New technique identifies potential new treatment targets in hard-to-treat cancers

A “powerful” new technique can identify and potentially block the proteins involved in the process by which some of the hardest to treat cancers are maintained, offering potential new targets for treatments.

As cells divide, which they constantly do, they are susceptible to a disruption in copying their DNA, leading to abnormalities which as these abnormal cells in turn divide, can become cancer.

The new technique, called BLOCK-ID (biotinylation of lac operator [LacO] array replication stress protein network identification), was developed by a team of researchers led by Kyle M. Miller, PhD, a member of the Cell and Molecular Biology Research Program at Winship Cancer Institute of Emory University and professor in the Department of Radiation Oncology at Emory University School of Medicine. The study is published in Molecular Cell.

BLOCK-ID allows scientists for the first time to engineer and identify a specific location in cancer cells that blocks normal cell replication causing replication stress. The site of these blocks, called replication forks, are Y-shaped structures formed during DNA replication in which the double helix unwinds to allow for DNA copying. In cancer cells these forks are often disrupted, leading to replication stress and ultimately mutation formation, which can contribute to cancer development.

Using BLOCK-ID to mark this location with a molecular signal, the team was then able to read the signal to identify which proteins associated specifically with this site. “Knowing which proteins are involved in replication stress is a major bottleneck in defining mechanisms that act to promote cancer through replication stress response,” Miller says.

The team not only identified these proteins, but they also identified a new protein, called TRIM24 that localized to the replication forks.

Using this information, Miller and his colleagues studied a replication stress pathway involved in cancer called Alternative Lengthening of Telomeres (ALT). “This pathway is activated in 10% - 15% of all cancers and it maintains the ends of chromosomes, called telomeres, and is essential for cancer progression,” Miller explains. These so-called ALT cancers are tumors that use this telomere maintenance mechanism to preserve telomeres from shortening and perpetuate themselves. They include osteosarcoma, glioblastoma and pancreatic neuroendocrine tumors.

“BLOCK-ID is the first of its kind and represents a powerful new technique to identify proteins involved in replication stress,” Miller says. He points out that identifying a new pathway involving TRIM24 and three other proteins involved in ALT provides better understanding of how telomeres are maintained in ALT cancers and “provides four new potential treatment targets in this cancer.”

Miller says research underway at Emory will build upon these findings for future studies. “Future work will be aimed at testing these potential targets in ALT cancers to determine if they represent therapeutically actionable targets—which could provide benefits to patients with these hard-to-treat cancers.”

Besides Miller, the project was co-led by the principal investigator Roderick O’Sullivan, PhD, UPMC Hillman Cancer Center, University of Pittsburgh; with contributions from other principial investigators including Chan Hyan Na, MS, PhD, Johns Hopkins University School of Medicine; and Minkyu Kim, PhD, MS, Long School of Medicine, UT Health San Antonio.

The work was supported by funding from the University of Texas at Austin, Livestrong Cancer Institutes–Cancer Prevention and Research Institute of Texas, RP220330; UPMC Hillman Cancer Center, University of Pittsburgh–NCI RO1CA262316 and P30CA04790; Johns Hopkins University School of Medicine–NIH S10OD021844; and Long School of Medicine, UT Health San Antonio–NIGMS R35 GM156189.