BBS Faculty Member - Loren Walensky

Loren Walensky

Department of Pediatric Oncology

Dana Farber Cancer Institute
Longwood Center 3216
450 Brookline Avenue
Boston, MA 02215
Tel: 617-632-6307
Fax: 617-582-8240
Email: loren_walensky@dfci.harvard.edu
Lab Members: 3 staff scientists, 3 postdoctoral fellows, 9 graduate students, 2 technicians, 1 administrative specialist
Visit my lab page here.



The Walensky laboratory focuses on the chemical biology of deregulated apoptotic and transcriptional pathways in cancer. Our goal is to develop an arsenal of new compounds-a “chemical toolbox”-to investigate and block protein interactions that cause cancer. To achieve these objectives, we take a multidisciplinary approach that employs synthetic chemistry techniques, structural biology analyses, and biochemical, cellular, and mouse modeling experiments to systematically dissect the pathologic signaling pathways of interest.

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 pharmacologic tools to investigate and manipulate critical signaling networks in vivo. Peptide motifs within proteins serve as essential components of protein interaction surfaces, and are nature’s keys to cancer’s lock on cellular survival. Because natural peptides display evolutionarily honed binding specificity for their targets, synthetic peptides are uniquely poised to subvert cancer proteins. However, the ability to harness small peptides to block cancer has been hindered by their loss of natural architecture, vulnerability to degradation, and difficulty entering cells to exert their anti-tumor effects.

Our work focuses on developing and applying chemically “stapled” natural peptides so that their shape, and therefore their anti-cancer activities can be restored. Optimizing natural peptides in this way provides alternative compounds to study protein interactions and manipulate biological pathways within cells to treat human disease. We have demonstrated that stapled peptides retain their natural shape, are resistant to degradation, and can enter and kill cancer cells by neutralizing selectively targeted proteins. We have shown that, when administered to mouse models of human cancer, stapled peptides designed based on the BH3 death domains of BCL-2 family proteins or the transactivation domain of p53 successfully blocked cancer growth and prolonged the lives of treated animals. Such stapled peptide drug prototypes have now been advanced to clinical testing in human cancer.

In ongoing studies, we broadly apply peptide stapling to produce a diversity of cancer biology discovery tools, in order to dissect and target aberrant apoptotic and transcriptional pathways in a variety of human tumors. We emphasize the structural basis for ligand-protein interactions, validation of intracellular targets, characterization of novel protein interactors, analysis of ligand-mediated alteration of signaling pathways in cellular and murine models of disease, in vivo imaging technologies, and clinical translation.



Last Update: 12/9/2016



Publications

For a complete listing of publications click here.

 


 

Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD. BAX activation is initiated at a novel interaction site. Nature. 2008 Oct 23; 455(7216):1076-81.

Bernal F, Wade M, Godes M, Davis TN, Kung AL, Wahl GM, Walensky LD. A Stapled p53 Helix Overcomes HDMX-Mediated Suppression of p53. Cancer Cell. 2010, Nov 15; 18: 411-22.

Barclay LA, Wales TE, Garner TP, Wachter F, Lee S, Guerra RM, Stewart ML, Braun CR, Bird GH,Gavathiotis E, Engen JR, Walensky LD. Inhibition of pro-apoptotic BAX by a noncanonical interaction mechanism. Mol Cell. 2015 Mar 5;57(5):873-86.

Lee S, Wales TE, Escudero S, Cohen DT, Luccarelli J, Gallagher CG, Cohen NA, Huhn AJ, Bird GH,Engen JR, Walensky LD. Allosteric inhibition of antiapoptotic MCL-1. Nat Struct Mol Biol. 2016 Jun;23(6):600-7.

Bird GH, Mazzola E, Opoku-Nsiah K, Lammert MA, Godes M, Neuberg DS, Walensky LD. Biophysical determinants for cellular uptake of hydrocarbon-stapled peptide helices. Nat Chem Biol. 2016 Oct;12(10):845-52.

Huhn AJ, Guerra RM, Harvey EP, Bird GH, Walensky LD. Selective Covalent Targeting of Anti- Apoptotic BFL-1 by Cysteine-Reactive Stapled Peptide Inhibitors. Cell Chem Biol. 2016 Sep 22;23(9):1123-34.



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