Biomarker Discovery

Biomarkers are important to facilitate translation, validate the therapeutic hypothesis and monitor therapeutic effect in clinical trials and beyondThe identification of biomarkers is a timedemanding but crucial part of the preclinical drug discovery process. The biomarker should be related to the disease or mechanism of action of the target and be measurable in easily accessible samples such as body fluids.  

Miettinen et al. applied CETSA® Explore to investigate the molecular effects of palbociclib (Ibrance®, a CDK4/6 inhibitor approved for the treatment of metastatic breast cancer), which is known to cause cell cycle arrest and cellular senescence. In addition to identifying the known CDK4/6 targets, Miettinen et al. showed that palbociclib affects the function of the 20S proteasome (a protein complex which degrades unneeded or damaged proteins via proteolysis). Specifically, the analysis found that palbociclib induced the ECM29 protein to dissociate from the proteasome, which then affected the thermal stability of the 20S proteasome. The ECM29 dissociation caused proteasomal activation, which in turn induced cellular senescence and blocked cell proliferation.  

In a follow-up study, Miettinen et al. investigated whether ECM29 levels were linked to patient survival, given that patients with low levels of ECM29 are more susceptible to cell senescence in general. In ground-breaking work, the researchers revealed that ECM29 levels are predictive of relapse-free survival in breast cancer patients treated with endocrine therapy. This work demonstrates how CETSA® Explore in an unbiased way can reveal cause-effect biomarkers that inform optimal treatment strategies for specific patient populations to improve survival rates.  

Publications

Miettinen TP, Peltier J, Härtlova A, Gierliński M, et al. Thermal proteome profiling of breast cancer cells reveals proteasomal activation by CDK4/6 inhibitor palbociclib. (2018) EMBO J. DOI: 10.15252/embj.201798359 

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