A comprehensive drug development strategy that starts with extensive screening of potential targeting agents and then narrows down to a small-molecule prototype has yielded two potential drugs that block cancer-promoting pathways in novel ways, a team led by scientists at The University of Texas M. D. Anderson Cancer Center reports in two papers published back-to-back online at the Proceedings of the National Academies of Science.
"The conceptual advance here is to demonstrate how to go rapidly from screening to structural-functional analysis to drug prototype in a few years," said co-senior author Wadih Arap, M.D., Ph.D., of the David H. Koch Center at M. D Anderson.
"The practical outcome is a pair of new drug candidates, one that acts as a decoy to inhibit a cancer-promoting pathway and another that blocks angiogenesis, the development of new blood vessels, which has the potential to treat both cancer and retinopathies that cause blindness," said co-senior author Renata Pasqualini, Ph.D., also of the David H. Koch Center.
The strategy begins with the screening of millions of peptides – short combinations of at least two amino acids, the building blocks of proteins. Once a peptide is found that binds the target, a durable drug called a peptidomimetic is made from short combinations of non-natural amino acids.
For proof of concept, the team targeted the epidermal growth factor receptor pathway (EGFR) and the vascular endothelial growth factor receptor pathway (VEGFR).
EGFR is overexpressed on the cell surfaces of a number of cancers, including lung, colon, and head and neck. Epidermal growth factor binds to the receptor and causes cells to divide. It is currently treated with two types of drugs, antibodies that block the receptor and small kinase inhibitors. VEGFR is overexpressed in the cancer vascular system and is central to the formation of new blood vessels (angiogenesis) that accompany tumor growth
Drugs reduce tumor volume, blood vessel growth in mice
The researchers created a decoy that lures EGF away from its receptor. In a mouse model of head and neck cancer, mice that received the decoy had a median tumor size half that of those in control groups.
They also demonstrated that the drug prototype could also serve as a decoy for cetuximab, an antibody drug that blocks the pathway by plugging into the EGFR. When the peptidomimetic and cetuximab were introduced into human colon and head and neck cancer cell lines, the small drug inhibited the antibody's action.
For VEGFR, the team discovered a peptide that binds to the receptor, inhibiting angiogenesis. In a series of mouse model experiments, treated mice showed reductions in the number of blood vessels ranging from 37 percent to 72 percent.
In an animal model of retinopathy – overgrowth of blood vessels in the eye that can cause blindness – mice treated with the peptide had a 59 percent reduction in angiogenesis compared to control mice. A separate test of the peptidomimetic in an eye drop formulation resulted in a 53 percent reduction in abnormal retinal blood vessel growth.
This raises the possibility of developing an easily administered treatment for diabetic retinopathy or retinopathy of prematurity, Arap said. Preclinical studies continue for both cancer and retinopathy applications. Using small molecules to bind to the receptor site is a new approach to inhibiting VEGFR.
Screening, winnowing and developing the peptides
The group's approach begins by screening the target receptors with a phage display library used by Arap and Pasqualini. This method screens billions of viral particles that each display a different peptide on its outer coat to find those that fit into the receptor like a key goes into a lock.
Candidate peptides are next winnowed by using structural and functional analysis. Once a peptide is identified and tested, the researchers take an additional step to synthesize a new version of the peptide more suited for use as a drug.
L-amino acids and proteins are the building blocks of life but are easily degraded by cellular protein recycling machinery, making peptide-based drugs more vulnerable to destruction. Through a process called retro-inversion, the group chemically synthesizes a mirror image peptidomimetic using D amino acids along with a reversed peptide sequence. The resulting products are more durable but still target the receptor.
For example the peptide that targets VEGFR is called RPL, letters that represent three natural amino acids that make up the peptide. The retro-inverted D-peptidomimetic is D(LPR). For the EGFR decoy, the natural peptide CVRAC becomes the D-peptidomimetic D(CARVC).
The two prototype drugs will need to be further refined in preclinical models and later tested in clinical trials before they can become available for general use.
Both studies were funded by grants from the U.S. Department of Defense and the National Institutes of Health, and awards from the Gillson-Longenbaugh Foundation, the Marcus Foundation and AngelWorks. Marina Cardó-Vila, Ph.D., first author of the EGFR paper, is a fellow of the Susan G. Komen for the Cure. Ricardo J. Giordano, Ph.D., the first author of the VEGFR paper, is currently an Assistant Professor of Biochemistry at the Chemical Institute, University of São Paulo, Brazil.
Co-authors of the VEGFR paper with first author Giordano, Pasqualini and Arap are Cardó-Vila and Ahmad Salameh, Ph.D., of M. D. Anderson's David H. Koch Center; Christiane Anobom, Ph.D., Ana Valente, Ph.D., and Fabio Almeida, Ph.D. of the National NMR Center, Rio de Janeiro Federal University, Rio de Janeiro, Brazil; Benjamin Zeitlin, Ph.D., and Jacques Nör, D.D.S., Ph.D., of the Angiogenesis Research Laboratory at the University of Michigan School of Dentistry; David Hawke, Ph.D., of M. D. Anderson's Center for Targeted Therapy; and Richard Sidman, M.D., of Harvard Medical School and the Department of Neurology at Beth Israel Deaconess Medical Center.
Co-authors on the EGFR paper with first author Cardó-Vila, Arap and Pasqualini are Giordano; Sidman of Harvard; and Zhen Fan, M.D., and John Mendelsohn, M.D., M. D. Anderson's president, both of the Department of Experimental Therapeutics.
The University of Texas M. D. Anderson Cancer Center and its researchers have filed patents on the technology and other intellectual property reported in these papers. If licensing or commercialization of such intellectual property occurs, the researchers and M. D. Anderson may be entitled to financial consideration, including royalties. M. D. Anderson manages these relationships in accordance with appropriate statutes, rules, regulations and policies.
About M. D. Anderson
The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For six of the past eight years, including 2009, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.
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