ASCO 2011 Annual Meeting, 3—7 June 2011, Chicago

Investigating metabolism for cancer therapy

Dr Marston Linehan (National Cancer Institute, Maryland USA)

Over the past thirty years we’ve been studying hereditary forms of kidney cancer; our goal was to identify the genes, in those days we thought it was genes that caused kidney cancer, so we could then understand those gene pathways so we could work on developing targeted agents to treat those cancers. When we started kidney cancer was thought to be a single disease, we certainly handled all kidney cancers the same surgically, the drugs that were used at the time, all kidney cancers were treated with the same drugs. We started by studying Von Hippel-Lindau, VHL, and we spent ten years to find that gene and since that time we’ve been studying that gene pathway, the VHL pathway. We also started studying a family that had multiple kidney cancers. It wasn’t clear cell like VHL, it was papillary kidney cancer, they didn’t have VHL mutation, and that, we described as hereditary papillary renal carcinoma, and that was the MET gene. We also studied the BHD hereditary form of chromophobe kidney cancer; that gene we called FLCN. More recently we’ve also been studying too, incredibly interesting types of kidney cancer that are caused by Krebs cycle enzyme mutations. One is hereditary leiomyomatosis renal cell cancer, HLRCC, and the other is succinate dehydrogenase kidney cancer, SDH.

They really are fascinating. Do you want to tell us a little bit in lay terms that I would understand?

They really are. The HLRCC is a hereditary cancer syndrome in which patients develop skin bumps; they are cutaneous leiomyomas. The women get uterine leiomyomas or fibroids and they get a very aggressive type of kidney cancer.

Unilateral or bilateral?

Well it tends to be unilateral and we think the reason is because it spreads so fast patients don’t have time to get multifocal but we have a number of patients who have had multifocal disease. This is caused by the Krebs cycle enzyme fumarate hydratase and it’s been a very humbling thing for us. I saw my first patient in 1989, an eighteen year old girl, young woman, who I took out her kidney, she died fourteen months later of advanced kidney cancer. Her mum died seventeen months later of advanced kidney cancer and it took us eighteen years to figure out what that was. The fumarate hydratase, or FH, type of kidney cancer caused by a mutation of the Krebs cycle enzyme is the real model of the Warburg type of cancer. These cancers, the Krebs cycle doesn’t work and so these cancers are very dependent on glycolysis and that is the real Achilles’ heel here. So we are very encouraged about the possibility of targeting these by targeting glycolysis.

And the succinate?

And the succinate dehydrogenase kidney cancers, it’s a very similar story. Those patients can get kidney cancer and they can get pheochromocytoma and that’s caused, again, by succinate dehydrogenase. And we’ve looked at those cells in the laboratory and it’s the same sort of thing - the Krebs cycle doesn’t work, those cells for energy need to use glycolysis and they are very, very aggressive cancers. Now when we grow these cancers in the lab, they’re very dependent on glucose. Now when we manage these patients it turns out you can also track that by doing PET scans.

With FDG.

FDG-PET, these tumours are very, very PET-avid, it’s incredible.

And you can think of a therapeutic modality using the FDG carrier for the radioisotope?

That’s a very good question. People are looking at that and that’s a very exciting thing. We’re taking a little different approach, what we’re doing is we’re working on targeting the fact that these cells, even though they are the most aggressive cancer in our field, they have this real Achilles’ heel and that is they are dependent on glucose. What we are doing is targeting them with Avastin or bevacizumab, a drug that targets VEGF, and another drug erlotinib that targets the epidermal growth factor receptor. And we’ll see; we’re encouraged about the possibilities here but we think that in looking at the different types of kidney cancer caused by the VHL gene, the MET gene, the BHD gene, the two Krebs cycle enzymes, all these cancers have in common that they are based on fundamentally metabolic genes. So we think that kidney cancer is a metabolic disease and we are very hopeful and optimistic about targeting metabolism in kidney cancer. We think that has the real potential to target the heart of these cancers.

Most interesting. Do you still operate?

I don’t operate as much as I used to; I’m in the operating room a lot. My team operates a lot, we have a very busy surgical service. But I’m hoping, in the not too distant future, to be able to get back to doing more surgery myself. I go in the OR a lot but we’ll see.

I think we need to clone a few more surgeons like you. Thanks so much for speaking to us. I really appreciate it.

Thank you, it’s been great talking with you.