October 29, 2004
Gene-Silencing Technique Offers
to Fight Drug-Resistant Leukemia
(Philadelphia, PA) - Ever since the approval of Gleevec
in 2001, a cancer-cell-specific drug used to treat chronic
myelogenous leukemia (CML), the field of cancer therapeutics
has been rushing full speed into the era of so-called
"targeted" medicines. The challenge of developing
these medicines, which spare normal cells because they
are designed to kill only cancer cells, has been complicated
by the recognition that resistance to even targeted
therapies can develop. In the case of Gleevec, for example,
which disables the BCR-ABL1 protein that causes CML,
resistance has become a growing problem. Currently,
physicians estimate that 5 percent to 10 percent of
patients who begin treatment in the chronic phase of
their disease will develop resistance to Gleevec; and
if treatment is begun at more advanced stages of CML,
this percentage is much higher.
Now researchers at the Abramson Cancer Center
of the University of Pennsylvania have found
a way around this problem. By disabling a BCR-ABL1-associated
enzyme called Lyn kinase, they have induced cell death
in drug-resistant CML cells taken from CML patients.
Normal blood cells do not appear to be harmed by this
approach because they are not so dependent on the Lyn
kinase as CML cells. The Lyn kinase is therefore a good
candidate for a targeted therapy.
“We know that patients treated with Gleevec can
develop mutations in the BCR-ABL1 protein,” explains
Alan M. Gewirtz, MD, Professor of Medicine
in Penn’s Division of Hematology/Oncology. “Once
the BCR-ABL1 gene mutates, Gleevec can no longer
combine with the BCR-ABL1 protein, so it remains active,
and the cancerous blood cells survive and grow."
Gewirtz and colleagues’ research appears in the
November issue of Nature Medicine.
"Lyn kinase is a member of a family of proteins
that we know plays a role in cell survival, growth,
and development," explains Gewirtz. “CML
cells, especially those that arise in Gleevec-resistant
patients, are very dependent on its function."
To disable it, the researchers used short interfering
RNA (siRNA) to "silence" the gene that codes
for the Lyn kinase protein.
An siRNA is a short, double-stranded piece of RNA with
a unique chemical sequence, or tag, that allows it to
combine specifically with a particular messenger RNA
(mRNA) that shares the same tag. After the siRNA is
introduced into a cell it attaches to the mRNA whose
tag it shares, and this targets the mRNA for destruction
using a natural disposal system present in all cells.
Without an mRNA to direct the production of Lyn kinase
protein, the Lyn gene is effectively shut down, or "silenced."
With Lyn out of the picture, the cancer cell
“We hope that this therapy will be able to enter
the clinic rapidly, perhaps even within the next couple
of years,” say Gewirtz. “The basic methodologies
are in place but an siRNA molecule still needs FDA approval.”
Andrezej Ptasznik, Yuji Nakata, Ann Kolata, and Stephen
G. Emerson from Penn were all co-authors on the paper.
This research was funded in part by grants from the
Doris Duke Charitable Foundation, the National Institutes
of Health, and the Leukemia and Lymphoma Society.
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The Abramson Cancer Center of the University
of Pennsylvania was established in 1973 as
a center of excellence in cancer research, patient care,
education and outreach. Today, the Abramson Cancer Center
ranks as one of the nation’s best in cancer care,
according to U.S. News & World Report, and is one
of the top five in National Cancer Institute (NCI) funding.
It is one of only 39 NCI-designated comprehensive cancer
centers in the United States. Home to one of the largest
clinical and research programs in the world, the Abramson
Cancer Center of the University of Pennsylvania has
275 active cancer researchers and 250 Penn physicians
involved in cancer prevention, diagnosis and treatment.
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 (created in 1993 as the nation’s
first integrated academic health system).
Penn’s School of Medicine is ranked #3 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 medicine.
Penn Health System is comprised of: 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; Presbyterian
Medical Center; a faculty practice plan; a primary-care
provider network; two multispecialty satellite facilities;
and home health care and hospice.