Robert Benezra on Cancer Biology in the Id and MAD2 Gene Families
Scientist Interview: March 2011
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What the paper said was that this loss of chromosomes and the development of chromosomal instability as a result of the perturbation of this pathway could actually cause cancer, as opposed to simply being a consequence of the development of the disease. That was a longstanding debate, which this paper began to resolve.
Over the past decade how much of your work has been on this issue of the bone-marrow-derived cells and the Id protein, and how much on basic cancer biology independent of that particular controversy?
I'd say it's about 50-50. Our focus on bone-marrow-derived cells was interesting mostly in terms of the mechanism of action in these Id proteins. We also learned how to target these proteins, and we think we've come up with an anti-angiogenic strategy.
But these proteins are also important in other types of cancer-related properties. We know they're involved in tumor cell maintenance and in metastatic progression. These proteins are important for cell growth re-initiation at distant sites.
So half the lab is focused on the role of these Id proteins, not only in blood-vessel development and tumors, but also in these other components of tumor biology. The other half is working on mitotic checkpoint control. So we're interested in cancer biology and we look at it from the perspective of these two gene families and the processes they control.
If these Id proteins are so widely involved in tumor development, doesn't that suggest that even if the compounds targeting them have clinical efficacy, it's not necessarily confirming your earlier observation and resolving the controversy?
We now have a strategy for specifically targeting Id1 in endothelial progenitor cells. That's the hook, the means of trying to prove our point with respect to those cells. We're certainly interested in pursuing the targeting of Id1 in other processes but, as you say, that would not directly prove our point. But specifically targeting the protein in the endothelial progenitor cells will help do that.
Where do you see your research going over the next five years other than the clinical trials targeting these Id proteins?
We really do think we have gotten to the point where some of the findings we have made in basic cancer biology are translatable—targeting the Id protein, which we think is a feasible but difficult project. .
"We're really at the point that we'd like to move some of the basic cancer biology findings closer to clinical applications and we have some means of doing it now."
With respect to the MAD2 project, we've learned that anuploid cells can be very big players in tumor recurrence, so after one successfully treats the tumor, anuploid cells might be cells that are able to escape therapy. Now we're aiming at trying to translate that to finding compounds that specifically target anuploid cells.
We're really at the point that we'd like to move some of the basic cancer biology findings closer to clinical applications and we have some means of doing it now.
What do you see as the most challenging aspect of your research?
Finding a means to get from the initial findings to early clinical trial has been quite a challenge. So we have a novel target but it's a high-risk project, and the big pharmaceutical companies are not interested until we can prove clinical utility. So, we have to try and learn to do it ourselves. That to me is the biggest challenge.
If we lived an ideal world, and you had an unlimited research budget, what one experiment would you do?
I would target the Id proteins both in tumor vasculature and in the most aggressive tumor cells as well—probably in triple-negative breast cancers, where we know the Id levels are very high and they're associated with a high metastatic progression. We know that Id expression in the vasculature is required for the establishment of those lesions. If we could target Id in both the vasculature and within the tumor cells themselves effectively, then I think we would have a very good anticancer strategy.
If you had the chance to go back and publish your 2001 Nature Medicine paper on these bone-marrow-derived cells again, would you do anything differently?
We probably would have attempted to demonstrate that even small numbers of these cells are important. That would have quelled some of the controversy. If we could have shown initially how a small number of cells are contributing to the development of a functional vasculature in a tumor I think there would have been fewer objections. .
When people saw that very few of these cells were in tumor vessels, they wouldn't have said that they're not important. We would have already addressed that point by saying, "Look, they're capable of secreting factors, and those factors are important in the establishment of vasculature."
Have you shown that in the years since then?
Yes, we have. Although the most direct proof, as I said, would be to specifically target these cells and none other, and we're only now in the process of doing that. The evidence is consistent with what I just told you, but the formal proof would be the elimination of these cells very specifically, without affecting any other of these cells within the bone-marrow-derived population. That would be final proof in our minds.
How would you describe what differentiates your publication strategy from other researchers in your field?
Well, I publish just one or two papers a year. And if you do that, it's important to have papers that are "high impact," otherwise it's difficult to progress in this business. . I have built my career on the belief that one or two papers is enough, particularly when you're working with animal models which take years of breeding just to generate the starting cohort. I have relied on that—so far so good.
There are people who publish a lot more than I do even in the animal world, but it takes quite a long time to get as much of the story as possible, and I generally believe it's worth waiting to do that. That's been my approach, and I've stuck with it. I'm too old to change at this point.
Robert Benezra, Ph.D.
Sloan-Kettering Institute
Memorial Sloan Kettering Cancer Center
New York, NY, USA
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ROBERY BENEZRA'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:
Lyden D, et al., "Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth," Nature Med. 7(11): 1194-1201, November 2001 with 901 cites. Source: Essential Science Indicators from Clarivate.
ADDITIONAL INFORMATION:
- Robert Benezra is a Rising Star in Clinical Medicine in January 2011.
- Read a previous interview with Robert Benezra (January 2004).
KEYWORDS: MOUSE MODELS, ID KNOCKOUT MOUSE, BONE-MARROW-DERIVED CELLS, TUMOR VASCULARIZATION, BLOOD-VESSEL-FORMING CELLS, ANGIOGENESIS, TUMOR GROWTH, THERAPEUTIC TARGETS, ANTI-ANGIOGENIC STRATEGY, PHENOTYPE, MITOTIC CHECKPOINT PATHWAY CONTROL, CHROMOSOMES, MAD2, CANCER BIOLOGY, GENE FAMILIES, ID1, ENDOTHELIAL PROGENITOR CELLS, ANUPLOID CELLS.
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