2010 San Antonio Breast Cancer Symposium, 8-12th December, USA
Interview with Professor Garth Powis (MD Anderson Cancer Centre, Houston, USA)
Exploiting cancer stress for new therapies
I’m talking today about cancers are stressed too. We’re all stressed, we have a lot of stress in our lives, but tumours also are stressed. Because of the abnormal vasculature and the fact that blood vessels can be blocked by tumour cells, they suffer a lot of hypoxia, decreased blood flow and this stresses them to a great degree and they have lots of mechanisms to evade this. So the sorts of stresses they experience - hypoxia, paradoxically a redox stress, they have a deficient nutrient supply and they have difficulty removing waste products. So all of these are stresses for the tumour and, as I say, they have developed mechanisms to avoid this.
Today I’m talking about hypoxic stress. One of the things we’ve found about hypoxic stress is that it can set up cycles, vicious cycles, whereby the hypoxia actually stimulates the process which is trying to protect the tumour. So this builds up and becomes one of the major factors that tumours are resistant to chemotherapy and to radiation therapy.
So today I’m talking about the glycolysis cycle and about hedgehog signalling. So in 1930 Warburg discovered the Warburg Effect which is a high level aerobic glycolysis. So glycolysis is a process whereby glucose is used for energy supply but it’s very inefficient compared to oxidative phosphorylation by the mitochondria. Also during hypoxia, which I’ve already mentioned, glycolytic enzymes are off regulated and that’s well known. What we have shown is that the increase in glycolytic enzymes actually stimulates further hypoxia and also increased HIF levels so you get a cycle of glycolysis going to HIF going to glycolysis going to HIF again. So the reason that hypoxic tumours have so much glycolysis and increased waste product formation through lactate is because of this cycle effect.
A second cycle we’ve discovered is through hedgehog signalling and HIF. Hedgehog signalling is very important in developing organisms as we develop new tissues but also in tumours. What happens in tumours is that hypoxia, which we have shown increases HIF, which we have shown increases hedgehog, becomes a cycle also. So that hedgehog signalling produces desmoplasia, which is the fibrosis of tumours, and so particularly in a tumour… we have been studying pancreatic tumour, not necessarily breast cancer. But it’s applicable to all tumours so that when you have increased hedgehog signalling you get increased fibrosis. The stroma builds up and this in itself can block blood supply, it becomes a very fibrous mass of tumour, particularly pancreatic cancer but other tumours also experience fibrosis. This blocks blood supply and then this further increases hypoxia, which increases HIF, which increases more hedgehog signalling and desmoplasia.
The work we have done has shown that the tumour cells actually produce the hedgehog ligand, which is a protein which is secreted. This acts on fibroblasts and other cells in the stroma to increase the production of collagen, fibronectin and other components of the stroma which become fibrotic. Because of this we now have two cycles, both involving HIF, through glycolysis which self-perpetuates the increase in HIF and also through hedgehog signalling which, because it increases hypoxia, again will be a cycle whereby hedgehog signalling is further increased.
One way to block this would be to use a HIF inhibitor and I actually show an experimental drug, actually, which is in phase I trial as well, but for us it’s an experimental drug, will actually block the hedgehog signalling and also the glycolysis. So this could be an approach to treating one of the key factors of tumours, that is the hypoxia and the fibrosis that develops from that. The drug is already in phase I trials, it’s a drug I developed but it’s being developed by a company and I’m not really involved in that aspect. But it is in phase I trials at the moment.
What is the end game for the patient?
It’s a new drug, it’s a new therapy, many tumours are hypoxic. You can select patients now by imaging who have hypoxic tumours and this would be a treatment, either this or any of the new drugs developed because of this would be a way of treating patients with hypoxic tumours. We could select patients and eventually we would hope this would be a personalised medicine approach for patients, just treating the tumours which are the most hypoxic.
