Gatenby’s Gambit.
Pardon the unconventional title. I haven’t blogged for long but now I have some time to write a blog post I am going to write about some research that seeks to change the way we employ chemotherapy to control tumours.
We have loads of targeted and broad-spectrum chemotherapeutic agents available for treating cancer and quite often cancer cells evolve resistance to chemotherapeutic agents; they may acquire mutations that render the drugs ineffective [1] or begin to express drug efflux pumps that can just chuck chemotherapeutic agents outside [2] or activate repair pathways that can unhook crosslinks induced by classical chemotherapeutic agents like cis-platin [3]. These phenotypes come to dominate the otherwise heterogeneous landscape of tumours because the administration of chemotherapy imparts a selective pressure in favour of resistant clones.
Robert Gatenby’s group at Florida began working with the premise that the evolution of resistance is inevitable, but that the expansion and dominance of resistant clones is not. Instead of using chemotherapy at extremely high doses they sought to use drugs at concentrations low enough to maintain a population of non-resistant cancer cells that could then compete with and inhibit the growth of resistant clones.
Non-resistant cells can do this in the absence of high-dose chemotherapy that eliminates all of them because it takes energy to maintain resistance through some routes (efflux pumps or repair) at least. The researchers in question first established that there was an energy cost associated with the expression of efflux pumps. They found that in low-glucose conditions, cells negative for PGP (an efflux pump) grew nearly as well in low-glucose conditions as they did in high-glucose conditions, but PGP +ve (MCF7/Dox in the figure) took a hit in proliferation.
They then put resistant and non-resistant cells together in culture in the presence and the absence of verapamil, a substrate for PGP that results in increased energy expenditure and found that the proportion of PGP+ cells was vastly reduced relative to PGP – cells when verapamil was included.
After carrying out studies of how quickly the cells doubled in culture, how sensitive they were to energy restriction (low glucose) and a metabolic inhibitor (2-deoxyglucose) that could compete for and block glucose utilisation they developed a therapeutic strategy that used verapamil and 2-deoxyglucose and went on to test if they could delay disease progression in computer simulations using non-resistant clones to suppress the growth of resistant clones. Especially interesting was the fact they could use non-chemotherapeutic doses of verapamil to reverse fitness, turning PGP expression into a growth disadvantage.
They found that adaptive chemotherapy (where chemotherapy is used in doses that does not eliminate all of the susceptible cancer cells, reducing toxicity in the process) in the presence of 2-deoxyglucose and verapamil could significantly delay time to disease progression (increasing tumour burden in the presence of the drug). The work provides an interesting perspective on how chemotherapy might best be used and challenges the assumption that maximal doses are optimal.
Primary Reference - http://cancerres.aacrjournals.org/content/early/2012/12/06/0008-5472.CAN-12-2235.full.pdf+html (paywalled)
Other References
[1] http://www.nature.com/onc/journal/v28/n1s/abs/onc2009198a.html
[2]http://www.nature.com/clpt/journal/v89/n4/full/clpt201114a.html (paywalled)
[3] http://www.nature.com/bjc/journal/v97/n7/full/6603973a.html
2012-12-13 13:12:53
Source: http://exploreable.wordpress.com/2012/12/13/gatenbys-gambit/
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