Gene-Silencing Technique Offers New Way to Fight
(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 dies.
“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
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.
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
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.