Developing novel anti-cancer therapies: Promises and challenges


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Jeff Evans
The Beatson Institute for Cancer Research, University of Glasgow & NHS Greater Glasgow and Clyde, Glasgow, UK

Abstract

Current strategies in the development of novel anti-cancer therapies are based on exploiting our increasing understanding of the molecular and cellular basis of cancer development and progression. Recent advances have provided a detailed understanding of these molecular and cellular events, including self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tumour metabolism, and tissue invasion and metastasis, and this information has led to a number of novel therapeutic strategies, based on relatively non-toxic agents that inhibit particular signal transduction pathways. However, the development of these novel agents presents a number of challenges.

The classical paradigm for developing cancer therapeutics is dependent on demonstrating an optimal dose, usually based on toxicity, a reduction in tumour size on serial clinical or radiological assessments as an indication of anti-tumour activity, and subsequent comparison with standard therapies. However the current generation of molecular-targeted therapies have been designed to inhibit specific molecular processes and may not consistently result in objective tumour reduction in patients with advanced refractory tumours despite producing their desired biological effect. This is likely to be particularly relevant for agents that are designed to inhibit cancer cell migration, invasion, and metastasis.

Current strategies in drug development include enriching the patient population based on the molecular profile of the tumour, innovative clinical trial designs, and pharmacodynamic and functional imaging endpoints to demonstrate proof of desired biological activity. Finally, the development of genetically-engineered murine models of, for example, pancreatic ductal adenocarcinoma enhances our ability to understand the biological function of key tumour suppressor genes and oncogenes in vivo, and to better understand how putative inhibitors of signalling pathways that are deregulated in these specific genetic backgrounds should be used in the clinic.

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