Loren D. Walensky, MD, PhD
Professor of Pediatrics, Harvard Medical School
Center/ProgramPediatric Hematologic Malignancies
Office phone: 617-632-6307
Preferred contact method: email
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Area of ResearchChemical Biology of Deregulated Apoptotic and Transcriptional Pathways
450 Brookline Avenue
Boston, MA 02215
BiographyDr. Walensky received his MD and PhD degrees from Johns Hopkins University School of Medicine in 1997. He trained at the Boston Combined Residency Program in Pediatrics and then completed a fellowship in pediatric hematology-oncology at DFCI and Children's Hospital Boston in 2003. He is board-certified in general pediatrics and pediatric hematology-oncology. He joined DFCI in 2003 and was named medical director of the new Program in Cancer Chemical Biology in 2005.
- Burroughs Wellcome Career Award in Biomedical Science, 2005
- V Foundation Scholar Award, 2004
- "Alex's Team" Foundation Oncology Research Award, 2003
- American Society of Hematology Scholar Award, 2003
ResearchChemical Biology of Deregulated Apoptotic and Transcriptional Pathways
Extensive research into the origin of cancer has led to the identification of genetic and molecular mistakes that trigger the overproduction or hyperactivity of specific cancer-causing proteins. The structural complexity and intracellular localization of these protein targets can hamper the development of anticancer drugs. The small subunits of proteins, called peptides, are essential components of the interaction surfaces between proteins, and are nature's keys to cancer's lock on cellular survival. Thus, the chemical production of peptides is another strategy for subverting cancer proteins, since natural peptides display evolutionarily-honed binding specificity for their targets. However, the ability to use small peptides made in the laboratory to block cancer has been hindered by their loss of natural architecture, vulnerability to degradation, and difficulty entering cells to exert their anticancer effects.
Our work focuses on developing and applying new approaches to chemically brace or "staple" natural peptides so that their shape, and therefore their anticancer activity, can be restored. Optimizing natural peptides in this way may provide alternate compounds to study protein interactions and manipulate biological pathways within cells to treat human disease. To that end, we have used a chemical strategy, termed "hydrocarbon-stapling," to make a panel of anticancer peptides with markedly improved pharmacological properties. We have demonstrated that the stapled peptides retain their natural shape, are resistant to degradation, and can enter and kill leukemia cells by neutralizing their cancer-causing proteins. When administered to mice with leukemia, a stapled peptide successfully blocked cancer growth and prolonged the lives of treated animals.
Our ongoing work employs this new peptide-stapling strategy to produce diverse panels of anticancer peptides, in order to study and deactivate aberrant apoptotic and transcriptional pathways in a variety of human tumors. Thus, our goal is to produce an arsenal of new compounds - a "chemical toolbox" - to investigate and block protein interactions that can cause cancer. To achieve this goal, we use structural biology analyses, synthetic chemistry techniques, and biochemical, cellular, and mouse-model experiments to systematically explore the biological effects of the novel peptidic compounds we generate.
- MacGinnitie AJ, Walensky LD, Turvey SE, Orange JS, Bonilla FA, Silverman LB, Oettgen H. Management of an anaphylactoid reaction to methotrexate with a stepwise graded challenge. Pediatr Allergy Immunol 2003;14:409-11.
- Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, Wagner G, Verdine GL, Korsmeyer SJ. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 2004;305:1466-70.