The role dysregulated transcription from the ribosomal RNA (rRNA) gene (rDNA) loci in eliciting a nucleolar stress response (NSR), which is heightened in cancer cells, is emerging as an exciting and significant area of cancer research. In the canonical NSR, disruptions to ribosome biogenesis (RiBi) result in p53 accumulation, as free ribosomal proteins (RPs) can bind and sequester MDM2, the ubiquitin ligase that targets p53 for degradation. In addition, though high throughput functional genome wide screening approaches we have uncovered a novel, atypical p53-independent NSR, associated with activation of DNA damage checkpoints, which has excellent potential for treating p53-null tumours. The validity of Pol I as a therapeutic target has been demonstrated by the selective Pol I transcriptional inhibitor, CX-5461which has entered clinical trials in Australia and Canada. Our mechanistic studies have demonstrated that CX-5461 kills tumour cells, in part, by triggering an acute NSR. Importantly, while drugs selectively targeting rDNA transcription to treat cancer are new, retrospective analyses of the targets for various chemotherapies (eg. classic platinum-based drugs) suggest that their efficacy is mediated in part through targeting rDNA transcription and the NSR.
Despite the overwhelming evidence for dysregulated RiBi in cancer, only 1 selective Pol I inhibitor, CX5461, has entered clinical trials. Although extremely promising, our investigation into mechanism of action has revealed additional activities of CX5461, that may not only contribute to its efficacy but also to the toxicity profile and mechanism of acquired resistance. To address the need for new, improved Pol I inhibitors we have developed a series of orally available selective inhibitors with improved toxicology, tissue distribution and efficacy compared to CX-5461. Preliminary studies on our new lead compound, PMR-116, which has demonstrated improved survival (at MTD) will be discussed along with our studies on mechanism(s) which confer sensitivity and resistance to Pol I inhibition therapy.
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The role dysregulated transcription from the ribosomal RNA (rRNA) gene (rDNA) loci in eliciting a nucleolar stress response (NSR), which is heightened in cancer cells, is emerging as an exciting and significant area of cancer research. In the canonical NSR, disruptions to ribosome biogenesis (RiBi) result in p53 accumulation, as free ribosomal proteins (RPs) can bind and sequester MDM2, the ubiquitin ligase that targets p53 for degradation. In addition, though high throughput functional genome wide screening approaches we have uncovered a novel, atypical p53-independent NSR, associated with activation of DNA damage checkpoints, which has excellent potential for treating p53-null tumours. The validity of Pol I as a therapeutic target has been demonstrated by the selective Pol I transcriptional inhibitor, CX-5461which has entered clinical trials in Australia and Canada. Our mechanistic studies have demonstrated that CX-5461 kills tumour cells, in part, by triggering an acute NSR. Importantly, while drugs selectively targeting rDNA transcription to treat cancer are new, retrospective analyses of the targets for various chemotherapies (eg. classic platinum-based drugs) suggest that their efficacy is mediated in part through targeting rDNA transcription and the NSR.
Despite the overwhelming evidence for dysregulated RiBi in cancer, only 1 selective Pol I inhibitor, CX5461, has entered clinical trials. Although extremely promising, our investigation into mechanism of action has revealed additional activities of CX5461, that may not only contrib ...
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