Genes, chromosomes and the treatment of bladder cancer

Dr Jonathan Rosenburg – Memorial Sloan Kettering Cancer Center, New York, USA

Can you tell us about your presentation?

I will be discussing new targets in bladder cancer and potential therapeutic advances that we may achieve based on those new targets that are being identified.
 

What new targets are these?
 

We’re finding that there are large numbers of mutations in chromatin remodelling genes which is a new finding in bladder cancer over the last year. Approximately 30-40% of patients, maybe even as high as 50-60% of patients, have mutations in chromatin remodelling genes and this is a story that is being recapitulated in other tumour types as well. This is a new finding in bladder cancer. While at the moment these mutations are not druggable, they may very well be down the road and the biology that underlies them is probably very interesting as far as the development and progression of bladder cancer. In addition, PI3 kinase mutations are frequently observed, HER2 amplifications, possibly even HER2 mutations that are activating, are observed in bladder cancer. One of the concerns and problems with targeted therapies in bladder cancer is that the majority of patients do not have a single alteration but rather there are many subgroups with many different alterations either in ERBB2, c-Met, BRAF, PI3 kinase and other potentially druggable oncogenes or tumour suppressor genes that are inactivated. The cyclin D1 pathway is probably important in a subset of bladder cancer patients as well. So there is a plethora of opportunities for developing drugs, the problem is that there is no one oestrogen receptor, progesterone receptor, as in breast cancer, in bladder cancer and so we may end up having to subdivide the disease in advanced disease to really begin to tackle the problem of developing new therapies.
 

Are these new drugs or is there a potential for using old ones?

Hopefully some current drugs that will target these pathways will be tested in bladder cancer but so far those studies have not yet been done. Certainly there has been some work done targeting HER2 in bladder cancer but the studies have yet not really informed us whether or not alterations in the pathway are critical for outcomes. There appears to be some evidence that HER2 targeted therapies in bladder cancer, when given to patients with HER2 amplifications and alterations, may improve outcomes but it is far from clear at this point. EGFR targeting in bladder cancer, as of yet, has not been successful in really demonstrating clinical benefit and the anti-angiogenics are still in testing. There is a phase III study on-going with bevacizumab trying to determine whether it improves on chemotherapy.

With so many targets how do you decide what to focus on?

I think some of that has to come out of very good preclinical work to tell us, at least in vitro and in animal models, which are the relevant pathways and a lot of that work is on-going. There is some clinical data, including an abstract just presented today, suggesting that PI3 kinase mutation may not be the best therapeutic target in bladder cancer but it’s very, very, very preliminary data from small numbers of patients in a GSK sponsored phase I expansion cohort in bladder cancer where they observed responses in patients without mutations but no responses in patients with mutations. So the principle of personalised therapy in bladder cancer remains unrealised; we really haven’t determined whether or not activating mutations lead to clinical benefit when targeted. So we’re still at the very early stages in this disease.

Would these drugs be for any stage of the disease?

There are different frequencies of mutations depending on the stage of the disease. So patients with non-muscle invasive bladder cancer, the very early stage, so-called superficial disease, have very high frequencies of FGFR3 mutations and that may be a druggable target in non-invasive disease. It is rarer in invasive and metastatic bladder cancer for the FGFR3 receptor to be mutated and so it may not be a viable target in advanced disease but might be a very good target in non-invasive disease. Conversely, the cyclin D1, PI3 kinase, RB pathways are altered more in advanced disease compared to early disease and so understanding the stage and the mutation profile within the population will allow you to better have a sense of what kind of patient cohort you’re going to need to accrue. So it may be that if targeting FGFR3, for example, it doesn’t matter whether you’re non-invasive or invasive, only if you have the mutation. But the study designs required to answer the questions with those different disease states are quite different.
 

What would be the conclusions of your talk?

We have a very large opportunity here to make some treatment advances in bladder cancer. We’ve had no therapeutic advances in over twenty years in the disease and so we have a lot of potential targets and we need to get together as a community to do these studies to determine whether or not targeting these alterations results in clinical benefit.
 

Do we know why BCG works?

We don’t have a good sense of exactly why BCG works, it is probably a bystander effect or a non-specific immune response that is also targeting the cancer cells within the bladder but the precise mechanism of action is still unknown and remains a black box.