High levels of two specific histone modifications in the tumor cells of patients who underwent surgical resection of their pancreatic cancer predicted which patients were more likely to derive survival benefit from the 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.
Study IDs new method for predicting treatment response in patients with pancreatic cancer
Dr. David Dawson
“These histone modifications were useful in predicting whether or not a patient was likely to respond favorably to 5-FU,” said the study’s senior author, Dr. David Dawson, an assistant professor of pathology and laboratory medicine and a Jonsson 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 an immunohistochemistry assay, or antibody test, designed to measure the levels of the specific histone modifications within cells. The university has submitted this for patenting, and the rights to that technology have been licensed by an outside company.
Kurdistani and Seligson, who were also authors on this 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 were more likely to suffer a recurrence 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 multicenter, phase 3 study of pancreatic cancer comparing adjuvant gemcitabine with 5-FU, and from a separate 140-patient cohort of patients with stage 1 or 2 pancreatic cancer from UCLA.
Generally, low levels of histone modifications were found to be predictors of poor survival in both patient cohorts. They were also found 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.”
While the initial data looks promising, the process to develop a commercially available test that could be used on prostate, kidney, lung and pancreatic cancer patients is very lengthy, 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 multidisciplinary 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.