Apoptosis has emerged as a key pharmaceutical target. Although molecules are being developed to block this process in order to treat conditions such as; neurodegenerative diseases (see for example our recent dossier "Glycogen synthase kinase-3 inhibitors: Proof of concept and therapeutic opportunities for the treatment of diabetes, Alzheimer's disease, stroke & bipolar disorder"), stimulators of apoptosis represent a more common target due to their therapeutic potential for the treatment of cancer. This therapeutic class has, however, remained experimental and of the 100 or so molecules in development as apoptosis agonists, approaching 70% of these remain in preclinical development. The low rate of clinical entry associated with these molecules is related to lack of specificity, low efficacy and/or susceptibility to drug resistance. The "Inhibitors of apoptosis" (IAPs) family are expressed in a variety of tumors and suppress apoptosis through direct caspase and pro-caspase inhibition, (primarily caspase 3 and 7) and modulation of NF-kappaB. One of the most well known IAPs is survivin. Although not observed in adult differentiated tissue, this IAP is present in most transformed cell lines and cancers tested to date. Even more importantly, survivin expression appears to be homogenous within the tumor environment, a feature unusual in a disease characterized by spontaneous mutation. Survivin has been shown to inhibit caspase directly and apoptosis in general. It has recently been suggested that survivin expression may predict the response to radiochemotherapy and perhaps more importantly, targeting survivin may increase the efficacy of such therapies. This point has recently been investigated using colorectal adenocarcinoma as an example, by researchers at the University of Erlangen. This group has shown that survivin expression inversely correlated with the radiosensitivity of three colorectal cell lines of different intrinsic radiosensitivity. Furthermore, the expression of survivin in biopsies of 54 patients with adenocarcinoma of the rectum was high in samples that had a low level of spontaneous apoptosis and visa versa. Low survivin expression and high spontaneous apoptosis rates were significantly related to a dramatically increased disease free survival rate (77% vs. 18% at 5 years in tumors with high survivin expression), to a reduced risk for distant metastases (18% vs. 78% at 5 years in tumors with high survivin expression) and to local failure following neoadjuvant radiochemotherapy and surgical resection. Survivin therefore represents an excellent target for the treatment of cancer as a neoadjuvant therapy or perhaps even a monotherapy.

November, 2002

Adapted from Rodel et al, Strahlenther Onkol 2002 Aug;178(8):426-35

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