2/11/2010
Specific
chemical modifications to proteins called histones, which are found in
the nucleus of cells and act as spools around which DNA is wound, can
be used to predict prognosis and response to treatment in subsets
patients with pancreatic cancer, a study by researchers at UCLA’s
Jonsson Comprehensive Cancer Center has found.
High levels of two specific histone modifications found in tumor cells of patients who underwent surgical resection of their pancreatic cancer
predicted those patients would be more likely to derive survival
benefit from the commonly-used chemotherapy drug Fluorouracil, or 5-FU.
Along with Gemcitabine, 5-FU is a common chemotherapy used to treat
patients with pancreatic cancer, the fourth deadliest cancer in the
United States.
“These histone modifications were useful in
predicting whether or not a patient was likely to respond favorably to
5-FU” said Dr. David Dawson, an assistant professor of pathology and
laboratory medicine, senior author of the study and a Jonsson
Comprehensive Cancer Center researcher. “Using a specially devised test
and algorithm, we were able to discriminate two groups of pancreatic
cancer patients who were more or less likely to have longer
disease-free remissions and overall survival.”
The histone modifications themselves also may prove to be future targets for drug therapies, Dawson said.
The
study, which needs to be validated in a prospective study, was
published this week in the peer-reviewed Journal of Clinical Oncology.
Jonsson Cancer Center researchers, led by Dr. Siavash Kurdistani and Dr. David Seligson,
developed and patented the immunohistochemistry assay, or antibody
test, to measure the levels of the specific histone modifications
within cells. The rights to that technology have been licensed by an
outside company.
Kurdistani and Seligson, also authors on the
study, previously used the test to identify the same histone
modifications in subsets of patients with prostate, kidney and lung
cancers. They showed that low cellular levels of the histones could
determine which prostate cancer patients, even those who go to the
best urologist, were more likely to suffer arecurrence and which
patients with lung and kidney cancers would experience poorer
survival rates.
The current study centered
on a field known as epigenetics, which focuses on inherited information
other than that directly encoded by DNA. In addition to genetic
mutations, epigenetic changes such as alterations to histone
modifications contribute to the development of cancer, said Kurdistani,
an assistant professor of biological chemistry.
“Overall,
these histone modifications are providing useful information as to how
a cancer may behave,” he said. “In addition, there may be a direct
causal link between these changes and tumor aggressiveness.”
The
tissues used in the study came from a 195-patient cohort enrolled in
the Radiation Therapy Oncology Group 9704 trial, a multi-center, phase
III study of pancreatic cancer comparing adjuvant Gemcitabine with
5-FU, and a separate140-patient cohort of patients with stage I or II
pancreatic cancer from UCLA.
Generally, low levels of histone
modifications were found to be predictors of poor survival in both
patient cohorts, and to identify those less likely to respond to 5-FU
in the 9704 patient cohort, the study reports.
“Pancreatic
cancer is a highly aggressive and lethal cancer for which there are
limited therapeutic options,” the study states. “Along with genetic
events, tumor-associated epigenetic alterations are important
determinants in the initiation and progress of pancreatic cancer and
represent promising biomarkers and therapeutic targets.”
It
may take three to five years to develop a commercially available test
that could be used on prostate, kidney, lung and pancreatic cancer
patients, Kurdistani said.
Next, Kurdistani and Dawson will be
pursuing studies in cell lines and animal models to determine what if
any role the histone modifications have in causing the development of
aggressive forms of pancreatic cancer.
“If you can uncover the
mechanism of how the histone modifications are associated with cancer
development and/or progression, you may be able to design strategies to
interfere with that process,” Kurdistani said. “Such a strategy could
be the basis for a targeted therapy or chemoprevention approach.”
Kurdistani
said the current study could not have been done if not for the
collaborative and multi-disciplinary research within the Jonsson Cancer
Center and UCLA. The study was funded through grants from the National
Institute of Diabetes and Digestive and Kidney Diseases, the Radiation
Therapy Oncology Group Translational Research Program, the California
Institute of Regenerative Medicine and the Hirshberg Foundation for
Pancreatic Cancer Research.
UCLA’s Jonsson Comprehensive
Cancer Center has more than 240 researchers and clinicians engaged in
disease research, prevention, detection, control, treatment and
education. One of the nation’s largest comprehensive cancer centers,
the Jonsson center is dedicated to promoting research and translating
basic science into leading-edge clinical studies. In July 2009, the
Jonsson Cancer Center was named among the top 12 cancer centers
nationwide by U.S. News & World Report, a ranking it has held for
10 consecutive years. For more information on the Jonsson Cancer
Center, visit our website at http://www.cancer.ucla.edu.
By Kim Irwin
