Penn Researchers Lay Foundation for Herceptin’s Most-Recent Promise
(Philadelphia, PA) - Yesterday three new studies were released describing
the benefits of Herceptin, already used to treat advanced cancer, in fighting
an aggressive form of early breast cancer. The results of these trials
were so promising that the National Cancer Institute stopped the research
ahead of schedule earlier this spring to make the findings public. Pioneering
research conducted at the University of Pennsylvania School of
Medicine over the last two decades has laid the foundation for
these most-recent announcements.
The emerging story of new classes of “targeted” drugs like
Herceptin-able both to treat advanced cancer and prevent cancer development
and reoccurrence-illustrates that progress in science is rarely a “eureka”
moment of singular discovery. The reality is much more complex. In this
case, progress is cumulative. It is the product of more than 20 years
of extensive research and contributions from multiple teams of researchers
building on the initial work of Mark Greene, MD, PhD,
the John Eckman Professor of Pathology and Laboratory Medicine at Penn,
and his former student at Harvard University and now colleague, Jeffrey
Drebin, MD, PhD, Chief of the Division of Gastrointestinal Surgery,
also at Penn.
Cancer treatment is in a new era. Conventional chemotherapy targets the
DNA of dividing cells, which increases the risk of harm to non-cancerous
tissue. Mutations leading to drug resistance are also a consequence. The
newer outlook is called targeted therapy and is aimed not at the DNA but
at proteins made by genes, specifically receptor molecules found on the
surface of tumor cells.
Some targeted therapies rely on monoclonal antibodies, proteins produced
in the laboratory that bind only to the cancer cells in a patient, seeking
them out and destroying them, without harming normal cells. Herceptin,
which is effective in 20 to 30 percent of breast cancers, is a monoclonal
antibody. It targets a specific protein found on the surface of breast
cancer cells called HER-2/neu, by working only against breast cancers
that have too much of this protein.
The road to Herceptin’s success goes back to early work of Greene
and Drebin in 1984. In that year, in collaboration with a group at MIT
headed by Robert Weinberg, they demonstrated how HER-2/neu caused cells
to become cancerous. Working with mice, Greene and Drebin showed that
an anti-HER-2/neu monoclonal antibody could be a therapeutic weapon against
cancer. In 1985, Greene and Drebin found that mouse monoclonal antibodies
caused malignant neu cells to transform back into essentially normal cells
by disabling the protein that actually caused the malignancy. These efforts
represent the initial observation for targeted therapy’s promise.
Moreover, the antibodies worked without additional chemotherapy and had
no harmful effects on normal cells. Initially Greene and Drebin worked
on animal cancers but showed this was relevant to human disease as well
since other researchers found that some of these antibodies were able
to bind to human tumor cells, thus setting the stage for possible application
against cancer in humans.
Soon after, in 1987, two groups, one from UCLA and another from the Netherlands,
published an important observation that some human breast tumors contained
increased HER-2/neu. This discovery and the pioneering work of Greene
and Drebin paved the way for several laboratories to begin development
of monoclonal antibodies for human HER-2/neu. Herceptin is one such antibody.
In 1986 through 1990 Greene and Drebin went a step further and showed
that using two antibodies, one that bound one site of the neu protein
and another antibody that bound to different surfaces together had an
even better result than simply using one antibody. Ten years later, in
1998, they were awarded a patent for this “two antibody” approach.
Currently, clinical trials for this synergistic line of attack are underway
and may represent even more effective cancer-fighting success.
Greene also found that neu would often associate with another protein
called EGFR to create very aggressive tumors. His group showed that this
new transforming complex built of neu and EGFR could also be disabled.
When his group treated tumors caused by this complex with antibodies for
HER-2/neu and another for EGFR, they could dramatically inhibit tumor
growth. Antibodies for EGFR therapy have also reached the market as a
consequence of similar work done by John Mendelson and colleagues then
at the University of California at San Diego.
In 1995, Makoto Katsumata, PhD, and colleagues in Greene’s
group, showed that they could prevent tumor emergence in a genetically
engineered animal model they had developed in which breast cancers develop
in female mice in a similar manner to human cancers. Administering antibodies
to the mice prior to the development of cancer effectively prevented the
tumors from even arising in a significant proportion of treated animals.
These studies indicated that targeted therapy could also be used in individuals
who had a tumor removed and would prevent emergence of tumors that had
spread at the time of surgery or before.
“We’re proud to have played a role in helping to bring real
promise to the lives of women who have breast cancer now and those who
be diagnosed in the future,” says Greene. “This long process
shows that persistence, open sharing of information, and cooperation are
the roles of academics. The targeted therapy of proteins that cause malignant
cell behavior is simply the first step, we must now turn our attention
to eradicating the more advanced cancers altogether. ” Drebin adds,
“Medicine is essentially about teamwork. Dedicated people working
together can and do make real differences in the lives of other human
PENN Medicine is a $2.7 billion enterprise dedicated
to the related missions of medical education, biomedical research, and
high-quality patient care. PENN Medicine consists of the University of
Pennsylvania School of Medicine (founded in 1765 as the nation's first
medical school) and the University of Pennsylvania Health System.
Penn’s School of Medicine is ranked #2 in the nation for receipt
of NIH research funds; and ranked #4 in the nation in U.S. News &
World Report’s most recent ranking of top research-oriented medical
schools. Supporting 1,400 fulltime faculty and 700 students, the School
of Medicine is recognized worldwide for its superior education and training
of the next generation of physician-scientists and leaders of academic
The University of Pennsylvania Health System comprises: its flagship hospital,
the Hospital of the University of Pennsylvania, consistently rated one
of the nation’s “Honor Roll” hospitals by U.S. News
& World Report; Pennsylvania Hospital, the nation's first hospital;
Penn Presbyterian Medical Center; a faculty practice plan; a primary-care
provider network; two multispecialty satellite facilities; and home health
care and hospice.