Robert Benezra on Cancer Biology in the Id and MAD2 Gene Families

Scientist Interview: March 2011

Robert Benezra

Photo credit: Memorial
Sloan-Kettering Cancer Center.

In a recent analysis of Essential Science IndicatorsSM from Clarivate Analytics, the work of Dr. Robert Benezra had the highest percent increase in total citations in the field of Clinical Medicine. Currently, his record in the database includes 44 papers cited a total of 3,627 times between January 1, 2000 and October 31, 2010.

Benezra heads a lab in the Cancer Biology & Genetics Program of the Sloan-Kettering Institute, which is itself part of the Memorial Sloan Kettering Cancer Center, in New York City.


SW: Your most-cited paper of the past decade was a 2001 Nature Medicine article—"Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth," (Lyden D, et al., 7[11]: 1194-201, November 2001). What led you to that particular piece of research, what did you conclude and why do you think that paper is so highly cited?

We don't publish much, but it's nice to hear papers we do publish do get cited for whatever reason or at least spark new thinking and new development. It is a very long process when you're working with mouse models. It can take years.

In that paper we used a mouse model developed previously, namely the Id knockout mouse which failed to make a good tumor vasculature, to ask the question, "Can we rescue that defect with bone-marrow-derived cells?" That was the foundation of that paper, and what led us there was the discovery in 1999 that the Id proteins are important for tumor vascularization.

There are two reasons why that paper is so highly cited. The most favorable is the fact that we waited for the complete story to answer a question that had been out there for many, many years, which was, "Are any of the blood vessel-forming cells in a tumor derived from anywhere other than the local vasculature?" And the fact that we were able to rescue the defect in tumor blood-vessel formation in this mouse with what appeared to be endothelial progenitor cells from bone marrow answered this long-standing question.

SW: And what was the less favorable reason why it garners so many citations?

That it was a fairly controversial result. I should hasten to add, though, that just because it's controversial doesn't mean it's wrong. I'd say the field is split as to whether or not these cells are critically important or not for the formation of the vasculature. We still stand by our belief that they are.

I think we're unraveling mechanistically why these cells are so important, even though they don't constitute a very high percentage at all of the total tumor endothelium. The majority of blood-vessel-forming cells might not be bone-marrow derived, but a small percentage are, and they might be important contributing factors to the development of the vasculature. Some people have argued that because they're in such low abundance, they can't be important. We disagree. So this has evoked a fairly healthy controversy and one that keeps stirring new research. In part, that's why our paper has been cited so many times.

SW: Considering that the controversy is now almost a decade old, how do you convince your opponents that you're right? Is there a particular experiment you can still do to nail it down or do they have to die off for you to carry the day?

CDKs and the cell cycle. Schematic representation of some of the mammalian CDKs involved in progression throughout the different phases of the cell cycle. Some of these kinases are required for DNA replication (S-phase) whereas other participate in the preparation for chromosome segregation during mitosis. Their therapeutic validation, however, requires proper analysis of this basic version of the cell cycle in different cell types and under different oncogenic backgrounds in vivo.
Dr. Benezra with his team in his lab. Photo credit: Memorial Sloan-Kettering Cancer Center.

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I'd rather they live long healthy lives than carry any day on a spirited debate. But yes, there are some people in the opposition who will never be convinced, regardless of what we do. Others are a bit fairer in their interpretation of some of our results. And then there's the people in this field, maybe half of them, who believe in these results and are trying to use what they know about these cells in therapeutic approaches. We're certainly in that cadre. We think we know how to target these cells therapeutically, and we think an important component of anti-angiogenic strategy will eventually emerge from this approach.

SW: How do you use them as a cancer therapy?

We try to target them. We think that we know certain genes that are absolutely required for mobilization of these cells. That is one result that's absolutely rock solid. Nobody can really argue that the phenotype of the Id1 knockout mouse, in which the Id1 gene is disrupted, is the complete loss of this population of cells and that loss is tightly associated with a defective vasculature. We have no reasonable way to explain our phenotype other than the loss of these cells. These are the primary cells where the Id protein is expressed and the ones that are missing upon loss of the protein.

We think by targeting the Id1 therapeutically, and we have a novel method to do that, we can get rid of these cells and severely perturb the tumor vasculature. That's our means of attempting to get this to the clinic, and we're getting closer and closer to a clinical application now.

In a sense, this will offer for me an important component of the controversy. If we can target Id proteins therapeutically and have an impact on disease, it may not be the final answer to the controversy—yes we might be targeting another cell type inadvertently—but we can say at least that we get to an effective therapy by doing this. In some sense, we will have been vindicated with respect to the development of an important application.

SW: How long do you think it will take to run the necessary trials?

We have preclinical data in mice, and we're now at the stage of raising money to get further into stage one clinical trials. Within a year or so, if all goes well, we should be testing this in the clinic, for safety first, in a phase one trial.

SW: Your second most-cited paper is also from 2001, a Nature paper—"MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells," (Michel LS, et al., 409[6818]: 355-9, 18 January 2001). That one has less than half as many citations. Does that mean it's not as controversial? And what did that paper report?

Yes, that one's much less controversial. That's a cancer biology study, which demonstrates for the first time that partial loss of what's called the mitotic checkpoint pathway causes cells to lose chromosomes at an elevated rate. And since chromosome loss has been long associated with cancer development, the fact that this actually caused cancer development in mice was an important result.

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Figure 1:

From an interview with Robert Benezra

Figure 1: Dr. Benezra with his team in his lab.

Photo credit: Memorial Sloan-Kettering Cancer Center.


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