Scientists at Case Western Reserve University report that they have identified a two-pronged therapeutic approach that shows great potential for weakening and then defeating cancer cells. They say their complex mix of genetic and biochemical experiments has unearthed a way to increase the presence of a tumor-suppressing protein which, in turn, gives it the strength to direct cancer cells toward a path that leads to their destruction.

If the lab findings are supported by tests in animal models, the breakthrough could hold the promise of increasing the effectiveness of radiation and chemotherapy in shrinking or even eliminating tumors, according to the researchers. The key is to build up the p53-binding protein 1 (53BP1) so that it weakens the cancer cells, leaving them more susceptible to existing cancer-fighting measures. The study, “UbcH7 regulates 53BP1 stability and DSB repair,” was published in PNAS.

“Our discovery one day could lead to a gene therapy where extra amounts of 53BP1 will be generated to make cancer cells more vulnerable to cancer treatment,” said senior author Youwei Zhang, Ph.D., assistant professor of pharmacology, Case Western Reserve University School of Medicine, and member of the Case Comprehensive Cancer Center. “Alternatively, we could design molecules to increase levels of 53BP1 in cancers with the same cancer-killing end result.”

The cornerstone of the research involves double-strand DNA repair. DNA damage is the consequence of an irregular change in the chemical structure of DNA, which in turn damages and even kills cells. The most lethal irregularity to DNA is the DNA double-strand break (DSB) in the chromosome. DNA DSBs are caused by everything from reactive oxygen components occurring with everyday bodily metabolism to more damaging assaults such as radiation or chemical agents.

The body uses two pathways to fix these DSBs. One provides rapid, but incomplete repair, i.e., gluing the DNA strand ends back together. The problem here is that it leaves the DNA strands unable to transmit enough information for the cell to function properly, which leads to a high cell-fatality rate.

The second pathway relies on information from intact, undamaged DNA to instruct damaged cells on how to mend broken double strands. During his study, Dr. Zhang and fellow investigators discovered a previously unidentified function of a known gene, UbcH7, in regulating DNA DSB repair. Specifically, they found that depleting UbcH7 led to a dramatic increase in the level of the 53BP1 protein.

“What we propose is increasing the level of 53BP1 to force cancer cells into the error-prone pathway where they will die,” according to Dr. Zhang. “The idea is to suppress deliberately the second accurate repair pathway where cancer cells would prefer to go. It is a strategy that would lead to enhanced effectiveness of cancer therapy drugs.”

The next research step for Zhang and his team will be to test their theory in animal models with cancer. Investigators would study the effects of introducing the protein 53BP1 in lab mice with cancer and then applying chemotherapy and radiotherapy as treatment.

“Our studies reveal a novel layer of regulation of the DSB repair choice and propose an innovative approach to enhance the effect of radiotherapy or chemotherapy through stabilizing 53BP1,” wrote the investigators.








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