Targeted therapy by disablingcrossroadsignaling networks: the survivin paradigm

Abstract

Embedded in the concept of targeted cancer therapy is the expectation that disabling a single oncogenic pathway will eliminate the tumor cells and leave the normal tissues unscathed. Although validated by clinical responses in certain malignancies, challenges exist to generalize this approach to most tumors, as multiple genetic lesions, chromosomal instability, insensitivity of the cancer stem cell compartment, and emergence of drug resistance complicate the identification and therapeutic exploitation of a single, driving oncogenic pathway. Instead, broader therapeutic prospects may be offered by targeting crossroad signaling networks that are selectively exploited in cancer and oversee multiple aspects of tumor cell maintenance. One such pathway is centered on survivin, a cancer gene that intersects cell proliferation, cell survival, and the cellular stress response. Several clinical trials targeting survivin with a collection of approaches from immunotherapy to small-molecule antagonists are currently under way. By simultaneously disabling multiple signaling circuitries, targeting survivin may provide a novel perspective in rational cancer therapy selective for specific cancer mechanisms but broadly applicable to disparate tumors regardless of their genetic makeup. [Mol Cancer Ther 2006;5(3):478 -82]

Nuclear survivin expression is associated with HPV-independent carcinogenesis and is an indicator of poor prognosis in oropharyngeal cancer

“…Targeting survivin may provide a novel perspective in cancer therapy by simultaneously disabling multiple signalling circuitries. Currently, several clinical trials targeting survivin with various approaches ranging from immunotherapy to antagonists are under way and might be broadly applicable to different tumours (Altieri, 2006). High levels of cytoplasmic survivin expression have been reported previously in OSCC (Weinman et al, 2003) with similar staining patterns as shown in our study in which 58% of all tumours prominently expressed survivin in the cytoplasm.…”

Regulation of survivin expression by IGF-1/mTOR signaling

“…Because of its 'crossroad' role in multiple essential pathways of tumor cell maintenance, and its differential expression in cancer as opposed to normal tissues, survivin is being actively pursued as a novel target for rational cancer therapy (Altieri, 2003). A validating principle of this approach is that lowering intracellular survivin levels below a critical threshold using a variety of approaches, including antisense, dominant negative mutants or siRNA sequences, has been consistently associated with arrest of cell proliferation, spontaneous apoptosis and sensitization to cell death stimuli, including cytotoxics and ionizing radiation (Altieri, 2006). In this context, much attention has been devoted towards elucidating the molecular requirements of survivin gene transcription, but recent evidence points to additional, non-transcriptional mechanisms controlling survivin levels in tumor cells (Altieri, 2003).…”

Chemopreventive effects of silymarin and silibinin on N-butyl-N-(4-hydroxybutyl) nitrosamine–induced urinary bladder carcinogenesis in male ICR mice

“…Because of the large difference in its expression between normal and malignant tissues and its role in cancer progression, survivin is currently undergoing intensive investigation as a potential tumor marker (28,29). Survivin is a member of a class of inhibitors of apoptosis and seems to block apoptosis by interfering with the caspase activation pathway.…”