Edward A. McKenzie talks with
ScienceWatch.com and answers a few questions about
this month's New Hot Paper in the field of Pharmacology
& Toxicology. The author has also sent along
images of their work.
Article Title: Heparanase: a target for drug
discovery in cancer and inflammation
Authors: McKenzie,
EA
Journal: BRIT J PHARMACOL
Volume: 151
Issue: 1
Page: 1-14
Year: MAY 2007
* Univ Manchester, Fac Life Sci, Micael Smith Bldg,Oxford
Rd, Manchester M13 9PL, Lancs, England.
* Univ Manchester, Fac Life Sci, Manchester M13 9PL, Lancs,
England.
Why do you think your paper is highly
cited?
I think this is probably a reflection of the tremendous interest shown by
both big pharma and the biotech industry in this enzyme as an
anti-angiogenic/metastatic therapeutic target in cancer drug discovery. As
there is only one extracellular enzyme that has this role, it is recognized
as a key control point in this biological pathway, in contrast to the case
of matrix metalloproteinases, for example, where many enzymes can perform a
similar role.
Heparanase is elevated in almost every tumor type studied and as such, is
heavily implicated as one of the important players in disease progression.
Outside of cancer biology, the enzyme also has a role in inflammation and
wound healing and so crosses over many disciplines to attract a wider
audience. The recent availability of reagent tools (recombinant protein,
specific protein antibodies, assay kits, heparan sulphate substrate
antibodies, etc.) has also made research into heparanase that much more
accessible than before.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
This review brings together the key publications over recent years since
the cloning of the gene in 1999 and synthesizes the knowledge of heparanase
biology and pathology which has lead to the current diverse array of
inhibitors of heparanase activity. Looking to the future, more focus now
needs to be put on the discovery of in vivo clinical biomarkers of
this enzyme as the validation of heparanase as a drug candidate becomes
even more compelling.
Would you summarize the significance of your paper
in layman's terms?
Tumor cells require a number of essential proteins that allow them to
proliferate and spread—a process known as metastasis—throughout
the body. To keep ahead in the battle against cancer there is an increasing
need for drugs that block these proteins and so neutralize their action.
Blocking the action of heparanase with inhibitors, as highlighted in this
paper, has been shown to significantly reduce both tumor spread and
restrict the growth of new blood vessels (angiogenesis) that feed the
tumor.
Many different types of inhibitors have now been developed and are in the
exciting transition phase of going from laboratory testing to the clinic.
The flagship drug PI-88, which includes a heparanase inhibitory action, is
leading the way by showing great promise in clinical trials. New screening
tests to examine how well these drugs perform in cancer patients are also
being created. Only time will tell, however, whether these drugs live up to
the many expectations; hopes are high within the heparanase community.
How did you become involved in this research, and
where there any problems along the way?
My involvement in heparanase (HPSE1) and carbohydrate processing enzymes in
general first began in June 1999 when I joined Oxford GlycoSciences (OGS),
a small biotech company based in Abingdon, south of Oxford. Working in a
close-knit drug discovery team, my primary aim was to take a potential
oncology therapeutic target protein and help design and implement from
basics all the particular protein expression strategies, HTS assay, primary
and secondary assays required to screen and test for novel inhibitors.
"Many different types of inhibitors
have now been developed and are in the
exciting transition phase of going from
laboratory testing to the
clinic."
An exciting part of this work was the freedom to carry out basic research
and to publish my work. This led to the discovery of a novel heparanase
enzyme (HPSE2) and work describing for the first time a route to producing
large amounts of active HPSE1 enzyme. A series of potent inhibitors were
discovered that led to some encouraging preliminary efficacy data on animal
models.
Unfortunately OGS fell victim to a hostile takeover in 2003 by Celltech
(now part of UCB-Celltech) which led to closure of the program and a large
number of redundancies. I subsequently moved back into academia and
concentrated on re-building my heparanase career through a number of
collaborations. Forging these strong links with academic groups during my
OGS days meant, luckily, that I could rely on these to re-establish myself
in the field again outside of industry.
Where do you see your research leading in the
future?
One of my current research interests is to obtain a high resolution X-ray
structural model of the active enzyme. This will facilitate a rational drug
design strategy for discovering new inhibitors in addition to improving on
current drugs. It is very exciting to see that heparanase 2, which has
remained in the shadow for too long, is now attracting attention from a
number of groups studying its role in cancer. The challenge now is to
determine the individual role of the various heparanase 2 splice forms and
examine their precise role in extracellular matrix remodelling.
Do you foresee any social or political implications
for your research?
Any therapy (small molecule, antibody, antisense RNA, etc.) for
down-regulating the elevated levels of heparanase enzyme observed in cancer
and inflammation has tremendous potential for both single or combination
therapy. Since cancer biology involves so many different mechanisms, a drug
target such as heparanase, which is involved in more than one mechanism (in
this case, angiogenesis and invasion), provides a double-hit approach.
Expanding our basic knowledge of how this protein functions will only help
to further drive the drug discovery process.
The true success of anti-heparanase drugs however can of course only be
judged from their success in clinical trial studies. Like others in the
field, I am confident that these drugs will pass this test and go on to
make a significant contribution to the treatment and quality of life for
cancer patients. Anti-heparanase therapy could help to convert cancer from
being the killer disease that people fear to a chronic condition that is
contained and more manageable.
Dr. Edward A. McKenzie
Senior Experimental Officer
Faculty of Life Sciences
University of Manchester
Manchester, UK
Keywords: heparanase, anti-angiogenic/metastatic therapeutic
target, cancer drug discovery, cancer biology, extracellular enzyme,
matrix metalloproteinases, recombinant protein, specific protein
antibodies, assay kits, heparan sulphate substrate antibodies,
angiogenesis, tumor cells, metastasis, oncology, therapeutic target
protein, heparanase enzyme.