A50

Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule, guide combination treatments and may explain or predict clinical outcomes.
 Non-invasive assessment of treatment-induced tumour cell death is desirable both for accurate management of patients and for detailed characterisation of different treatment modalities.
 Here we describe Cytokeratin 18 (CK18) as a suitable blood borne biomarker for non-invasive determination of apoptosis and necrosis of epithelial cells during breast and prostate cancer treatment.
 Cytokeratin 18 is cleaved by caspases during apoptosis, and preclinical and clinical studies have shown that caspase-cleaved CK18 fragments are released from apoptotic cells into the extracellular compartment/blood circulation, where they accumulate with a favourable biological half-life.
 In contrast to other biomarkers used to assess tissue damage during cancer treatment, caspase-cleaved CK18 is generated only during apoptosis and only by epithelium-derived cells, whereas the detection of increased levels of predominant uncleaved CK18 in patient serum samples is thought to be caused by necrotic tumor cell death.
 Data will be presented that the non-invasive quantification of CK18 and caspase-cleaved CK18 (M30-antigen) biomarkers by ELISA can be useful to monitor individual patient response to therapy in early clinical studies.
 References:
 Cytokeratin-18 is a useful serum biomarker for early determination of response of breast carcinomas to chemotherapy. Olofsson MH, et al., Clin Cancer Res. (2007) 13:3198-206.
 Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles. Kramer G, et al., Br J Cancer. (2006) 94:1592-8.
 Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X-linked inhibitor of apoptosis protein XIAP. Cummings J, et al. Br J Cancer. (2005) 92:532-8.
 A novel assay for discovery and characterization of pro-apoptotic drugs and for monitoring apoptosis in patient sera. Apoptosis. Biven K, et al., (2003) 8:263-8.

First AACR Centennial Conference on Translational Cancer Medicine-- Nov 4-8, 2007; Singapore