2013 San Antonio Breast Cancer Symposium (SABCS)

Hypoxic metabolism in breast cancer: how to overcome resistance to anti-angiogenic therapy

Prof Adrian Harris - University of Oxford, Oxford, UK

I’m really interested in how we can predict patients’ responses to treatment and by dynamic monitoring of early changes modify their treatment to get the best outcome. For example with drugs that block angiogenesis, such as Avastin, it’s been used for over a million people yet still there’s no biomarker to predict who would respond. The work I’ve been doing involves window studies in cancer patients where they may have the drug for a two week window before they start their chemotherapy. Using imaging techniques such as magnetic resonance imaging we’ve been able to show patients respond very differently just to a single dose of bevacizumab, some patients showing either a marked response and even necrosis of the tumour, others the tumour just grows straight through. So this great heterogeneity is not taken into account in any clinical studies at the moment. So we’re investigating the reasons for this and could we, understanding that, have better treatments.

One of the things we’ve found is that within two weeks of treating patients the blood supply to the tumours is markedly reduced which makes the tumours hypoxic. By doing gene arrays before and after treatment we can discover which genes have been switched on by this hypoxia. It turns out many genes involved in metabolism are switched on and some of those are very important for regulating the pH or acidity of the tumours. One of them is a cell surface protein called carbonic anhydrase 9 so because it’s on the outside of the cell you can target it quite easily with antibodies or small molecules. In preclinical experiments we’ve shown very dramatic synergy if you block tumour growth with blocking angiogenesis that they become hypoxic, switch this pathway on, if you switch that pathway off the tumours just stop growing or even regress. So by targeting just one single gene induced by the therapy we can greatly enhance the treatment.

But we found many genes were induced by this treatment in our patients, others have also been very effective in the preclinical models. The other example is glycogen which normally you think of it storing up in your muscles for exercise and broken down when there’s low oxygen and you’re running but the opposite happens in cancer, when the cells become hypoxic they store it up. What we found was that store is critical for the cancer cells to survive and protect themselves from free radicals generated by oxygen and that when we block that pathway again we got dramatic inhibition of growth in vivo which had not been expected. So we discover these sorts of things by studying our patients directly rather than doing cell culture work but can go back to those models to assess and validate the findings.

We’ve already set up the procedure so that patients in our studies and in other places have their imaging done up front and biopsies done so we can actually change these treatments in real time. So we’ve just been discussing at the meeting here randomised trials of adding inhibitors to these pathways for therapy.

Are there any side effects to doing this?

There will be but at the moment the drugs seem well tolerated from the previous literature. The carbonic anhydrase 9 inhibitors, there’s one antibody that has already been tested in renal cancer and showed a survival benefit so that’s potentially very interesting to apply and has minimal toxicity. The glycogen pathway blockade are drugs that have been used to treat diabetes because that’s one of the problems in diabetes is the breaking down of glycogen stores and producing too much glucose. So those drugs will be retargeted to cancer.

Are these inhibitors strictly for breast cancer or could they be used with other diseases?

My work has been on breast cancer but there’s no fundamental reason to suppose that the response to hypoxia won’t be similar in many other tumour types. We already know that this enzyme I mentioned before, carbonic anhydrase 9, is high in many tumours because they’re already hypoxic and it seems to be a marker of a bad prognosis in pretty well every type of cancer so far studied over a dozen different ones. So I think that it may be important across the board.

Do you have a message for practising clinicians?

We shouldn’t be treating patients without knowing that they’re going to benefit from our treatment. That’s much more difficult with drugs that don’t target a genetic lesion like HER2 antibodies but I think doing studies even at one week after administering your treatment and doing dynamic monitoring, either on liquid biopsies from the blood, imaging or repeat biopsying, will tell you an awful lot about the response of the cancer to treatment allowing you to modify that or combine other agents. I think the way of the future is to be dynamically monitoring every therapy you do and this applies just to simple things like anti-oestrogens. A recent study by Professor Dowsett showed that if you look at what happens just two weeks after giving someone an aromatase inhibitor the change in the proliferation index predicts the outcome three years later, not nearly as effective was looking at the baseline. So it’s the change that’s induced by your treatment that seems critical to the biology of the cancer and you can’t do that unless you monitor it afterwards.

Is there a need for biomarkers?

We haven’t got the biomarkers because we haven’t gone about finding them in the right way. We need to see what happens after you give the treatment early on and then we’ll know how the system has re-engineered itself and re-edited itself and then we’ll know how to challenge it. So biomarkers as a baseline I don’t think will really come through because you can’t tell how the system responds until you actually challenge it.

Can you talk about your work with metformin?

Metformin is an anti-diabetic drug that has been shown to reduce the cancer incidence in diabetics in many epidemiologic studies and also it reduces pancreatic cancer, bowel cancer, prostate cancer and the mechanism is very poorly understood. So again we did a study in breast cancer patients where we gave the drug two weeks before their chemotherapy, had biopsies and imaging before and afterwards, and when we analysed the RNA changes at two weeks there were some dramatic changes which are very interesting which showed the tumours had switched to wanting to use glutamine which is an important amino acid in the blood. That has previously not been known in the clinic and when we checked this out in cell lines, breast cancer cell lines, we found that when they were treated with metformin they became very dependent on glutamine, if you block that you can stop cells growing completely. So we think we’ve found another new pathway that could be synergised with metformin. There are a lot of drugs around that have been tested to block glutamine anyway so there’s this combination that I think will be really interesting. Again, highlighting that looking at the changes on treatment can tell you many new approaches.

Is metformin being used in the clinic or in clinical trials?

A big clinical trial of 3,000 patients has already been completed and we’re waiting for the results to see whether it changes the outcome. There probably are about twenty or thirty other studies that have been done now trying to understand how it works because it’s a cheap, effective drug that’s been used for forty years, obviously the population take it so it would be quite a breakthrough, really, if we could make it work better with low toxicity.

It was a breast cancer adjuvant study so it was a wide range of patients with different sorts of breast cancer and it was very well tolerated but since it’s only likely to work on a subgroup of patients it’s particularly important to understand how it works.