Expert Stresses Significance of Genetic Differences in Kidney Cancer

Angelica Welch

There are 16 different known genes that cause kidney cancer and at least 13 different types of inherited kidney cancer, says W. Marston Linehan, M.D., emphasizing the need to understand the genetic differences between these diseases.

Starting with the investigation of Von Hippel-Lindau (VHL) hereditary cancer syndrome in the 1980s, researchers began studying the genetics of hereditary kidney cancers in an effort to better understand the differences between various forms of the disease. Lessons learned from VHL, hereditary papillary renal cell carcinoma (PRCC) and hereditary leiomyomatosis and renal cell carcinoma (HLRCC) over the past 30 years have lead oncologists further away from surgical intervention and closer to novel targeted therapies, for each disease, and possibly immunotherapy in a few.

In an interview with CURE, Linehan, chief, Urologic Oncology Branch, National Cancer Institute, discussed the landscape of kidney cancer, current clinical trials and hope for the future of immunotherapy in this disease.

Can you describe the current landscape of kidney cancer?

We started working on kidney cancer 33 years ago. Our goal was to understand the genes that cause kidney cancer, with the idea of studying their pathways and then developing therapies to target those pathways in patients with advanced, sporadic, non-inherited kidney cancer. What we've learned is that kidney cancer is not a single disease — it is a number of different diseases with different histologies, different clinical courses, responding differently to therapy, and of course, caused by different genes. We know now that kidney cancer is caused by at least 16 different genes. A huge amount has been learned about kidney cancer by studying families, because they are the window to understanding therapy in patients with sporadic, non-inherited kidney cancer.

When we started looking at kidney cancer in the 1980s, we started on a hereditary type called VHL hereditary cancer syndrome, in which patients are at risk to develop tumors in a number of organs, including, of course, the kidney. We studied these patients and these families — these very brave people — and we managed them, learned how to treat them surgically and learned how to do active surveillance. And what we found out was that we should recommend against surgery in patients with VHL whose kidney tumors are smaller than 3 centimeters — the so-called "3 centimeter rule."

And to date, we have not had one patient develop metastatic disease when managed in that fashion. We are very happy about that, and we really want to develop therapies so that we do not have to do surgery. We have managed nearly 800 patients with VHL, and so many of those have had to have so many kidney surgeries, so we are very enthusiastic about the potential to target that gene pathway.

Another topic of hereditary kidney cancer that we studied that is very helpful in understanding non-inherited non-hereditary kidney cancer is PRCC. We defined it in the 1990s, and then discovered the gene for this disease was called MET — and those patients with PRCC that have a germline MET-gene mutation are highly likely to develop bilateral, multifocal, type 1 papillary kidney cancer. We also know that that gene is mutated in a pretty significant number of patients with non-inherited kidney cancer. There are different types of alterations or increase copy numbers in over 80 percent of tumors from patients with type 1 papillary kidney cancer. So, we are very interested in targeted that pathway — the MET pathway. We have run a multicenter trial at the NCI targeting MET in patients with hereditary PRCC and we saw really dramatic responses. We are now doing trials of another MET drug targeting this population, but also in patients with non-inherited PRCC.

The third one that I will tell you about, which is the most humbling disease that I work with, is a hereditary cancer syndrome called HLRCC. This is a not uncommon hereditary cancer syndrome in which patients are at risk to develop cutaneous leiomyomas and uterine leiomyomas, and a very aggressive form of type 2 papillary kidney cancer. We know now that HLRCC is caused by a gene for the Krebs cycle enzyme fumarate hydratase (FH). It is pretty amazing when you think about it — a Krebs cycle enzyme gene mutated cancer. We know now that there are at least 3 different Krebs cycle enzyme mutation cancers — FH, succinate dehydrogenase (SDH), IDH 1 and IDH 2, and the first 2 of those cause hereditary kidney cancer — FH and SDH.

So, the patients with HLRCC are very different than the type of kidney cancers that we see in patients with VHL or hereditary PRCC, which tend to be indolent. When the tumors are larger than 3 centimeters though, they can spread and cause metastatic cancer, no question about it, but in the HLRCC patients, cancer can spread even when the tumors are very small. So, we do not recommend doing active surveillance until the largest tumor reaches 3 centimeters, but in in those patients with HLRCC, we recommend surgical intervention now, and not waiting. We do a very different operation — we go very wide on these, these can be very infiltrative, aggressive tumors.

What work is currently being done in these diseases?

A number of years ago, we showed that we find mutations of the VHL gene in 90 percent of those cancers — which is also the gene for the common type of sporadic non-inherited clear cell kidney cancer. By understanding the pathway, we have now seen the FDA approval for nine different drugs that target the VHL pathway for patients with clear cell kidney cancer. So, we are very optimistic about that and very hopeful for patients with clear cell kidney cancer.

We have run two clinical trials for patients with VHL, one with an agent targeting a pathway called HSP90 and another targeting the VEGF/EGFR pathway. We are very exciting about our new trial, which we are just about to start, that targets the HIF2 pathway with a drug called PT2385. We will be starting that trial in patients with VHL soon, and our hope is that we will soon get to the day where we do not have to do surgery in these patients. HLRCC is one of the most, maybe the most, aggressive type of kidney cancer, but I think it is the one that has the biggest Achilles heel. In studying the pathway of that Krebs cycle enzyme gene FH, we have developed a therapy targeting that pathway with Avastin (bevacizumab) and Tarceva (erlotinib) and we have seen very dramatic responses in our patients and we are very excited about this. And the patients with HLRCC, as well as the patients with regular PRCC, this trial was seeing responses of 65 percent before we lost all of the patients. It is a very aggressive disease. Now, we are seeing very dramatic responses, very prolonged disease-free progression and we are very encouraged about this. We are working now to develop even better therapies, and we have a second-line trial that we are running now that is targeting a similar pathway. We are working toward the day that these patients will not have to have surgery, and will have therapy for 100 percent of patients. Still, we are very encouraged by where we are now with this therapy.

Is there any other information coming out of this field that is particularly exciting?

There has been so much excitement about the news immunologic forms of therapy. I think we are getting ready to look at this in our patients with kidney cancer, and we have evidence that indicated that these may be very promising therapies in the hereditary realm. The pre-clinical work that is being done in the laboratory is leading to our new clinical trials, which are looking at immunotherapies in patients with advanced kidney cancer — hereditary and non-hereditary.

I think that some of our most aggressive cancers in the kidney cancer field actually have a very big Achilles heel that we are going to be able to successfully target. We are very encouraged about that, and I am excited to see all of the recent information about immunotherapies, checkpoint inhibitors, PD-1/PD-L1 inhibitors, the combinations of inhibitors. We think that for our studies, particularly in PRCC, this is encouraging.
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