Nemours Center for Childhood Cancer Research Team at the Alfred I. duPont Hospital for Children Identifies the Function of a Biomarker Present in Prostate Cancer Cells: New Insight into Therapeutic Benefit for Patients with Advanced Prostate Cancer

2008-07-17 11:35:00

    WILMINGTON, Del., July 17 /EMWNews/ -- The research team at the

Nemours Center for Childhood Cancer Research (NCCCR), a newly established

division of Nemours Biomedical Research at the Alfred I. duPont Hospital

for Children has discovered that the biomarker called prostate specific

membrane antigen (PSMA), abundantly present in cancer cells of patients

with advanced prostate cancer, has a contributory role in the progression

of cancer to an aggressive disease. A biomarker is any biomolecule that is

associated with a particular pathological or physiological state of cells

and may be used to diagnose and treat a disease or monitor response to

therapy.



    The discovery, titled "Prostate specific membrane antigen associates

with anaphase promoting complex and induces chromosomal instability," is

outlined in the July issue of Molecular Cancer Therapeutics, an American

Association for Cancer Research journal and provides new insights into

therapeutic benefit for patients with advanced prostate cancer.



    The research was conducted by Dr. Ayyappan K. Rajasekaran, the Director

of NCCCR, and his research team while they were at the University of

California, Los Angeles, and at NCCCR. The abundance of PSMA in prostate

cancer cells increases as the cancer progresses into a metastatic and

hormone-independent advanced disease. Dr. Rajasekaran said, "We strongly

suspected that PSMA has a potential role in the progression of prostate

cancer into an aggressive disease. But how it participates in disease

progression was not clear. Now in this study, we identified that PSMA does

have an important causative role in prostate cancer progression."



    This study was initiated when the researchers found that PSMA was

present at the poles of the dividing cells. These poles are complex

structures at the opposite ends of the cells that control the separation of

chromosomes equally into daughter cells during cell division. "Presence of

PSMA at the poles indicated it might have a role in cell division and

chromosome segregation, and we continued our quest to understand this

potential function of PSMA," said Dr. Rajasekaran.



    Human cells have 46 chromosomes. The chromosomes are vehicles that

carry the genetic material DNA from generation to generation. These

chromosomes are equally divided into daughter cells during cell division.

Cells have several checkpoints to ensure that the chromosomes are equally

separated during cell division. Anaphase-promoting complex (APC) is one

such checkpoint regulatory protein involved in the proper segregation of

chromosomes during cell division. This complex monitors the timing of cell

division and provides sufficient time for cells to segregate chromosomes

equally into daughter cells. Often, cancer cells have more than 46

chromosomes, a condition known as aneuploidy, which is a constant feature

of aggressive, advanced, and drug-resistant solid tumors, including

prostate cancer.



    Rajasekaran and his research team found that PSMA-expressing cells

spent less time dividing. They found that PSMA interferes with the function

of APC and induces aneuploidy in cancer cells. "When PSMA is present, cells

hurried to complete their division prior to having all their chromosomes

properly segregated," said Dr. Sigrid A. Rajasekaran, the first author of

the study and the head of the Cancer Cell Metabolism Laboratory at NCCCR.



    PSMA is present in prostate cancer cells but not in normal cells.

Therefore, it is an excellent therapeutic target for prostate cancer. There

are several ongoing clinical trials for PSMA-based therapeutic

interventions. "Since PSMA expression is higher in metastatic compared to

benign cancer cells, anti-PSMA-based therapeutic strategies should target

metastatic prostate cancer cells, which will benefit patients with advanced

prostate cancer," the study states.



    Dr. A. Rajasekaran and his team conducted their research on cell lines

and are in the process of translating their findings into human clinical

trials, which should be available in two to three years.



    This study was primarily supported by the Department of Defense DOD

W81XWH-04-1-0113 Idea Development Grant and in part by NIH DK56216.



    About the Nemours Center for Childhood Cancer Research



    The Nemours Center for Childhood Cancer Research is a newly established

research entity of Nemours Biomedical Research at the Alfred I. duPont

hospital for children. The NCCCR is located in a fully renovated laboratory

space in 1701 Rockland Road, Wilmington, DE. The goal of the center is to

evolve into a leader in research focusing on biomarkers for childhood

cancers and cancers that affect families. The NCCCR will closely work

together with Helen F. Graham Cancer Center, University of Delaware, Center

for Translational Research and the Delaware Biotechnology Institute. The

Alfred I. duPont Hospital for Children is a division of Nemours, which

operates one of the nation's largest health systems devoted to pediatric

patient care, teaching, and research. Set on a 300-acre campus near

Wilmington, Delaware, the 200-bed duPont Hospital for Children offers all

the specialties of pediatric medicine, surgery, and dentistry. Starting

with Alfred I. duPont's bequest over 70 years ago, Nemours has grown into a

multi-dimensional organization offering personalized clinical and

preventive care focused on children. For more information, please visit

Nemours.org.





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