Novel Oncology Drug Development Strategies in the Era of Personalised Medicine

Abstract

In this era of personalised medicine, the focus of oncology drug development is shifting from classic chemotherapeutic drugs to rationally designed molecularly targeted agents (MTAs). This development has been accelerated by improved understanding of the key features of human tumour biology which have emerged over the last decade. A seminal paper by Hanahan and Weinberg (2000) proposed six vital elements for tumour formation, survival and progression. The six ‘Hallmarks of Cancer’ were sustained proliferative signalling, evasion of growth suppressors, resistance to cell death, replicative immortality, angiogenesis and activation of invasion and metastasis. Hanahan and Weinberg updated their findings in 2011 with further evidence describing the complexity of these hallmarks and the addition of further hallmarks, including modification of energy metabolism to fuel cell growth and evasion of immunosurveillance. The tumour micro-environment is also a critical factor in the regulation of tumour growth and progression, with multiple stromal cell types creating a succession of supportive tumour micro-environments enabling invasion of normal tissue and subsequent metastasis. Recent successes have utilised these advances in understanding to create a strong biologic rationale for drug development, primarily focusing on targets of a single ‘Hallmark’. However, a number of challenges remain, not only in understanding the complex molecular pathways and networks, their interaction and mechanisms of resistance, but also in the drug development process through early incorporation of biomarkers to create rational drug development strategies. Challenges also lie in defining robust criteria to appropriately select patients for novel therapies. Effective trial design with integration of patient enrichment strategies is paramount to streamline drug development and deliver timely information to guide progress of drugs along the pipeline. The application of new technologies and novel strategies that address these problems will be discussed in detail in this chapter.