6th International Kidney Cancer Association Symposium,6—7 May, 2011, Warsaw
Renal cancer 2011: novel targets
Professor Michael Atkins (Harvard Cancer Centre, Boston, USA)
Kidney cancer is unique in that it has, for clear cell kidney cancer, a mutation in the Von Hippel-Lindau gene which causes up-regulation of hypoxia-inducible factors in the absence of hypoxia. So you get a pseudo-hypoxic situation where downstream proteins such as vascular endothelial growth factor are up-regulated, driving tumour vascularity in the absence of hypoxia. Because kidney cancer is so dependent on one form of angiogenesis, drugs that inhibit the VEGF pathway, either its receptor or the ligand directly, are uniquely active as single agents in this disease. Four such drugs, antiangiogenic drugs, have been approved in the US in the last five years: initially sorafenib, followed by sunitinib, followed by bevacizumab given in combination with interferon, and in the last two years pazopanib. In addition, two drugs that inhibit the mTOR pathway, which is also up-regulated in about a third of kidney tumours, have also been approved in the past five years. Those drugs are everolimus and temsirolimus and whether those drugs work through an antiangiogenic mechanism, through their effect on HIF or whether they actually work by targeting the TOR pathway within the tumour is something that we’re still working on, sorting out.
Can you identify which patients will respond to mTOR drugs?
That’s an area of active research. A few years ago we published a paper suggesting that tumours that have up-regulation of phospho-S6, which is downstream of mTOR, are more likely to respond to mTOR inhibitors but that was a retrospective analysis and we’re in the process of repeating that with a prospective study. It is in clinical trials.
What about non-clear cell tumours?
75% of kidney cancers are clear cell, the other 25% make up a variety of different types of tumours – papillary type 1, papillary type 2, chromophobe, collecting duct oncocytomas, and they each have a different genetic make-up, a different histologic appearance and likely have different therapies that are going to be required to treat them.
What is the future for kidney cancer drugs?
These drugs have really revolutionised the treatment of kidney cancer. In the past, patients with advanced kidney cancer had a median survival of somewhere between thirteen and sixteen months with immune therapies and that shifted to twenty to thirty months with these new treatments. However, these new treatments are largely palliative, they’re not producing complete responses and the responses that they do produce are relatively transient with median progression free survivals of somewhere between six and twelve months for these agents. So there’s room for improvement.
Some of the areas that we’re looking at for improvement are more selective inhibitors of the VEGF pathway and there are two drugs that we hope will be approved within the next year or two that are more selective inhibitors of the VEGF receptor, axitinib and tivozanib. In addition, the TOR inhibitors inhibit TORC1 and TORC1 is only a component of the TOR pathway; it looks like there might be actually feedback activation of TORC2 when you block TORC1. Therefore we think that there may be a role for combined TORC1 and TORC2 inhibitors that may be more effective than the TORC1 inhibitors alone.
Finally, we still think there’s a role for immune therapy, novel immune therapies, in kidney cancer and there are some new drugs that are actually targeted immunotherapies that inhibit pathways that the tumour uses to supress the immune system that are showing encouraging activity in patients with this disease which will likely be investigated over the next few years and hopefully will be able to produce more durable responses in at least a subset of patients.
What about sequencing?
Well the sequencing is complicated. My own view is that it’s much more important to determine the right first line therapy than it is to try to figure out for a group of patients based on large clinical trials what the best sequence is. But, in the absence of data that tells you what the right treatment is for a particular patient and their tumour, I think that the best initial treatment should be something that offers the possibility of curing the patient or durable response. And failing an option like that, the best treatment should be based on a ratio of benefit versus toxicity. At the moment, for the VEGF pathway inhibitors, it appears that that is the most likely approach to produce tumour shrinkage and for most patients that’s tolerable. But if an immune therapy were to come along that would produce durable responses in a large subset of patients, it would be important to identify who that subset is and try to use that therapy first.
And targeted therapies?
Well we need to identify new targets for kidney cancer. As I mentioned, the major targeted therapies are really antiangiogenic agents that target blood vessels, not directly the tumour. And so there’s a role for actually understanding what’s going on in the tumour besides the Von Hippel-Lindau mutation that might be able to be directly targeted the way we’ve developed targeted therapies in other cancers. So we’re doing a lot of study of the tumours to look for specific mutations or deletions or increased frequency of chromosomal duplications that might give us clues to what might be driving those tumours that we could target with targeted therapies.