|T H E N I H C A T A L Y S T||M A Y J U N E 2006|
|P E O P L E|
Steven Libutti received his M.D. from the College of Physicians and Surgeons of Columbia University in New York in 1990 and completed a residency in general surgery at the Presbyterian Hospital in New York in 1995. He then joined the Surgery Branch, NCI, as a clinical associate and after completing his surgical oncology fellowship in 1996 joined the senior staff. In 2001, he became a tenure-track investigator with a focus on tumor angiogenesis and the tumor microenvironment. He is currently a senior investigator and the chief of the Tumor Angiogenesis Section in the Surgery Branch, Center for Cancer Research, NCI.
In order for a tumor to grow larger than a few millimeters, it must develop a blood supply. This process of new vessel growth from pre-existing vessels is termed "angiogenesis," and it is important not only for the growth of the primary tumor but also for tumor invasion and spread to distant sites.
Aiming to identify novel targets for cancer therapy, my laboratory has focused on understanding the tumor microenvironment, the molecular processes involved in the development of new vessels, and the complex interactions between the tumor and host cells.
We have developed some new techniques and assays to help us model and measure these processes.
We contributed to the creation of a technique for isolating endothelial cells from tissues that have been fixed or frozen. This adaptation of a novel laser capture approach termed expression microdissection. or xMD, has allowed us to study DNA, RNA, and protein changes in tumor-associated endothelial cells in situ.
We were able to demonstrate that tumor endothelial cells exhibit differential patterns of promoter methylation compared with endothelial cells in adjacent normal tissues.
This provided the first definitive evidence in vivo of epigenetic alterations in tumor neovasculature. We hope this observation will lead to a better understanding of the mechanisms that result in phenotypic alteration of endothelial cells and thus facilitate the identification of new therapeutic approaches.
The use of angiogenesis inhibitors in the clinic has faced several challenges. Although the anti-VEGF antibody Avastin (bevacizumab) has recently been approved by the FDA for the treatment of colon cancer, many other antiangiogenic agents have shown mixed results. This may be due, in part, to the need to deliver such agents directly to the tumor microenvironment to exert sustained paracrine effects.
We have therefore explored the use of targeted gene therapy to deliver antiangiogenic gene products to tumor vessels. In collaboration with investigators at the University of Texas M.D. Anderson Cancer Center, Houston, we have been developing a phage-based vector system that is capable of targeting tumor vessels selectively.
We are now testing this vector in animals within the NCI Comparative Oncology Program by delivering vascular-targeted, TNF-expressing phage to dogs with spontaneous cancers. Data from this study will be submitted to the FDA to support an IND (investigational new drug application) to conduct the first clinical trial of this vector.
Along with others in the angiogenesis field, we have pursued the identification of unique targets in the tumor vasculature.
Utilizing genomic and proteomic approaches, we have attempted to elucidate common pathways involved in the response of endothelial cells to angiogenesis inhibitors.
This work has enabled us to characterize more completely the activity of two important mediators of endothelial cell apoptosis.
We recently elucidated the mechanism by which EMAP-II (endothelial cell monocyte-activating polypeptideII) gets into endothelial cells and exerts its effects via an HIF1-amediated pathway. By enhancing HIF1-a degradation, EMAP-II induces endothelial cell apoptosis.
We have also identified the putative tumor-suppressor gene DOC1 as an important mediator of endothelial cell apoptosis and a common link between the effects of several different angiogenesis inhibitors.
Recently, our laboratory became a part of the new Tumor Angiogenesis Section in the Surgery Branch, opening up new opportunities to better translate our findings to the clinic. We believe the next one to two years will bring the translation of several new vascular-targeted therapies to our patients with cancer.
Xinzhuan Su received his Ph.D. in parasitology from the University of Georgia in Athens, Ga., in 1990. He did postdoctoral training at the University of Georgia before coming to the Laboratory of Parasitic Diseases, NIAID, in 1992. He is currently the head of the Malaria Genomics Section and a senior investigator in the Laboratory of Malaria and Vector Research.
Lack of an effective vaccine and widespread parasite resistance to multiple antimalarial drugs have led to a resurgence of malaria worldwide. Indeed, after decades of research and much progress in molecular biology, we are not much better off in treating and controlling malaria than we were 50 years ago. Dynamic and rapidly evolving parasite populations present tremendous problems for developing effective control measures.
Under the guidance of Thomas Wellems, my initial research as a postdoctoral fellow at NIH involved genetic mapping of a gene linked to chloroquine resistance in Plasmodium falciparum parasite.
I developed various tools and methods, including a high-density microsatellite map, and mapped the locus of resistance to a 36-kb region. I realized then how much remained to be discovered in malaria genetics and genomics and decided these were areas I wanted to explore for years to come.
My laboratory applies genome-wide approaches to fundamental problems of parasite biology and evolution.
Current goals are to develop genome-wide single-nucleotide polymorphism (SNP) and microsatellite genetic maps and to use these maps to identify genes affecting such phenotypes as parasite drug resistance, red blood cell invasion, and sexual development.
Collections of genome-wide polymorphisms from malaria parasites worldwide will also provide a useful database for studies of parasite origin, transmission, and evolution.
Using malaria parasite lines adapted to in vitro culture and large numbers of genotypes obtained from both nuclear and mitochondrial genomes, we studied parasite population structure, recombination rate variation, linkage disequilibrium, and evolutionary history. We have shown that P. falciparum probably migrated with humans out of Africa to other parts of the world about 50,00000,000 years ago.
Our studies also found that parasite population expansions probably occurred in Africa 5,00010,000 years ago, along with changes in mosquito ecology and species distribution from agriculture and its impact on the environment.
Malaria parasites can be grouped into populations according to their continental origins, yet no obvious population structure exists in Africa due to high transmission and recombination rates.
We have collected thousands of SNPs from geographically diverse parasite isolates and are in the process of developing a microarray chip to genotype additional isolates from field sites, including a new field site in Cambodia. Our plan is to perform association studies with well-characterized parasite phenotypes.
For example, to map important drug-resistance genes, we will look for loci with signatures of selection such as chromosomal regions with reduced polymorphism.
Indeed, we have already shown reduced diversity in a large chromosomal region surrounding a gene for a chloroquine-resistance transporter on chromosome 7, suggesting spread of drug-resistant parasites from one or two foci.
Malaria parasites have a complex life cycle, with asexual replication in the human host and mandatory sexual recombination in the mosquito host. The sexual stages are vital phases in malaria parasite transmission and are the targets of various interventions such as transmission-blocking vaccines.
Malaria parasites have a haploid genome in the human host. The switch from asexual replication to sexual differentiation is therefore likely to involve signal transduction and gene regulation.
Recently, we used genetic mapping to identify a candidate gene that plays an important role in parasite sexual development. We are now using genetic mapping, microarrays, and other approaches to study the regulation of this complicated process and gain knowledge to inform the development of strategies for malaria control.
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