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Antonio Tito Fojo, M.D., Ph.D.
Drug Resistance: Studies of Molecular Etiology?Basic Science, Translational Research, and Clinical Studies
Nearly everyone agrees that drug resistance is a major impediment to effective chemotherapy. Indeed, it could be argued that our problem is not that we lack effective agents, since nearly all agents in common use can cure a variety of cancers, but instead that some cancers are more resistant. An extension of this thesis is the prediction that resistance will be an obstacle all future chemotherapeutic agents will have to overcome. To that end, efforts spent understanding drug resistance now are likely to reap long-term benefits. The available evidence suggests that resistance can be simple or complex but, more importantly, understandable. Clinical evidence suggests that it is also surmountable. High-dose chemotherapy with or without stem cell support represents the most common clinical approach to reverse drug resistance. However, it could be argued that this represents a very nonspecific approach, and that the toxicity of this approach could be lessened, and its efficacy improved, if drug resistance were better understood. The efficacy of high-dose chemotherapy in a subset of malignancies simply demonstrates that resistance is almost never absolute, an observation supported by laboratory studies that show that higher doses overcome all mechanisms of resistance. However, higher doses in patients invariably are associated with and limited by toxicity. Specific therapy designed to interfere with resistance mechanisms should help overcome this obstacle. Based on this, our laboratory efforts have concentrated on the identification of mechanisms of resistance and, equally important, understanding how resistance is acquired. In our opinion, the ultimate goal is not to reverse resistance, but to prevent it from emerging. Our emphasis is on both understanding the basic science and productively conducting translational research. Our clinical efforts emphasize drug resistance reversal trials.
In our laboratory, our efforts began with studies of multidrug resistance mediated by P-glycoprotein, which is encoded by the MDR-1 gene. Our current efforts are directed at understanding how resistance arises. In this regard, we have been able to show that breaks in chromosomes can result in the juxtaposition of drug resistance genes next to very active genes. This phenomenon, known as gene rearrangement, results in the capture of the drug resistance gene and in its expression at very high levels. In this manner, the cancer cell can readily achieve very high levels of drug resistance. The identification of this as a mechanism of drug resistance is novel but also consistent with the use of this phenomenon by cancer cells to achieve other goals. More importantly, it provides the necessary starting point for understanding how it occurs and, eventually, how it may be prevented. We are actively pursuing this, specifically investigating the role drugs play in the phenomenon of gene rearrangement and how it might be lessened. We have evidence that giving chemotherapy drugs to normal monkeys results in significant damage to the chromosomes of their bone marrow cells, and that the extent of damage can be significantly reduced by administering drugs in different ways. If indeed there are better ways in which to administer drugs that result in less damage to chromosomes, this may prove valuable in preventing the emergence of drug resistance, reducing the likelihood of secondary cancers in cancer survivors as well as lessening the damage to the fetus in the case of a pregnant mother receiving chemotherapy. We know that drug resistance is likely to be caused by different mechanisms, but we think that understanding how it occurs and can be prevented will have wide applications.
Nevertheless, we continue to strive to identify mechanisms of drug resistance that are likely to be clinically relevant. In that regard, in collaborative studies we succeeded in identifying a new drug transporter, which evidence to date indicates is likely to be as important as P-glycoprotein in mediating resistance. In addition, we have developed additional in vitro models of drug resistance. We have extensively characterized novel, non-P-glycoprotein mechanisms of Taxol and epothilone resistance, demonstrating for the first time, at a molecular level, acquired mutations in tubulin that confer insensitivity to Taxol and the epothilones. The epothilones are new agents under development that appear very promising. The identification of these mutations provides for a greater understanding of the interactions of these drugs with tubulin, and has been the catalyst for studies to understand this at the atomic level. Molecular characterization of the phenotype has already demonstrated some common as well as unique features compared with resistance mediated by P-glycoprotein. Further characterization has identified a role for the p53 tumor suppressor protein in resistance to Taxol and also identified important interactions between p53 and the cytoskeleton. These observations provide further insight into the complex nature of drug action and drug resistance.
Taxol and the epothilones are agents that belong to the microtubule-stabilizing class of compounds, and we have conducted similar studies with hemiasterlin, a microtubule destabilizing agent. In these models, mutations are observed that confer resistance by altering the stability of the native tubulin. All of these studies have led to a further understanding of tubulin dynamics, and given us additional insight into the phenomenon of post-translational changes, and the latter are being exploited to characterize and understand the effect of drugs in patients.
Increasingly we are conducting better and more intense translational studies, both in the field of multidrug resistance and tubulin interacting agents. Ongoing studies that are linked to intense translational efforts include studies in various malignancies and also in patients with adrenocortical cancer using the novel and potent P-glycoprotein antagonist, tariquidar, and Phase I and Phase II studies with the novel epothilone BMS247550 (Ixabepilone)
This page was last updated on 2/19/2013.