Novel targeted radiosensitisers in cancer treatment.
The last few years have seen a significant increase in our understanding of the molecular pathways governing cell function in cancer. This has led to an explosive interest in novel molecularly-targeted agents and, until recently, the focus of research effort has been to combine these agents with conventional cytotoxic chemotherapy. However, following a recent trial of an anti-EGFR targeted antibody in combination with radiation, a new paradigm is emerging in which these novel agents will be combined with external beam radiotherapy (RT). In this article we review classes of novel targeted radiosensitisers that are directed at specific aspects of cell function. Such agents are aimed at either single or multiple targets (the latter is a more attractive approach in view of cross-talk between different cell signaling pathways). We review available preclinical and clinical literature with a particular focus on novel agents targeting components of the ErbB and IGF-1R family cell signaling pathways. In this model, radiosensitisers can exert their effects at the cell membrane surface by preventing receptor activation or by interfering with the function of second messengers such as the Ras/PI3K/mTOR pathway. In addition, the effects of novel DNA repair inhibitors will be considered in the context of combination strategies with signal transduction pathway blockade. Other small molecule inhibitors, such as HSP90 inhibitors, that can disrupt signaling in a number of different pathways, will also be discussed. Ultimately, through the synergistic use of these innovative molecules and RT, the therapeutic index may be enhanced by modulating cellular metabolism, proliferation, repair, angiogenesis, and apoptosis. The rapid proliferation of available targeted agents and their entry into phase I clinical trials means that this is an extremely interesting area for research in radiation oncology.
Zaidi
Shane H
SH
Institute of Cancer Research, Cancer Research UK Center for Cell and Molecular Biology, Chester Beatty Laboratories, 237 Fulham Road, London, SW3 6JB, UK.
Huddart
Robert A
RA
Harrington
Kevin J
KJ
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1