My early work at Children’s Hospital Boston has focused on the identification of thalidomide analogs that exhibit improved anti-cancer activity. This work was critical to the initiation of clinical trials with the thalidomide analog 3-aminothalidomide (Actimid) and resulted in two publications.
The major focus of my research has been elucidation of the genetics of angiogenesis and its control of tumor growth. This work began with the characterization of differential angiogenic responsiveness in inbred mouse strains and the identification of quantitative trait loci (QTLs) controlling that responsiveness. I have identified several QTLs regulating differential response to VEGF and bFGF in C57BL/6J x DBA/2J strain crosses and have used new bioinformatics techniques to narrow down the number of candidates in some of these regions to a few genes. Recently, I have identified the albino allele as the polymorphism responsible for AngVq4. In addition, I have identified a strong single candidate, a Hey2 enhancer polymorphism, as responsible for AngVq3. In collaboration with Dr. Robert Kerbel, we have demonstrated that circulating endothelial cells may serve as a surrogate marker of angiogenic responsiveness that can be measured in humans. This work has resulted in several papers and the AACR-AstraZeneca Scholar-in-Training award. My preliminary data suggest that the major effect of differences in angiogenic responsiveness is on tumor latency rather than subsequent growth rates. The identification of additional regulators of angiogenic response and the characterization of their physiologic effects is ongoing.
Another major facet of my research has been the role of the anthrax toxin receptors in angiogenesis. I collaborated with Dr. Ken Christensen and Dr. John Collier to demonstrate that the Protective Antigen subunit of anthrax toxin is a potent anti-angiogenic agent. This establishes the anthrax toxin receptors as new targets for antiangiogenic therapy. Dr. Christensen and I are continuing this collaboration to clarify the role of each of the two anthrax toxin receptors in angiogenesis. In addition, we are collaborating with the National Screening Laboratory for the Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases (NSRB) facility to identify small molecules that bind to the anthrax toxin receptors and inhibit its interaction with Protective Antigen. Such molecules are likely to serve as good leads for both anthrax-protective agents as well as anti-angiogenic agents. This work forms the basis of my currently funded R01, and my recently completed DOD BCRP Synergistic Idea Award. Future work on this project will include the identification of downstream mediators of anthrax toxin receptor signaling, as well as the identification and refinement of small molecule inhibitors of these receptors. I anticipate that these molecules will serve as leads for antiangiogenic drugs.