Erkki Ruoslahti's Research Focus
The Ruoslahti laboratory studies peptides that home to specific targets in the body, such as tumors, atherosclerotic plaques and injured tissues. These peptides, which usually bind to receptors in the vessels of the target tissue, can be used to selectively deliver diagnostic probes and drugs to the target. The latest development is the discovery of homing peptides with tumor-penetrating properties. The CendR tissue penetration pathway is a new endocytosis/trans-tissue transport pathway (Pang et al., Nat Comm. 2014). The current focus is on enhancing the effects of coupled and co-injected drugs with the tumor-homing peptides, particularly in mouse models of breast cancer and glioblastoma. This laboratory also studies the receptors for the peptides and the mechanism of their tumor penetration activity.
Erkki Ruoslahti's Research Report
The underlying themes of Dr. Ruoslahti’s work are tumor vasculature and metastasis. Tumors, like other tissues, contain both blood vessels and lymphatic vessels. A tumor needs blood vessels to be able to grow, and destroying tumor blood vessels is the basis of a promising new cancer therapy. Lymphatic vessels are not needed for tumor growth, but like blood vessels, the lymphatics are an important conduit of distant metastasis.
Vascular Zip Codes
The Ruoslahti laboratory screens large collections ("libraries") of random peptides to identify those that bind to specific targets in the vasculature. The peptides in the library are displayed on the surface of phage (a virus that infects bacteria), and the screening is done in vivo. When the library is injected into the circulation of a mouse, phage particles that display peptides capable of binding to a selected target tissue, such as a tumor, accumulate at the target where they can be collected and their peptide identified. The method has revealed a wealth of specific features, or "vascular zip codes," in the vessels of individual tissue and tumors. We have identified peptides that specifically home to tumors because they recognize angiogenesis-associated or tumor-type specific markers in tumor blood vessels. We even have peptides that distinguish the vessels of pre-malignant lesions from those of fully malignant tumors. Homing peptides have also revealed a zip code system of molecular changes in tumor lymphatics.
We have used synthetic homing peptides identified by phage display to target drugs and biologicals into tumors. The targeting can increase the efficacy of a drug while reducing its side effects. Even a non-specifically toxic compound can be converted into a compound that affects only the targeted tissue. We also identify the target molecules (receptors) for the peptides. The receptors of our tumor-homing peptides often play a functionally important role in tumor vasculature, and because of this are candidates for drug development.
A major focus is to use homing peptides as targeting elements to deliver nanoparticles into tumors and other sites of disease. Nanoparticles are considered a promising new approach in medicine because they can be designed to perform more functions than a simple drug. The vasculature is an excellent target for nanoparticles because tumor vessels are readily available for circulating particles. In collaboration with several chemistry and bioengineering laboratories, we have constructed multifunctional nanoparticles for tumor targeting. These particles can be directed into tumors in a highly selective manner as demonstrated by histology, non-invasive imaging, and tumor treatment results. We have constructed nanoparticles with the ability to amplify their own homing to tumors, and are currently working on nanoparticles coated peptides that confer the particles tissue-penetrating properties. The goal is to incorporate multiple functions such as specific targeting, self-amplification of the targeting, exit from vessels into tissue, ability to send signals for imaging, and controlled drug delivery. It is also important that the particles resist uptake by the reticuloendothelial system, which otherwise keeps them from reaching their intended target.
Cell Attachment and Anoikis
Cancer is so lethal because, unlike normal cells, cancer cells can migrate to distant sites where they do not belong and multiply there. The metastatic growths that result are what often makes cancer incurable. Normal cells attach to an insoluble protein scaffold, extracellular matrix, the protein/carbohydrate meshwork that fills the spaces in between cells. If normal cells detach from the extracellular matrix, they promptly die by apoptosis which, when caused by lack of attachment, is called anoikis. One of the fundamental characteristics of cancer cells is that they can detach and stay alive to eventually metastasize.
In the 1980s this laboratory demonstrated that the cell-binding site of fibronectin and several other extracellular matrix proteins consists of a tripeptide, RGD, presented in a different context in each protein. We also isolated RGD-binding cell-surface receptors that subsequently became known as the integrin family of cell-adhesion receptors. The RGD paradigm became the basis of an intense worldwide drug development program seeking new treatments for arterial restenosis, thrombosis, angiogenesis, and cancer.
The current cell attachment work in this laboratory focuses on the signaling pathways that control anoikis, and through it tumor metastasis. The signaling proteins we work on include Bit1 a mitochondrial protein we consider a "guardian of anoikis," a protein we named "metadherin" because it promotes lung metastasis from breast cancers, and the receptor for one of our tumor-homing peptides that appears to promote tumor growth by causing metabolic changes in tumor cells.
Designing Multifunctional Nanoparticles for Tumor Delivery
Erkki Ruoslahti's Bio
Erkki Ruoslahti earned his M.D. and Ph.D. from the University of Helsinki in Finland in 1967. After postdoctoral training at the California Institute of Technology, he held various academic appointments with the University of Helsinki and the University of Turku in Finland and City of Hope National Medical Center in Duarte, California. He joined Sanford-Burnham in 1979 and served as its President from 1989-2002. He has been a Distinguished Professor at University of California Santa Barbara in Biological Sciences since 2005. His honors include elected membership to the U.S. National Academy of Sciences, Institute of Medicine, American Academy of Arts and Sciences, and the European Molecular Biology Organization. He is the recipient of the G.H.A. Clowes Award, Robert J. and Claire Pasarow Foundation Award, Jacobaeus International Prize, The Jubilee Award given by the British Biomedical Society. He was a Nobel Fellow at the Karolinska Institute in Stockholm in 1995, and is an Honorary Doctor of Medicine from the University of Lund, as well as a Knight of the Order of the White Rose of Finland. Dr. Ruoslahti is the recipient of the 2005 Japan Prize in Cell Biology.