Summary of Invention
This invention relates to a test which probes the altered balance of exoproteases and/or their modulators in the blood of cancer patients. This information can be used to make predictions for prognostic and diagnostic purposes.
The invention tracks degradation of artificial substrates, under strictly controlled conditions, using semi-automated MALDI-TOF mass spectrometric analysis of the resulting patterns. Each fragment is quantitated by comparison with double-labeled, non-degradable internal standards, spiked into the samples at the same time as the substrates to reflect adsorptive and processing-related losses. The full array of metabolites is then quantitated and subjected to multivariate statistical analysis. Using this approach, class predictions with 94% sensitivity and 90% specificity were obtained from the serum of metastatic thyroid cancer patients and healthy controls. At least three different cancer types could be readily distinguished based on the test.
This approach can be generalized for many diagnostic and predictive purposes, as an in vitro phenotypic read-out of endogenous catalytic and metabolic activities in body fluids or tissues, utilizing either endogenous or exogenous substrates, followed by qualitative and quantitative product analysis. Various analytical read-outs, product selection schemes, and activity attenuation procedures can be envisioned to provide more, or different, data points and to tailor the process to each specific case of pattern discovery. (For additional information about this novel invention, please click here.)
Oncopeptidomics, the analysis of the blood serum peptidome of cancer patients, most often for biomarker discovery purposes, is a special brand of activity-based proteomics as it basically provides a peptide-metabolomic readout of protein synthesis, secretion, processing and proteolytic (i.e., enzymatic) degradation. This is particularly relevant to cancer as increased and/or altered expression and secretion of various proteases has been associated with tumor growth, invasion and metastasis.
The patterns may:
- have diagnostic value for identifying cancer subtype and stage,
- mark a given clinical outcome of interest, or
- reliably distinguish clinically insignificant from significant cancer.
Area of Application
Diagnostics. Proteolytic degradative patterns in the serum peptidome hold important information that may have direct clinical utility as a surrogate marker for detection and classification of cancer.
Paul Tempst, PhD, Laboratory Head, Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering
Zhenyan Yan, PhD