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Gene Editing Harnessed to ID Cancer Targets

Acute myeloid leukemia cells

Acute myeloid leukemia cells (Cancer Genome Atlas, NIH)

12 May 2015. Researchers from Cold Spring Harbor Lab in New York developed a technique that reveals targets for leukemia drugs with an emerging gene editing technology. A team from the lab of geneticist Christopher Vakoc published its findings yesterday in the journal Nature Biotechnology (paid subscription required).

Vakoc and colleagues study proteins regulating chromatin, the substance of DNA and proteins in the nucleus of cells that form chromosomes, and their role in cancer. In 2011, a team from the lab identified a protein that supports production of acute myeloid leukemia cells, as well as a pocket on the surface of cancer cells where the protein binds. Their discovery led to identification of an existing drug on the market — JQ1, a male contraceptive — that blocks the protein from binding, thus preventing the growth of that type of leukemia and causing the death of cancer cells.

While that discovery highlighted the role of identifying proteins that bind to pockets on cancer cells, the team sought a more scalable process for screening genes and proteins than the one used in the first study. That search led to CRISPR, short for clustered regularly interspaced short palindromic repeats, working with CRISPR-associated protein 9 or Cas9, an emerging technology that makes it possible to identify and repair specific genes needing repair, such as those causing inherited diseases.

In this case, the researchers were more interested in identifying proteins associated with binding to pockets on cell surfaces, which is why they found CRISPR-Cas9 is attractive. In editing genomes, CRISPR-Cas9 identifies specific genes and variations of those genes, especially disease-causing mutations, needing repair. The Cold Spring Harbor team used that same capability to identify genes encoding protein chemistries that bind to the pockets on specific cancer-causing cells.

The technique devised by the researchers alters DNA codes to simulate mutations in the gene changing the pockets used by proteins to bind to cells, and screening for proteins that fit into those pockets. Those proteins could either encourage proliferation of cancer cells or block the binding of cancer-supporting proteins. “If you change the pocket so the protein is no longer functional and you find the cancer can’t survive, then you have a good shot at a useful drug target,” says Vakoc in a Cold Spring Harbor statement. “We can’t tell if any particular pocket will lead to a fully effective drug; but this is a way to annotate every critical pocket in cancer cells.”

The researchers tested the concept on 192 chromatin protein collections from mouse models of acute myeloid leukemia cells. The team identified 6 known proteins associated with the disease. But the researchers also identified 19 other proteins with at least the potential of blocking cancer-supporting proteins from binding to cells. The 19 targets were not previously known to have these binding-blocking properties.

Vokoc’s lab is now applying this technique to targets of greatest interest to pharmaceutical companies. “We want to have an impact on cancers in the near-term,” says Vakoc. “We want to provide pharmaceutical companies the kind of targets that they have extensive experience figuring out how to hit.

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