Existing chemotherapeutics target protein signalling pathways that are essential for cancer cell survival and proliferation. These chemotherapeutics preferably induce a form of programmed cell death, termed apoptosis. Apoptosis is executed by the activation of cellular proteases, known as caspases that cleave DNA and cytoskeleton. However, inhibitor proteins may bind and deactivate caspases to prevent “accidental” apoptosis. If apoptosis is impaired, or upon severe stress, a more rapid form of cell death, necrosis is induced. Necrosis follows a crisis of cellular bioenergetics that leads to failure of ionic homeostasis, increased osmotic pressure and disruption of the cell membrane.

Cancer cells manage to evade both mechanisms of cell death and this is believed as a cause of chemo-resistance and clinical relapse. Often, apoptosis is impaired by de-regulation of the caspase-dependent enzymatic machinery such as loss of function mutations, or by elevated levels of caspase-inhibitors. Likewise, necrotic cell death can be evaded through alterations of cancer cell metabolism making them better cope with a bioenergetic crisis induced by chemotherapeutics.

Studying deregulations of apoptosis and changes and alteration in cancer cell bioenergetics is therefore essential to understanding molecular mechanisms behind chemo-resistance and clinical relapse. However, studying the action of one protein or one metabolite at a time by conventional biochemistry is often not sufficient. This approach disregards the often complex interaction between proteins in a cell, such as feedback mechanisms, and further discounts essential quantitative information such as the relative abundances of pro-survival and pro-apoptotic proteins.

My research therefore provides theoretical Systems Biology models. These models shall lead to molecular hypotheses that can be directly tested in our experimental lab.