Abstract
Advances in technology have facilitated the molecular profiling (genomic and transcriptomic) of tumours, and has led to improved stratification of patients and the individualisation of treatment regimes. To fully realize the potential of truly personalised treatment options, we need targeted therapies that precisely disrupt the compensatory pathways identified by profiling which allow tumours to survive or gain resistance to treatments. Here, we discuss recent advances in novel therapies that impact the genome (chromosomes and chromatin), pathways targeted and the stage of the pathways targeted. The current state of research will be discussed, with a focus on compounds that have advanced into trials (clinical and pre-clinical). We will discuss inhibitors of specific DNA damage responses and other genome stability pathways, including those in development, which are likely to synergistically combine with current therapeutic options. Tumour profiling data, combined with the knowledge of new treatments that affect the regulation of essential tumour signalling pathways, is revealing fundamental insights into cancer progression and resistance mechanisms. This is the forefront of the next evolution of advanced oncology medicine that will ultimately lead to improved survival and may, one day, result in many cancers becoming chronic conditions, rather than fatal diseases.
Highlights
Improved treatments for cancer are moving rapidly beyond “one size fits all” treatment regimes to precision medicine [1,2,3,4]
RecQL1 is a DNA repair protein whose activity is regulated by PARP1, and plays a key role in the recovery from replication stress induced by topoisomerase I inhibitors [201]
Bloom’s syndrome (BLM) is the key element in a complex that includes topoisomerase IIIα and the RecQ-mediated genome instability (RMI) sub-complexes (RMI1 and RMI2), and its coordinated action is critical for unwinding a wide range of DNA structures that can arise during DNA replication and repair [215]
Summary
Improved treatments for cancer are moving rapidly beyond “one size fits all” treatment regimes to precision (or personalised) medicine [1,2,3,4] This approach involves profiling the patient or tumour (genomic or transcriptomics), which allows dysregulated pathways to be categorised and specific targeted treatments to be selected and implemented, with the aim of improved targeted killing of cancer cells. Genomic instability can be induced through defects (such as downregulation/mutation of key genes/proteins) in either the homologous recombination (HR), or the error-prone (intrinsically mutagenic) Non-Homologous End Joining (NHEJ) DNA repair pathways. Genetic defects affecting the HR pathways result in reliance on the error prone NHEJ pathway for DNA repair, inducing/amplifying genome instability. Inhibitors targeting genome stability components, compounds targeting enzyme classes, descriptions of the drug molecular mechanisms of action, and the current or potential future clinical applications are reviewed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
