Mathematical medicine

Johannes Reiter, PhD student in the group of IST Austria Professor Krishnendu Chatterjee, is co-first author of a publication with Krishnendu Chatterjee, Martin Nowak and Bert Vogelstein appearing today in eLife, a new open access journal in the life sciences established as a joint initiative of the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust. In their paper, entitled “Evolutionary dynamics of cancer in response to targeted combination therapy”, the researchers developed a mathematical model describing the cancer cell dynamics during combination therapy of solid tumors. With their collaboration, the team of cancer physicians, biologists, and mathematicians, who also published a paper on treatment resistance of cancer in Nature last year, is taking a pioneering approach in combining methods of mathematics and biology to set the theoretical ground for a new generation of cancer treatment which offers more hope for a sustained cure.

UPDATE (July 19): The paper is quoted in this week’s edition of Nature. It is considered a rare event that Nature refers to a competing open-access publication in its prestigious “News and Views” section.

Targeted treatment of solid tumors with agents such as vemurafenib often leads to dramatic reductions in tumor size. However, this response is often only short-lived as cancer cells resistant to treatment arise and subsequently cause treatment failure. To overcome the near-certainty of disease recurrence when only a single targeted agent is delivered, tumors need to be treated with two or more agents that target different pathways. Such targeted combination therapies are widely believed to be the best hope for achieving long-term remissions in cancer patients as similar approaches have also been very successful in treating patients suffering from AIDS or liquid tumors such as leukemia. Based on their mathematical model, the researchers explored the effects of targeted combination therapies in clinical scenarios.

Using clinical data from solid tumor patients, the researchers evaluate the potential and limitation of various targeted combination treatments. They find that even if there is only one possible mutation in the genome that has the potential to cause resistance to all administered drugs, combination therapy will not lead to long-term disease control in most patients. However, if no possible cross-resistance mutations exist, and full resistance can only be gained if a cell has sequentially received mutations where each makes it resistant to one of the administered drugs, dual therapy can result in long-term disease control for the vast majority of patients.  Triple therapy will then only be needed for patients with very large tumor burden. Furthermore, the researchers demonstrate that the current practice of administering targeted agents sequentially is a recipe for certain treatment failure and that simultaneous administration of targeted agents is essential for long-term disease control. Even when there are potential mutations conferring cross-resistance, simultaneous use of targeted drugs offers some hope for cure where sequential therapy fails with certainty. This research thus realizes the advantages of simultaneous combination therapy in solid cancer treatment, with a hope to stimulate efforts to combine agents much earlier in the drug development process.