Image: Transcription Network guarding the genome by sensing DNA damage. Courtesy of: [Mats Ljungman & David P. Lane Nature Reviews Cancer 4, 727-737 (September 2004) doi:10.1038/nrc1435]
Case Western Reserve researchers have uncovered a new potential cancer therapy that reveals a 2-pronged approach of worsening and then, ultimately, conquering cancer cells. Their complex formulation of genetic and bio-chemical reagents allowed this team of researchers to discover a method of boosting the existence of a tumor-suppressing protein, p53-binding protein 1 (53BP1). In effect, this would give clinicians the power to direct cancer tissues down a path leading to their destruction.
The breakthrough may be the key to raising the effectiveness of modern cancer therapies in a way that can ultimately eliminate the use of blind therapies to eradicate tumors, such as chemotherapy and radiation. The key, they say, is to build up the "good" protein 53BP1 so that it weakens the cancer tissues, leaving them much more susceptible to existing cancer therapies.
"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, PhD, 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 basis for their study involves the repair of irregular changes in the chemical language of double-stranded DNA. Damaged DNA only works to harm and then kill cells of the body. In this way, double-strand breaks within the chromosome are seen as the most lethal type of mutation and can be triggered by the mere oxidation of normal physiological metabolism, or it can also involve more damaging assaults to the body, including chemical poisons or radiation.
Two repair pathways in the body operate like a mechanic's repair shop to mend these double-strand breaks. One pathway provides incomplete, although quick repair -- specifically, gluing the frayed ends of the DNA back together. The second prong, or pathway, uses the information provided from intact, undamaged genes to cue damaged cells to begin mending broken double strand breaks. Through their study, Zhang and team found a previously unidentified function of a known gene, UbcH7, which regulates the repair of double-strand breaks. Namely, they discovered that depleting UbcH7 led to some dramatic rise 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," Zhang said. "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 measure for Zhang and his group is to test their theory in animal models. Investigators would examine the ramifications of presenting the protein 53BP1 in lab mice with cancer, and then using radiotherapy and chemotherapy as follow-up care.
"Each cell in our bodies already contains these UbcH7 proteins that regulate 53BP1," Zhang said. "In patients with cancer, we want to induce more of 53BP1 proteins within their bodies to make their cancer cells vulnerable to radiation therapy and chemotherapy drugs."
Sources / Further Reading
Xiangzi Han, Lei Zhang, Jinsil Chung, Franklin Mayca Pozo, Amanda Tran, Darcie D. Seachrist, James W. Jacobberger, Ruth A. Keri, Hannah Gilmore, Youwei Zhang. UbcH7 regulates 53BP1 stability and DSB repair.Proceedings of the National Academy of Sciences, 2014; 111 (49): 17456 DOI: 10.1073/pnas.1408538111