Pancreatic Cancer Cells Killed by Drug Combination
in Mayo Clinic Laboratory Test
One of the most feared cancers, due to the
difficulty of effective treatment, may have met its match - Also, herbal
extract stops cancer growth and another two drug combo reduces stem cell
growth in this cancer
Mamta Gupta, Ph.D.
April 20, 2009 – There is new hope in the battle
against pancreatic cancer, one of the most feared tumors. Mayo Clinic
researchers say a combination of two drugs already on the
market packed a powerful punch in laboratory tests to kill pancreatic
cancer cells.
The Mayo program is now ready to move on to human
clinical trials with high hopes they may be on the path to an effective
new treatment for one of the most difficult to treat tumors.
In a study being presented at the
AACR 100th Annual Meeting 2009, Mayo Clinic Cancer Center
investigators found that rapamycin and panobinostat (also known as
LBH589) act synergistically when used in combination, destroying up to
65 percent of cultured pancreatic tumor cells.
The finding is particularly significant, says the
study's first author, Mamta Gupta, Ph.D., because the three cell lines
studied were all resistant to the effects of chemotherapy - as are many
pancreatic tumors - and because the drugs studied are already available
for treatment of patients.
Panobinostat is approved as therapy for
cutaneous T cell lymphoma (CTCL), and rapamycin is best known as an
immunosuppressant to help prevent rejection of transplanted organs.
"We need new therapies and strategies for the
treatment of pancreatic cancer because these tumors are resistant to
almost all known treatments," says Dr. Gupta, a research associate in
the Division of Hematology.
See
these reports below main story:
• Herbal Extract
Found to Inhibit the Development of Pancreatic Cancer
• Drug
Combination Reduces Pancreatic Cancer Stem Cells, Stops Cancer
Growth
"No targeted treatment has shown much value
to date."
Pancreatic cancer is one of the deadliest cancers,
and less than 4 percent of the 200,000 patients diagnosed annually live
more than five years. The only available clinical treatment is
gemcitabine, but this has yet to show a survival benefit (see sidebar).
Dr. Gupta studied the combination of agents in
pancreatic cancer cells because her previous research at Mayo Clinic had
shown that this combination worked well in laboratory tests of
non-Hodgkin's lymphoma. A phase one clinical trial to test this
combination in patients with lymphoma will open soon at Mayo Clinic
under the direction of Thomas Witzig, M.D.
"While our pancreatic cancer cell line results look
very promising, these are laboratory, not clinical, studies," she says.
"We are preparing to take this combination of drugs to clinical trial to
evaluate whether they can be safely given to patients."
While clinical studies will ultimately determine
the benefits of panobinostat and rapamycin, Dr. Gupta and her colleagues
remain focused on trying to understand the mechanism for how these
agents together are so powerful.
About Gemcitabine (Gemzar)
Gemcitabine is used as chemotherapy. It is marketed
as Gemzar by Eli Lilly and Company.
Gemcitabine is used in various carcinomas:
non-small cell lung cancer, pancreatic cancer, bladder cancer and breast
cancer. It is being investigated for use in oesophageal cancer, and is
used experimentally in lymphomas and various other tumor types.
Gemcitabine represents an advance in pancreatic cancer care. It is also
not as debilitating as other forms of chemotherapy.
A study reported in the Journal of the American
Medical Association (JAMA) in January 2007 suggested that
gemcitabine shows benefit in patients with pancreatic cancer who were
felt to have successful surgical removal of at least part of the tumor.
Postoperative gemcitabine significantly delayed the
development of recurrent disease after complete surgical removal of
pancreatic cancer compared with observation alone. These results support
the use of gemcitabine as adjuvant chemotherapy in surgically removable
carcinoma of the pancreas.
Rapamycin and a closely related drug, everolimus
(RAD001), have both been tested in pancreatic cancer cells, but by
themselves have shown minimal activity, Dr. Gupta says.
