Metabolic control analysis indicates a change of strategy in the treatment of cancer

Abstract

Much of the search for the “magic cancer bullet” or “block buster” has followed the expectation of a single gene or protein as “the rate-limiting step” for tumor persistence. Examples continue to abound: EGFR, VEGFR, Akt/PI3K, HIF-1α, PHD, PDK, or FAS continue to be targeted individually. However, many such attempts to block a metabolic or signal transduction pathway by targeting, specifically, a single rate-limiting molecule have proven to be unsuccessful. Metabolic control analysis (MCA) of cancer cells has generated a generic explanation for this phenomenon: several steps share the control of energy metabolism (for glycolysis: glucose transporter, hexokinase, glycogen synthesis and ATP demand; for oxidative phosphorylation: respiratory complex I and ATP demand), i.e., there is no single “rate-limiting step”. Targeting a type of step that does not exist is unlikely to be a successful paradigm for continued research into drug targeting of cancer. MCA establishes how to determine, quantitatively, the degrees of control that the various enzymes in the intracellular network exert on vital flux (or function) and on the concentration of important metabolites, substituting for the intuitive, qualitative and most often erroneous concept of single rate-limiting step. Moreover, MCA helps to understand (i) the underlying mechanisms by which a given enzyme exerts high or low control, (ii) why the control of the pathway is shared by several pathway enzymes and transporters and (iii) what are the better sets of drug targets. Indeed, by applying MCA it should now be possible to identify the group of proteins (and genes) that should be modified to achieve a successful modulation of the intracellular networks of biotechnological or clinical relevance. The challenge is to move away from the design of drugs that specifically inhibit a single controlling step, towards unspecific drugs or towards drug mixtures, which may have multiple target sites in the most exacerbated, unique and controlling pathways in cancer cells. Successful nonspecific drugs should still be specific for the networks of cancer cells over those of normal cells and to establish such cell-type specificity within molecular non-specificity will continue to require sophisticated analyses. Clinical practice has anticipated the latter strategy of mixtures of drugs: combinations of anti-neoplastic drugs are already administered with encouraging results. Therefore, the most promising strategy for cancer treatment seems to be that of a multi-targeted, MCA-advised, therapy.