Perspectives for targeted therapies in cancer of unknown primary site.

Cancer of unknown primary site (CUP) ranks as the fourth most common cause of cancer deaths. Regression of the primary, early development of systemic metastases and resistance to therapy are hallmarks of this heterogeneous clinical entity. Targeted therapy offers promise for improvement of outcome of such patients, but it is currently hindered by lack of known molecular targets on which tumours are dependent for growth. In this review, we present the gene and protein profiling studies done on expression of oncogenes, tumour-suppressor genes and angiogenesis effectors and discuss the therapeutic potential of developed targeted agents. Existing data show occasional overexpression of Ras, BCL2 oncoproteins, absence of active EGFR/c-KIT/PDGFR signalling, uncommon presence of tumour-suppressor gene mutations and highly active angiogenesis in CUP. High-throughput multi-gene, multi-protein platforms offer promise for unravelling the complex molecular pathophysiology of CUP, for identification of targets suitable for modulation and ultimately hope for abrogation of its aggressive natural history.