They belong to a
class of agents known as mTOR inhibitors. The mTOR pathway is a major
cellular survival mechanism that is persistently activated in pancreatic
cancer cells.
In this study, rapamycin killed less than 5 percent
of pancreatic cancer cells, and previous tests with RAD001 showed the
same minimal effect, Dr. Gupta says. Panobinostat is a histone
deacetylase (HDAC) inhibitor.
In cancer, HDAC proteins "silence" tumor
suppressor genes, so an HADC inhibitor restores expression of these
beneficial genes. The agent is also believed to block angiogenesis - the
growth of new blood vessels needed for tumors to grow," Dr. Gupta says.
Panobinostat killed about half of pancreatic cancer
cells studied, she says. But both agents combined inhibited growth of
pancreatic cancer cell lines and induced apoptosis (cell death) in up to
65 percent of the cells, Dr. Gupta says.
Dr. Gupta noted that panobinostat is effective at
extremely low concentrations that are consistent with optimal
pharmacological doses. "Our aim is always to use as little of a drug as
possible in order to reduce potential side effects in patients," she
says.
Although the researchers say they don't yet know
the synergistic mechanism responsible for the combined drugs'
effectiveness, they hypothesize that the agents are primarily
interfering with the mTOR pathway, which is involved in growth and
angiogenesis.
"Overall, these results indicate that rapamycin and
panobinostat disrupts essential survival and proliferating pathways in
pancreatic cancer cells, and this is a good start toward a novel
treatment of this cancer," Dr. Gupta says.
The study was funded by the National Cancer
Institute.
Information Source:
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More Advances in War on Pancreatic Cancer
These studies are also being presented at AACR
meeting
Herbal Extract Found to Inhibit the Development of
Pancreatic Cancer
An herb recently found to kill pancreatic cancer
cells also appears to inhibit development of pancreatic cancer as a
result of its anti-inflammatory properties, according to researchers
from the Kimmel Cancer Center at Jefferson University Hospital,
Philadelphia.
Thymoquinone, the major constituent of the oil
extract from a Middle Eastern herbal seed called Nigella sativa,
exhibited anti-inflammatory properties that reduced the release of
inflammatory mediators in pancreatic cancer cells, according to Hwyda
Arafat, M.D., Ph.D., associate professor of Surgery at the Jefferson
Medical College of Thomas Jefferson University and a member of the
Jefferson Pancreatic, Biliary & Related Cancers Center.
Nigella sativa seeds and oil are used in
traditional medicine by many Middle Eastern and Asian countries. It
helps treat a broad array of diseases, including some immune and
inflammatory disorders, Dr. Arafat said. Previous studies have also
shown it to have anti-cancer effects on prostate and colon cancers.
Based upon their previously published findings that
thymoquinone inhibits histone deacetylases (HDACs), Dr. Arafat and her
colleagues compared the anti-inflammatory properties of thymoquinone and
trichostatin A, an HDAC inhibitor that has previously shown to
ameliorate inflammation-associated cancers.
The researchers used pancreatic ductal
adenocarcinoma (PDA) cells, some of which were pretreated with the
cytokine TNF-alpha to induce inflammation. Thymoquinone almost
completely abolished the expression of several inflammatory cytokines,
including TNF-alpha, interleukin-1beta, interleukin-8, Cox-2 and MCP-1,
an effect that was more superior to the effect of trichostatin A.
The herb also inhibited the activation and
synthesis of NF-kappaB, a transcription factor that has been implicated
in inflammation-associated cancer. Activation of NF-kappaB has been
observed in pancreatic cancer and may be a factor in pancreatic cancer's
resistance to chemotherapeutic agents. When animal models of pancreatic
cancer were treated with thymoquinone, 67 percent of the tumors were
significantly shrunken, and the levels of proinflammatory cytokines in
the tumors were significantly reduced.
Inflammation has been implicated in the development
of several solid tumor malignancies. Chronic pancreatitis, both
hereditary and sporadic, is associated with the risk of developing
pancreatic cancer.
