Reference #: 01405
The University of South Carolina is offering licensing opportunities for Re-sensitizing p53-null Stem Cells with Spindle Assembly Checkpoint Inhibition
Background:
TP53 is one of the most well-studied tumor suppressor genes and is known to be pivotal in response to DNA damage for cell cycle arrest, deterioration with age, or cell death. The TP53 gene is the most commonly mutated gene across all cancers. The product of the TP53 gene is a sequence-specific DNA binding protein (p53) that regulates gene transcription. Targeting this gene directly is difficult with pharmaceutical products. This research proposes inhibiting spindle assembly checkpoints (SAC), which is the point at which the cell prevents the separation of duplicated chromosomes until each chromosome is properly attached to the spindle apparatus. This will allow the use of standard chemotherapy drugs by sensitizing the gene to them.
Invention Description:
TP53 mutations are common in most human cancers, but few therapeutic options for TP53-mutant tumors exist. To identify potential therapeutic options for cancer patients with TP53 mutations, we profiled 127 FDA approved chemotherapy drugs against human embryonic stem cells, in which we engineered TP53 deletion by genome editing. We identified twenty-seven cancer therapeutic drugs for which TP53 mutations conferred resistance; most of these drugs target DNA synthesis and cause DNA damage. We then performed a genome-wide CRISPR/Cas9 knockout screen in the TP53-null stem cells in the presence and absence of sublethal concentrations of cisplatin and identified 137 genes whose loss selectively re-sensitized the p53-null cells to this chemotherapeutic agent. Gene ontology classification of the re-sensitizing loci revealed significant overrepresentation of spindle checkpoint pathway genes. Development of small molecule inhibitors of spindle assembly checkpoint proteins may be a useful strategy for rescuing DNA-damaging chemotherapeutics in TP53 mutant cancers.
Potential Applications:
TP53 mutations are common in most human cancers and these mutations can cause cancer resistant to common chemotherapy drugs, but few therapeutic options for TP53-mutant cancers exist.
Advantages and Benefits:
This invention overcome resistant to FDA-approved chemotherapy drugs of TP53 null cancers.