UCLA – Histone Modifications Can Be Used to Predict Outcome and Treatment With Pancreas Cancer – Personalized Medici
Posted Feb 11 2010 3:11pm
This is a beginning groundwork for a commercial test. This could also lead to tests for other types of cancersuch as prostate and kidney cancer. This is similar to the breast cancer study for inherited genes in short. Pancreas cancer is so deadly and with having information up front relative to DNA findingsperhaps this might give some different treatment directions as the the title here suggests. BD
Specific chemical modifications to proteins called histoneswhich are found in the nucleus of cells and act as spools around which DNA is woundcan be used to predict prognosis and response to treatment in subsets patients with pancreatic cancera study by researchers at UCLA’s Jonsson Comprehensive Cancer Center has found.
High levels of two specific histone modifications in tumor cells of patients who underwent surgical resection of their pancreatic cancer predicted those patients more likely to derive survival benefit from the commonly used chemotherapy drug Fluorouracilor 5-FU. Along with Gemcitabine5-FU is a common chemotherapy used to treat patients with pancreatic cancerthe 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 Dawsonan assistant professor of pathology and laboratory medicinesenior author of the study and a Jonsson Cancer Center researcher. “Using a specially devised test and algorithmwe 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 therapiesDawson said.
The studywhich needs to be validated in a prospective studywas published this week in the peer-reviewed Journal of Clinical Oncology.
Jonsson Cancer Center researchersled by Dr. Siavash Kurdistani and Dr. David Seligsondeveloped and patented the immunohistochemistry assayor antibody testto measure the levels of the specific histone modifications within cells. The rights to that technology have been licensed by an outside company.
Kurdistani and Seligsonalso authors on the studypreviously used the test to identify the same histone modifications in subsets of patients with prostatekidney 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 epigeneticswhich focuses on inherited information other than that directly encoded by DNA. In addition to genetic mutationsepigenetic changes such as alterations to histone modifications contribute to the development of cancersaid Kurdistanian assistant professor of biological chemistry.
“Overallthese histone modifications are providing useful information as to how a cancer may behave,” he said. “In additionthere 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 triala multi-centerphase III study of pancreatic cancer comparing adjuvant Gemcitabine with 5-FUand a separate140-patient cohort of patients with stage I or II pancreatic cancer from UCLA.
Generallylow levels of histone modifications were found to be predictors of poor survival in both patient cohortsand to identify those less likely to respond to 5-FU in the 9704 patient cohortthe study reports.
“Pancreatic cancer is a highly aggressive and lethal cancer for which there are limited therapeutic options,” the study states. “Along with genetic eventstumor-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 prostatekidneylung and pancreatic cancer patientsKurdistani said.
NextKurdistani 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 progressionyou 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 Diseasesthe Radiation Therapy Oncology Group Translational Research Programthe 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 researchpreventiondetectioncontroltreatment and education. One of the nation's largest comprehensive cancer centersthe Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2009the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Reporta ranking it has held for 10 consecutive years. For more information on the Jonsson Cancer Centervisit our website at http://www.cancer.ucla.edu.