD4 (which is known to inhibit proteins responsible for "reading" the epigenome, a key step in the expression of all proteins in a cell) was found in abundance in AML, and was necessary for cancer cell replication. A drug called JQ1 was being tested as a possible treatment for other conditions but Vakoc's team discovered that it suppressed BRD4, leading to the death of the cancer cells while normal cells survived. How exactly the drug worked was still a mystery.

Watch this video hear more from Vakoc about his work on this possible treatment:

Vakoc's lab suspected that the long form of an enzyme called NSD3 played a critical role in BRD4 suppression in AML, but Chen Shen, MD, PhD, a researcher in Vakoc's lab, conducted a series of experiments with surprising findings. In stark contrast to the dogma, the unassuming NSD3-short was shown to be critical for AML cancer epigenetics. "It's a David-and-Goliath story," Vakoc stated. "We figured the long, or full-length, form of NSD3 was of interest because it has a portion, or domain, that enables it to act as an enzyme, and another that suggests its involvement in epigenetic gene regulation." When applied to AML cells, JQ1 caused NSD3-short and BRD4 to break apart, along another protein called CHD8. Not only did the researchers gain greater insight into how JQ1 worked, but they also identified CHD8 as an additional protein that could be a target in AML treatment.

Although Vakoc and his team will have a long and difficult road ahead of them in further investigating if JQ1 and other protein inhibitors are effective enough to one day become treatments approved by the Food and Drug Administration for AML, even the most modest of proteins hold promise for epigenetics. In epigenetic research, the epigenome continues to reveal the complexities of tumors but revelations about fighting cancer above and beyond the genome.


Christopher Vakoc, PhD, will speak at the upcoming event "Epigenetics: Cancer and Beyond." Click here for more information and to register for the event. The event will also be available as a Webinar.