A framework for the development of effective anti-metastatic agents

Abstract

Most cancer-related deaths are a result of metastasis, and thus the importance of this process as a target of therapy cannot be understated. By asking ‘how can we effectively treat cancer?’, we do not capture the complexity of a disease encompassing >200 different cancer types — many consisting of multiple subtypes — with considerable intratumoural heterogeneity, which can result in variable responses to a specific therapy. Moreover, we have much less information on the pathophysiological characteristics of metastases than is available for the primary tumour. Most disseminated tumour cells that arrive in distant tissues, surrounded by unfamiliar cells and a foreign microenvironment, are likely to die; however, those that survive can generate metastatic tumours with a markedly different biology from that of the primary tumour. To treat metastasis effectively, we must inhibit fundamental metastatic processes and develop specific preclinical and clinical strategies that do not rely on primary tumour responses. To address this crucial issue, Cancer Research UK and Cancer Therapeutics CRC Australia formed a Metastasis Working Group with representatives from not-for-profit, academic, government, industry and regulatory bodies in order to develop recommendations on how to tackle the challenges associated with treating (micro)metastatic disease. Herein, we describe the challenges identified as well as the proposed approaches for discovering and developing anticancer agents designed specifically to prevent or delay the metastatic outgrowth of cancer.

Abstract

Most cancer-related deaths are attributable to metastasis, but few treatments are specifically designed to disrupt this process. In this Position Paper, representatives of the joint Cancer Research UK and Cancer Therapeutics CRC Australia Metastasis Working Group describe the challenges associated with discovering and developing anticancer agents designed specifically to prevent or delay the metastatic outgrowth of cancer and provide guidance on how these challenges might be overcome.

Key points

• Metastasis is associated with a poor patient prognosis and is the foremost cause of cancer-related death, with approximately 90% of patients who succumb to cancer dying of metastatic disease.

• Metastasis is inherently complex, with different distant sites having a distinct and specific extracellular matrix and cellular composition compared with that of the originating site, and therefore metastases must be considered biologically different from the primary tumour.

• The standard cancer drug discovery and development pathway, including that for molecularly targeted and immunotherapies, generally ignores the ability of experimental medicines to inhibit metastasis.

• A wealth of potential preclinical targets for anti-metastatic drug discovery and development have already been identified but remain to be validated using appropriate preclinical models that reflect the pathogenesis of metastatic disease in patients.

• Despite some successes in the treatment of bone metastases, following extensive analyses in preclinical models, multiple late-stage failures in clinical development have resulted in anti-metastatic drug development efforts being deprioritized by the pharmaceutical industry.

• Successful development of effective anti-metastatic therapies will require the regulatory agencies to work together with researchers, drug developers and statisticians to redefine the clinical development paradigm in order to encourage development of this complex but high-potential category of oncology drugs.