AACR 2015
How is ganetespib regulating the response of tumour cells in lung cancer?
Dr Erica Golemis - Fox Chase Cancer Center, Philadelphia, USA
We were trying to identify factors that regulate the response of tumour cells to ganetespib, which is an inhibitor of Hsp90, which is in clinical trials at the moment. There are a number of presentations at this meeting about promising activity of ganetespib in lung cancers and in the interests of improving the use of this compound we were trying to find factors that regulate whether you respond or you don’t respond. So we did a cDNA library screen and what we did was we identified these two genes. AMH is a secreted factor, AMHR2 is the cell surface receptor for AMHR2, so they’re right next to each other in the pathway. They clearly, strongly influence whether cells are killed by ganetespib which is a strong clinical candidate. What we found fascinating about it is that these are family members of TGF-β and BMPs, which are proteins that are strongly associated with proliferation and metastasis in lung cancer. These have never been suspected to be in lung cancer before.
What actually happens? You use the expression epithelial mesenchymal transition, how does this all fit together in understanding proliferative processes?
Typically stem cells and protected compartment go along with cells changing their identity from being more epithelial to more mesenchymal and that is called the process of EMT, epithelial mesenchymal transition. What we found was that when you depleted, when you reduced, the levels of AMH and AMHR2 in cells, the cells actually became more mesenchymal but at the same time they were more sensitive to the drug. Then we treated them with the drug and the drug was having a reverse effect on the epithelial mesenchymal identity. So this has taken two players that were not known to be present in the system and have now revealed this interesting dialogue with epithelial mesenchymal identity. So this suggests, first, some interesting new biology as to why TGF-β signalling may be so complicated in lung cancer. And, second, it suggests something else that you may target that might be useful for adjusting sensitivity to ganetespib and provides a potential biomarker for its use.
So does this mean you’re harnessing a differentiation agent?
It is potential that by perturbing this differentiation agent you would be able to influence the response of cells to therapy.
Could you bring this into the realm of day-to-day cancer medicine, then? How might this impact? You already have a drug that’s being used, what should doctors take home from this?
It’s still clearly preclinical stage so we are doing experiments that we have been doing in cells, we are now moving them into mouse models. A next step would be to investigate the expression of this particular biomarker system in the context of primary tumour samples for lung cancer, preferably those that have been treated with this agent and agents working by a similar mechanism, inhibition of Hsp90. We’re hoping to move to that work over the next year.
