MGH. US: Researchers from the Massachusetts General Hospital (MGH) Cancer Center and Boston University School of Medicine
(BUSM) have identified the first potential treatment targeting a
pathway by which several aggressive tumors maintain their ability to
proliferate. Treatment with a small molecule that blocks a key step in
that pathway – the alternative lengthening of telomeres (ALT) pathway –
was able to inhibit the growth and survival of ALT-positive tumor cells.
“Identification of genetic markers that predict cancer cell
vulnerabilities and new drugs to exploit such vulnerabilities is a focal
point of cancer research today,” says Lee Zou,
PhD, associate scientific director of the MGH Cancer Center, senior and
co-corresponding author of the report in the Jan. 16 issue of Science.
“Cancer cells must rely on either the telomerase enzyme or the ALT
pathway to bypass the normal processes of cell aging and death. Our
findings may provide a new direction for the treatment of ALT-positive
cancers – which include osteosarcoma, glioblastoma and certain
pancreatic tumors.”
Telomeres are repetitive DNA sequences that
sit at the ends of chromosomes and serve a protective function to make
sure cells do not lose valuable genetic information each time they
divide. When telomeres have been eroded to a critically short length,
they send out a signal to the cell telling it to stop dividing, ensuring
that the genetic information remains intact but limiting the cell’s
lifespan. Cancer cells have evolved to overcome this constant attrition
by continuously extending those eroded telomeres, promoting cellular
immortality.
There are two major pathways for telomere
elongation in cancer cells. The more common pathway relies on the enzyme
telomerase to extend telomeres. The less understood ALT pathway
lengthens telomeres through recombination with DNA sequences from other
chromosomes.
In their investigations, the researchers studied
how the action and expression of several key proteins is altered in
cancer cells that use the ALT pathway. Focusing on a protein called ATR,
a master regulator of DNA repair and recombination, the investigators
verified that the protein also plays a crucial role in regulating the
ALT pathway. They found that the ATR inhibitors VE-821 and AZ20
selectively eliminated ALT-positive osteosarcoma and glioblastoma cells
from panels of cancer cell lines, suppressing their ability to extend
their telomeres though recombination and leading to the cells’ death.
Co-corresponding
and lead author Rachel Flynn, PhD, assistant professor of Pharmacology
& Experimental Therapeutics and Medicine at BUSM, explains, “This
study suggests that inhibiting ATR may be a novel and important strategy
in treating cancers that rely on the ALT pathway, including up to 60
percent of osteosarcomas and 40 to 60 percent of glioblastomas. Such
targeted treatments would only affect cancer cells and have little
effect on the surrounding healthy tissue, potentially minimizing the
harsh and debilitating side effects experienced with traditional cancer
therapies.” Flynn began the project as a postdoctoral fellow in Zou’s
MGH Cancer Center lab and completed the investigation after joining the
faculty at BUSM.
While clinical trials of telomerase inhibitors
for the treatment of cancer are currently underway, the up to 10 percent
of tumors that do not use the telomerase pathway would not respond to
such drugs. “Testing tumors for their use of telomerase or the ALT
pathway is not yet routine,” Flynn says. “If VE-821 or other ATR
inhibitors are clinically successful, it would support such testing and
may lead to more personalized and targeted therapeutic regimens for
several cancers refractory to traditional chemotherapeutics.”
In addition to Zou, who is a professor of Pathology at Harvard Medical School, co-authors of the Science article
include Daniel Haber, MD, PhD, and Cyril Benes, PhD, of the MGH Cancer
Center and Neil J. Ganem PhD an assistant professor in Pharmacology
& Experimental Therapeutics at BUSM. Funding for the study includes
Wellcome Trust grant 102696 and National Institute of Health grants
GM076388 and CA166729. Flynn is supported by the Karin Grunebaum Cancer
Research Foundation and the Foster Foundation, and Zou is a Jim and Ann
Orr Massachusetts General Hospital Research Scholar and a senior scholar
of the Ellison Medical Foundation.
Originally established in
1848 as the New England Female Medical College, and incorporated into
Boston University in 1873, Boston University School of Medicine today is
a leading academic medical center with an enrollment of more than 700
medical students and 800 students pursuing degrees in graduate medical
sciences. Its 1,246 full and part-time faculty members generated more
than $137.3 million in funding in FY2013 for research in amyloidosis,
arthritis, cardiovascular disease, cancer, infectious diseases,
pulmonary disease and dermatology, among others. The School’s teaching
affiliates include Boston Medical Center, its primary teaching hospital,
the VA Healthcare System in Boston, Roger Williams Medical Center in
Rhode Island, as well as Boston HealthNet, a network of 15 community
health centers.
Massachusetts General Hospital, founded in 1811,
is the original and largest teaching hospital of Harvard Medical
School. The MGH conducts the largest hospital-based research program in
the United States, with an annual research budget of more than $785
million and major research centers in HIV/AIDS, cardiovascular research,
cancer, computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, reproductive biology, systems biology, transplantation biology
and photomedicine.
Media Contacts: Katie Marquedant, 617 726-0337, kmarquedant@partners.org