Drug screening strategy finds two prototype cancer drugs
21 April 2010
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.
The strategy was developed by a team led by scientists at The
University of Texas M. D. Anderson Cancer Center and is reported in
two papers published online in the Proceedings of the National
Academy of Sciences.
“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 tumour growth
Drugs reduce tumour 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 tumour size half that of those in
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% to 72%.
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% reduction in angiogenesis compared to control mice. A
separate test of the peptidomimetic in an eye drop formulation
resulted in a 53% 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.
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.