"These are very exciting and novel results," Dr.
Arafat said. "Not only patients with chronic pancreatitis could benefit
from this, but also several other groups with risk of development or
recurrence of pancreatic cancer, such as high-risk family members and
post-surgical patients. These potent effects show promise for the herb
as a potential preventive and therapeutic strategy for pancreatic
cancer. More importantly, the herb and oil are safe when used
moderately, and have been used for thousands of years without reported
toxic effects."
Drug Combination Reduces Pancreatic Cancer Stem
Cells, Stops Cancer Growth
Pancreatic cancer remains one of the deadliest
cancers, but researchers may have found a combination therapy to reduce
cancer stem cells and stop pancreatic cancer growth. Results will be
presented at the American Association for Cancer Research 100th Annual
Meeting 2009.
Rajesh Kumar N.V., Ph.D., a faculty member at the
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University,
said a combination therapy using tigatuzumab, a novel humanized death
receptor-5 (DR-5) agonist antibody, along with gemcitabine, may result
in reducing pancreatic cancer stem cells to achieve tumor remission and
prevent tumor recurrence.
"Many advanced cancers, including pancreatic
cancer, recur and result in patient death despite the use of
chemotherapeutic and radiation modalities that initially lead to
therapeutic responses," said Kumar.
"A growing body of evidence supports the concept
that cancer stem cells are the seeds of the most clinically deadly form
of therapy-resistant human cancers. Emerging studies show that cancer
stem cells are indeed more resistant to therapy than other cancer cells
and might be the reason why conventional chemotherapy, while reducing
tumor size, does not result in long-term cures."
Kumar and colleagues analyzed the cancer stem cells
in ten patient-derived tumors implanted in laboratory mice and found
that DR-5 is enriched in cancer stem cells compared to non-stem cell
tumor populations. These mice either received tigatuzumab alone;
gemcitabine, the current clinical treatment for pancreatic cancer; or a
combination of the two agents.
They found that treatment with gemcitabine alone
reduced tumor size, but the tumor cells that remained were rich in
pancreatic cancer stem cells. In nearly all cases, the tumors returned.
However, treatment with gemcitabine and tigatuzumab
resulted in the reduction of pancreatic cancer stem cells, caused tumor
remission, and significantly increased time-to-tumor progression in 50
percent of treated cases from a median of 54 days to 103 days.
From a clinical standpoint, targeting
cancer-sustaining pancreatic cancer stem cells will be of paramount
significance since there are few effective therapies for pancreatic
cancer and most of the patients die within the first year of diagnosis.
"Clinically, this discovery could transform the way in which pancreatic
cancer is treated and contribute towards making pancreatic cancer a more
manageable disease," said Kumar.
The data were presented at the AACR 100th Annual
Meeting 2009 in Denver.
Information Source
American Association for Cancer Research
The mission of the American Association for Cancer
Research is to prevent and cure cancer. Founded in 1907, AACR is the
world's oldest and largest professional organization dedicated to
advancing cancer research. The membership includes more than 28,000
basic, translational and clinical researchers; health care
professionals; and cancer survivors and advocates in the United States
and nearly 90 other countries.
The AACR marshals the full spectrum of expertise
from the cancer community to accelerate progress in the prevention,
diagnosis and treatment of cancer through high-quality scientific and
educational programs. It funds innovative, meritorious research grants.
The AACR Annual Meeting attracts more than 17,000
participants who share the latest discoveries and developments in the
field. Special conferences throughout the year present novel data across
a wide variety of topics in cancer research, treatment and patient care.
The AACR publishes six major peer-reviewed
journals: Cancer Research; Clinical Cancer Research; Molecular Cancer
Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers
& Prevention; and Cancer Prevention Research. The AACR also
publishes CR, a magazine for cancer survivors and their families,
patient advocates, physicians and scientists. CR provides a forum
for sharing essential, evidence-based information and perspectives on
progress in cancer research, survivorship and advocacy.
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