| SLIDES
& TRANSCRIPTS
Saturday,
December 6, 2003
Kidney Cancer Genes: Molecular Targets for Therapy
W. Marston Linehan, M.D. |
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 Thank you, Dan. This morning I want to talk to you briefly about kidney cancer and the potential for development of rational agents for therapy of this disease.
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 Kidney cancer is not one disease. It is made up of a number of different cancers that happen to occur in this organ. Each cancer has a different histology, a different clinical course. Each may respond differently to therapy, and is caused by a different gene.
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|  The most common type of kidney cancer, clear cell,
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 is caused by a mutation, an abnormality of the VHL gene.
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 Mutations of the VHL gene are found in a high percentage of tumors from patients with non-inherited clear cell kidney cancer.
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This is a two- hit HIF gene. One copy is mutated, the other is deleted in the tumor. This is a classic Knudsen loss of function tumor suppressor gene.
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|  The VHL mutations aren't found in other types of kidney cancers such as papillary, chromophobe, collecting duct, oncocytoma.
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|  How does the kidney cancer gene function? How does damage to this gene lead to what you and I know as clear cell kidney cancer? We know that the VHL protein forms a complex with other proteins
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|  to target the alpha subunit of the hypoxia inducible factors, HIF, for ubiquitin mediated degradation.
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|  This is -- all cancer genes are normal genes which when they become damaged, they become cancer genes. The VHL gene is no different. This is a hypoxia regulated process. In other words, in normoxia, the complex targets HIF and degrades it. In hypoxia, the complex does not target HIF. HIF over accumulates, and the result is increased transcription of a number of genes, such as vascular endothelial growth factor, VEGF, the glucose transporter, GLUC-1, the EGF receptor.
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|  Now, in clear cell kidney cancer, when the VHL gene is damaged, is mutated, the complex can't target HIF, and HIF over accumulates, leading to the increased production of VEGF, EGFR, GLUT-1. These are things that you and I as urologic surgeons know of as cancer.
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|  If you are going to put a big effort, a multi-year effort into trying to develop molecular therapeutics, if you see a pathway, you need to understand that you are on firm footing. So we and others had the question, is HIF actually critical to the formation of kidney cancer.
Jody Maranchie
showed that when you prevent degradation of HIF by blocking the binding
sites to VHL, HIF over accumulates in the cells.
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These cells form tumors in mice, just like regular kidney cancer does. When you have cells with a normal copy of VHL, they get no tumors. When you put that normal copy of VHL in the cells and block it with this construct, you get these tumors.
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|  In other words, these and studies by a number of people, Bill Kalen's group and a number of people working on this, support the notion that HIF is an oncogene for the VHL kidney cancer gene.
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So that then gives us a target. There are a number of studies now that have led to new approaches for targeting the VHL HIF pathway.
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|  The most straightforward way would be to target HIF itself.
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|  This involves straining for small molecules and natural products that inhibit its function. This work is ongoing at the NCI and a number of places, and there are a number of really great leads, a number of compounds that look very good. A number of promising agents have been identified and should be in clinical trial soon.
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 Another approach involves making HIF HIP actually unstable.
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HIF is normally stabilized by a chaperone protein called HSP-90.
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A strategy has been developed by Len Neckers and his colleagues,
now in our group, utilizing the geldenamycin daunomycin analogs
to disrupt the HSP-90 HIF association.
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|  Len
Neckers and Jen Isaacs showed recently that this approach leads
to the rapid degradation of HIF in clear cell kidney cancers. These
agents will be tested in clinical trials soon. Hopefully we will
be starting these early next year.
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 Another potential therapeutic approach is to target VEGF
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with antibodies or small molecules, hoping to prevent metastasis.
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A clinical trial was recently run
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 by Jim Yang and his colleagues, in which patients with clear cell kidney cancer were treated with a neutralizing antibody to VEGF, and these patients had significant increases in the time to progression of disease.
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|  Our understanding is that this is the first study run in human trials showing an anti- angiogenesis androgenesis agent which had an effect biologically on the tumor.
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Other strategies involve targeting the EGFR receptor.
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A number of agents, one most well known called Erisa, which blocks that part of the pathway.
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|  If you think about it, there is also reason to believe that if you were to inhibit two arms of the pathway, VEGF and the EGF receptor, this might be more effective than either alone. Trials are currently under way, evaluating a combination of agents that hit both the VEGF arm of the pathway and the EGF arm. Agents now have been developed in which a single tyrosine kinase inhibitor hits both VEGF-R and EGF-R.
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 You will hear in the next talk the really exciting results of a phase two trial with a C - RAF inhibitor, which also blocks both arms of this pathway in clear cell kidney cancer.
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 That is clear cell kidney cancer VHL pathway. What I am saying is, there are a number of different approaches to targeting this. If we knew which one was going to work, we would work on just that, but there is a number of different strategies, and it is obviously a multi-year process.
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 To target a different type of kidney cancer in a different gene, the type one papillary kidney cancer, is caused by mutation of the MEP gene on chromosome 7. MEP is a proto oncogene which codes for the cell surface receptor for hepatocyte growth factor.
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|  Mutations in the tyrosine kinase domain of this gene have been found in both hereditary as well as sporadic type one papillary kidney cancer.
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This is pretty straightforward. This makes a very straightforward target for inhibition by small molecule therapy.
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 As
you know, this was the identical strategy which was recently successfully
used to develop STI-571 gleevec for CKEK mutations in the gastrointestinal
stromal tumors.
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 Don
Botaro and Jim Vasselli in our group have evaluated small molecules
developed by Terry Burke which have shown promising efficacy in
blocking the biological effect of MEP in preclinical kidney cancer
model systems.
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We identified recently the gene for another type of kidney cancer,
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 the chromophobe renal carcinoma and oncocytoma
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seen in the Birt Hogg Dube syndrome last fall.
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 Since we found this gene, intense study has been under way to determine its mechanism of action. Damage to this gene leads to chromophobe renal carcinoma, hybrid renal tumors, and oncocytoma.
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 Finally, the fourth kidney cancer gene
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 associated with the development of type two papillary kidney cancer
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 that
occurs in association with hereditary leiomyomatosis renal cell
carcinoma, another hereditary cancer syndrome,
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 has been found to be the Krebs cycle enzyme fumarate hydratase hydrotase or FH. While it is known that FH catalyzes the conversion of fumarate to malate, intense study of this pathway is under way to determine why mutation of this gene leads to type two papillary kidney cancer.
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 So what I have shown you is that different types of kidney cancer are caused by different genes, that understanding the pathways of these cancer genes gives us a unique opportunity to develop rational disease specific therapy for patients with these cancers.
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 I want to take the last minute here to acknowledge a wonderful group of current
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 and former urologic oncology fellows who have done much of this work,
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 colleagues in the urologic oncology branch, one of whom has recently left,
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my long term
collaborator and colleague and friend, Berton Zbar,
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Maria Merino
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 and
Peter Choyke.
Thank you very much.
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