Wednesday, February 10, 2010

The Dynamics and Uncertainty of Cancer

As we have discussed before, the pathways which are the controllers of cell growth and proliferation appear to be at the heart of cancer dynamics. Furthermore those pathways are capable of being modeled as dynamic systems and the functions or constants which are the descriptive constituents of those models are ascertainable by observing them progress of cells in situ via microarrays.

In a recent NCI Bulletin a discussion of an article in Nature states:

Some patients with advanced melanoma have had dramatic responses to a new class of targeted drugs in early stage clinical trials. While the long-term effects of these drugs, called BRAF inhibitors, are not yet known, two reports suggest that these drugs may have unintended consequences in patients whose tumors lack mutations in the BRAF gene.

In separate studies, scientists in Great Britain and the United States tested the drugs in the laboratory to better understand how BRAF inhibitors behave in cells. To their surprise, the drugs actually spurred the growth of some tumors. The preliminary findings raise the possibility that certain patients should not receive BRAF inhibitors because the drugs could make their cancers worse.

The pathways are shown below as best understood at this time.

In the Nature article the authors state:

Activating mutations in KRAS and BRAF are found in more than 30% of all human tumours and 40% of melanoma, respectively, thus targeting this pathway could have broad therapeutic effects. ... In BRAF(V600E) tumours, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signalling pathway and decrease tumour growth. Notably, in KRAS mutant and RAS/RAF wild-type tumours, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumour growth in some xenograft models. .... These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, we demonstrate that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signalling pathways, depending on the cellular context. Furthermore, this work provides new insights into the therapeutic use of ATP-competitive RAF inhibitors.

This seems to imply that there is a dynamic at play which we have seen frequently in complex systems, namely two stable states, on leading to diminished and controllable cell growth and one leading to metastasis.

It would be interesting to use this as a model for two things. First the development of the details of such a model. Second for the development of means to ensure that the metastatic state is inhibited.

As Dr Chapman at MSK states from the NCI article:

“The findings provide a framework for understanding possible mechanisms of resistance to BRAF inhibitors,” said Dr. Chapman. “The results give researchers an idea where to look in the signaling pathway.”

Yet we would argue that it can be taken even farther using the complex models which have been developed in systems modeling.