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Value Propositions - April 2015

April 2015, Vol 6, No 3

In This Article

Genetic Mutations Rampant in Pancreatic Cancers: Targeted Drugs Hold Key to Therapy

A new genetic analysis led by researchers from the University of Texas (UT) Southwestern Medical Center suggests that the majority of pancreatic cancers have genetic alterations that could be treated by current targeted drugs, using a precision medicine approach to pancreatic cancer, the fourth leading cause of cancer-related deaths among men and women in the United States.

“Pancreatic cancer will surpass breast and prostate to become the third-leading cause of cancer-related deaths in the next 15 years. If we want to change the death rate, we need to increase the investment in understanding the biology of pancreatic cancer and identifying novel treatment strategies,” said study coinvestigator Michael Choti, MD, Chairman of Surgery, and the Hall and Mary Lucile Shannon Distinguished Chair in Surgery, at the Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center.

Using a comprehensive DNA sequencing of pancreatic tumors showed many mutated genes and potential diagnostic biomarkers.

“We identified a wealth of genetic diversity, including multiple mutated genes that were previously unknown to pancreatic cancer—an important step in gaining a better understanding of this difficult and particularly deadly disease,” said lead investigator Agnieszka Witkiewicz, MD, Associate Professor of Pathology, the Harold C. Simmons Comprehensive Cancer Center. “The team was able to identify several genes that may be able to help us to predict outcomes in certain circumstances or serve as good candidates for therapeutic efforts.”

The genetic analysis of 109 different pancreatic tumors showed that the genetic makeup of pancreatic cancer is complex, and each tumor is unique. The genetic features uncovered in this study show how pancreatic cancer develops, helps to define survival factors, and points to potential targets for therapeutic intervention.

“I am considerably more optimistic of the utility of a genetically targeted therapy for pancreatic cancer today than when we began this work,” said senior investigator Erik Knudsen, PhD, Dr Charles T. Ashworth Professor in Pathology, the Harold C. Simmons Comprehensive Cancer Center.

Pancreatic cancer is often diagnosed late, when it can no longer be removed by surgery. Chemotherapy has a modest effect, but most patients experience disease progression and death.

The study identified many tumor-related events that could be selectively targeted, depending on the specific genetic mutations. For example, some tumors had the BRAF gene mutation, for which there are FDA-approved drugs that can also be selectively effective for BRAF-mutated pancreatic cancer cells.

“Most pancreatic cancers exhibit multiple genetic alterations; therefore, it is likely that combination approaches targeting multiple pathways will be required for effective disease control,” Dr Witkiewicz said. UT Southwestern Medical Center Press Release; April 9, 2015

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Tetanus Booster Against Cytomegalovirus Enhances the Immune System, Improves Survival in Glioblastoma

The results of a new study published in Nature (Mitchell DA, et al. 2015;519:366-369) outline a novel way to enhance the effects of immunotherapy in patients with glioblastoma, a rare but aggressive type of brain cancer, and possibly improve patient outcomes.

The investigators studied the use of dendritic cells to fight cancer cells. Dendritic cells are specialized immune cells that help other components of the immune system, such as T-cells, to fight off foreign invaders, including cancer cells.

“The promise of dendritic-cell–based therapy and other immunotherapies for brain cancer has been upheld for some time, but an important implication of this work is a demonstrated capacity to significantly improve the clinical impact of immunotherapy for patients with this very difficult disease,” said co-lead investigator Duane A. Mitchell, MD, PhD, Director of the Brain Tumor Immunotherapy Program, the University of Florida, Gainesville.

Dendritic cells have been used in immunotherapy to target different types of tumors. These cells are taken from the patient’s own immune system and are then engineered to express antigens from the tumor to create a vaccine. The vaccine is injected back into the patient, and the engineered dendritic cells then activate the patient’s T-cells, which can kill the tumor cells.

The objective of the study was to see whether increasing the dendritic-cell migration to the patient’s lymph nodes would improve the effects of the vaccine on patients with glioblastoma. The researchers randomized patients with glioblastoma to receive a tetanus booster shot before getting the tumor antigen–expressing dendritic-cell vaccine. The tetanus booster prepared the patient’s immune system to fight the cancer cells. The patients in the control group received an injection with their own dendritic cells instead of the tetanus shot, after which they received the tumor antigen–expressing dendritic-cell vaccine.

The vaccine was targeted against cytomegalovirus (CMV). Studies have shown that CMV is found in glioblastoma tumors, but it is unknown if CMV causes the tumor or only contributes to its progression.

The administration of the tetanus booster before the vaccine increased dendritic-cell migration to the patient’s lymph nodes and improved outcomes. The median survival among patients who received the tetanus booster was >36.6 months versus 18.5 months in those who received dendritic cells without the vaccine.

“We did not expect that enhancing dendritic-cell migration would be associated with such a dramatic improvement on clinical outcomes in our patients,” said Dr Mitchell. “Dendritic-cell vaccines targeting glioblastoma can be very effective by enhancing migration of dendritic cells.”

“These new findings, and especially the dramatic survival rates, suggest that the virus may be an effective target for immune therapy. The results…should stimulate more basic research on CMV and its potential therapeutic role in brain tumors and possibly other cancers,” said Jane Fountain, PhD, Program Director, National Institute of Neurological Disorders and Stroke (NINDS). This study was supported by grants from the NINDS and the National Cancer Institute. National Institutes of Health Press Release; March 18, 2015

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Polygenic Risk Score for Breast Cancer on the Horizon

A team of researchers from the UK Institute of Cancer Research and the University of Cambridge, United Kingdom, found a link between a “polygenic risk score” and a woman’s risk for breast cancer. Using the world’s biggest database of genetic information, the Collaborative Oncological Gene-Environment Study, the team analyzed 77 DNA changes that have been previously associated with a slight increase in risk for breast cancer. The risk is much smaller than other known risks, such as BRCA1 and BRCA2 genetic mutations. The findings suggest that a DNA-based genetic test may help to identify women who are at risk for breast cancer, regardless of BRCA mutation status.

Nell Barrie, Senior Science Communications Manager at Cancer Research UK, said, “This study shows how the genetic map of breast cancer that scientists have been building up over the years might be used to identify women most at risk, so we can take steps to reduce their chances of developing the disease, or catch it at the earliest possible stage.”

A woman in the top 20% of the polygenic risk score was 1.8 times more likely to develop breast cancer than women with a lower score. A woman in the top 1% of the score was >3 times more likely to develop breast cancer. Women with a family history of breast cancer had a 24.4% risk of developing breast cancer if they were in the fifth highest scoring group, and only 8.6% if they were in the fifth lowest scoring group.

The study co-leader Professor Douglas Easton, Director of the Centre for Cancer Genetic Epidemiology, University of Cambridge, said, “There’s still work to be done to determine how tests like this could complement other risk factors, such as age, lifestyle, and family history.” Cancer Research UK, in collaboration with Press Association; April 9, 2015

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