Building on the basic science of how cells function, researchers from Mayo Clinic and the University of Arkansas for Medical Scientists present a new tool for cancer research — and potentially therapy — in a recent Advanced Science article.
This tool, which was studied using prostate cancer animal and cell models, consists of human-made protein complexes, called "proteolysis-targeting chimeras," that remove problematic proteins using a cell's waste disposal mechanisms. The teams report that the chimeras, often called PROTACs, were altered to include probes, called "oligonucleotides." The probes target two prostate cancer promoters: DNA-binding proteins LEF1 and ERG. They are called transcription factors, and they are two examples of thousands of proteins that control gene expression, where genes are activated or suppressed.
"Approximately 2,000 transcription factors have been identified in eukaryotic cells, and they are associated with numerous biological processes," says Haojie Huang, Ph.D., the Gordon H. and Violet Bartels Professor of Cellular Biology at Mayo Clinic and one of the two senior authors on the paper. "Among them, approximately 300 transcription factors are associated with cancer development, which accounts for about 19% of oncogenes (mutated genes that are linked to cancer development)."
This makes targeting transcription factors a promising strategy for cancer treatment. But researchers have struggled because most transcription factors lack naturally occurring sites where a drug could dock and do its work. With PROTACs, researchers bypassed the need for a dock — think of a string with a magnet tied to either end. One magnet attracts the problem protein, and the other draws the cell's waste disposal manager, called "ubiquitin ligation enzyme." That link causes the problem protein to be tagged for disposal, broken down and recycled.
But instead of the standard "string," the authors harnessed oligonucleotide sequences that matched the DNA elements uniquely bound by each of the problematic transcription factors. So LEF1 would be drawn in more efficiently on one, and ERG protein would be linked more effectively on the version that corresponded to its binding sequence. To clarify this improvement, the authors call this technology "O'PROTAC" to signify that it is an oligonucleotide-based proteolysis-targeting chimera.
From Research to Therapy
Dr. Huang and his lab at Mayo have been investigating transcription factors in cancer, with a focus on prostate cancer, since 1997.
"Targeting disease-driven transcription factors has been a major goal of my laboratory at Mayo Clinic," says Dr. Huang. "This innovative study was possible through a successful collaboration of my group with a very talented team led by Dr. Hong-yu Li, a medicinal chemist at the University of Arkansas for Medical Sciences. We will continue to work closely with Dr. Li's group to optimize and define the lead O'PROTACs to improve the in vivo anti-cancer efficacy."
The teams are pursuing federal grants to develop the tool into a drug discovery and development platform, and they have patented this technology.
"To accelerate the translation of this major scientific breakthrough into the clinic, we are seeking investigational new drug approval and clinical trials for some of the lead O'PROTACs for cancer treatment," says Dr. Huang. "Since transcription factors also play essential roles in pathogenesis of diseases such as cardiovascular disease and obesity, it is our expectation that O'PROTACs can also be harnessed for the treatment of these diseases."
A complete list of authors and funding information is in the journal article. The authors declare no conflict of interest.