Jefferson Researchers Identify Critical Marker of Response to Gemcitabine in Pancreatic Cancer
A protein related to aggressive cancers
can actually improve the efficacy of gemcitabine at treating pancreatic cancer,
according to a Priority Report in Cancer Research, published by
researchers at Thomas Jefferson
University.
The protein, called Hu antigen R (HuR),
is a stress response protein found in the cytoplasm of pancreatic tumor cells.
In certain experimental settings, pancreatic cancer cells that overexpressed HuR
were up to 30-fold more sensitive to gemcitabine (Gemzar), according to Jonathan
Brody, Ph.D., assistant professor of Surgery at Jefferson Medical College of
Thomas Jefferson University.
In a clinical correlate study that
included 32 resected pancreatic cancer patients who received gemcitabine,
patients who had low cytoplasmic HuR levels had a 7-fold increased mortality
risk compared to patients with high levels. This was after adjustment for other
variables including age, sex, radiation therapy and other chemotherapy use.
“This marker appears to tell us upfront
whether a patient will respond to treatment with gemcitabine, which is the
routine treatment for pancreatic cancer,” said Dr. Brody, who is the senior
author of the study. “Of course, larger and comprehensive prospective studies
need to be performed, but we now have a real clue about how to make this
treatment better. Finding a mechanism that regulates gemcitabine’s metabolism in
pancreatic cancer cells is the real novel and exciting aspect of these
findings.”
Dr. Brody and colleagues found that in
pancreatic cancer, HuR helps to regulate an enzyme called deoxycytidine kinase
(dCK), which is responsible for metabolizing and activating gemcitabine. As with
most chemotherapy drugs, gemcitabine causes cell stress and activates the HuR
stress proteins. In turn, the high levels of HuR stimulate the production of
more dCK, thus making gemcitabine more efficient, according to Dr. Brody.
“Normally, patients higher HuR
cytoplasmic levels have a worse prognosis, since HuR expression is associated
with advanced malignancies,” Dr. Brody said. “However, in our study, they did
better than patients with low HuR levels when they were treated with
gemcitabine. We think it’s because they already have high HuR levels at the time
of treatment, which may be a response to the tumor cell environment.”
According to Dr. Brody, research is
underway to find a way to activate HuR in patients with a low expression. Other
goals include expanding these findings to a larger pancreatic cancer population,
and to other tumors that may be treated with gemcitabine, including breast,
ovarian and certain lung cancers. They also want to determine if other
chemotherapeutic agents engage this intriguing and manipulative pathway.
Co-authors of the paper include Charles
J. Yeo, M.D., Samuel D. Gross Professor and chairman of the department of
Surgery, and Agnieszka Witkiewicz, M.D., assistant professor of Pathology,
Anatomy and Cell Biology. Drs. Brody, Yeo and Witkiewicz are co-directors of the
Jefferson Pancreas, Biliary and Related Cancer Center.
Other study collaborators include Dr.
Myriam Gorospe from the National Institute on Aging (NIH) and Dr. Judith Keen
from the University of Medicine and Dentistry of New Jersey.
Media Only Contact:
Emily Shafer
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 6/1/2009