News
Targeting the Cell's 'Biological Clock' in Promising New Cancer Therapy
Fri, 01/02/2015 - 9:22am
Cell
biologists at UT Southwestern Medical Center have targeted telomeres
with a small molecule called 6-thiodG that takes advantage of the cell’s
“biological clock” to kill cancer cells and shrink tumor growth.
Dr. Jerry W. Shay, Professor and Vice Chairman of Cell Biology at
UT Southwestern, and colleague, Dr. Woodring E. Wright, Professor of
Cell Biology and Internal Medicine, found that 6-thio-2’-deoxyguanosine
could stop the growth of cancer cells in culture and decrease the growth
of tumors in mice.
“We observed broad efficacy against a range of cancer cell lines
with very low concentrations of 6-thiodG, as well as tumor burden
shrinkage in mice,” said Dr. Shay, Associate Director of the Harold C.
Simmons Comprehensive Cancer Center.
Dr. Shay and Dr. Wright, who hold The Southland Financial
Corporation Distinguished Chair in Geriatrics, are co-senior authors of
the paper appearing in the journal Cancer Discovery.
6-thiodG acts by targeting a unique mechanism that is thought to
regulate how long cells can stay alive, a type of aging clock. This
biological clock is defined by DNA structures known as telomeres, which
cap the ends of the cell’s chromosomes to protect them from damage, and
which become shorter every time the cell divides. Once telomeres have
shortened to a critical length, the cell can no longer divide and dies
though a process known as apoptosis.
Cancer cells are protected from this death by an RNA protein
complex called telomerase, which ensures that telomeres do not shorten
with every division. Telomerase has therefore been the subject of
intense research as a target for cancer therapy. Drugs that successfully
block its action have been developed, but these drugs have to be
administered for long periods of time to successfully trigger cell death
and shrink tumors, leading to considerable toxicities. This outcome is
partially because cells in any one tumor have chromosomes with different
telomere lengths and any one cell’s telomeres must be critically
shortened to induce death.
6-thiodG is preferentially used as a substrate by telomerase and
disrupts the normal way cells maintain telomere length. Because 6-thiodG
is not normally used in telomeres, the presence of the compound acts as
an “alarm” signal that is recognized by the cell as damage. As a
result, the cell stops dividing and dies.
Telomerase is an almost universal oncology target, yet there are
few telomerase-directed therapies in human clinical trials, researchers
noted.
“Using telomerase to incorporate toxic products into telomeres is remarkably encouraging at this point,” said Dr. Wright.
Importantly, unlike many other telomerase-inhibiting compounds, the
researchers did not observe serious side effects in the blood, liver
and kidneys of the mice that were treated with 6-thiodG.
“Since telomerase is expressed in almost all human cancers, this
work represents a potentially innovative approach to targeting
telomerase-expressing cancer cells with minimal side effects on normal
cells,” said Dr. Shay. “We believe this small molecule will address an
unmet cancer need in an underexplored area that will be rapidly
applicable to the clinic.”
Source: UT Southwestern