rRNA transcription as potential therapeutic target in triple negative breast cancers

Abstract

Cancer has been identified as a group of diseases characterized by abnormal cell growth. In eukaryotic cells, the nucleolus is the region of the nucleus where initial stages of ribosome production occur. These stages include synthesis of ribosomal RNAs by RNA Polymerase 1 (RNAP1) followed by its processing and modification. For decades, the size and number of nucleolus (sites of RNAP1 transcription) have been as the marker for the aggressive tumours. The nucleolus size correlates with the level of rRNA transcription and the level of ribosome biogenesis. In recent years the rRNA transcription has emerged as novel target for anti-cancer therapy and number of specific RNAP1 transcription inhibitors are currently undergoing clinical trials as anti-cancer agents and the selective inhibition of RNAP1 transcription is he novel strategy against number of cancers including hematological malignancies and breast cancer. The currently available inhibitors are characterised by a different mechanism and different levels of genotoxicity. Three drugs, (CX-5461, BMH-21 and PMR-116) are small molecules and selective inhibitors of RNAP1 transcription which have moderate effect on transcription by other nucleolar polymerases and protein translation and which are at different stages of clinical development. CX-5461 inhibits transcription by displacing essential promoter recognition factor SL1 thus preventing an initiation of transcription. BMH-21 inhibits elongation and induces rapid degradation of RNAP1. PMR-116 demonstrated a great potential as RNAP1 inhibitor, is characterized by low cytotoxity and very high anti-cancer effect. However, the exact molecular mechanisms of RNAP1 inhibition is unknown. Therefore, this experiment aims to identify the stage of the transcription cycle affected by PMR-116 by using a combination in vitro and vivo based assays. Also, to determine the drug target into the molecular mechanism of PMR-116 by using biochemical methods including Isothermal Titration Calorimetry (ITC).

Thesis embargoed until 31 December 2022.

Date of Award	Dec 2021
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Saudi Arabia Government
Supervisor	Simon McDade (Supervisor) & Konstantin Panov (Supervisor)