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CPDR Researchers Awarded NIH R01 Funding for Cell Type-Specific Gene Expression Signature Research
December 9, 2004
The Center for Prostate Disease Research (CPDR) recently
received a four-year R01 grant from the National Institutes of Health
(NIH) to support a research project focusing on gene expression signatures
in benign and malignant epithelial and stromal cells of prostate cancer
patients with aggressive and non-aggressive disease.
Dr. Shiv Srivastava,
the Scientific Director of CPDR, is the Principal Investigator on this
grant.
Dr. Vasantha Srikantan
and
Dr. Gyorgy Petrovics
are Co-principal investigators and
Dr. Syed Shaheduzzamen
is a co-investigator on this project.
The funded project builds upon the pioneering work CPDR has long been
doing to discover and learn the translational utility of genes commonly
altered in human prostate cancer (CaP). The CPDR laboratory has already
described novel gene expression alterations as well as mutational alterations
in CaP by employing global gene expression and genome scanning technologies,
followed by comprehensive evaluation of specific targets. The current
funded study focuses on CaP-associated gene expression signatures in specific
cell types of the human prostate gland with a goal to carefully define
the pathobiology of epithelial and stromal components in prostate tumorigenesis.
Discovery of cell-specific gene expression signatures distinguishing the
aggressive and non-aggressive forms of CaP will provide cell type-specific
biomarkers, as well as therapeutic targets that will help in improving
diagnosis, prognosis and treatment of CaP.
Thus far, Dr. Srivastava’s team – in collaboration with
Dr. Maryanne Vahey,
Deputy Director of Research Operations in the Division of Retrovirology
at the Walter Reed Army Institute of Research (WRAIR) and Idong Chen,
bioinformatics expert from the Human Genome Research Institute at NIH
– has performed gene expression analysis (GeneChip, Affymetrix)
in paired laser capture microdissected (LCM) benign and cancer epithelial
cells from two patient groups with “aggressive” CaP and with
“non-aggressive” CaP based on PSA recurrence, Gleason score,
pathological stage, and tumor cell differentiation. These patients were
carefully selected from a cohort of 300 CaP patients who underwent radical
prostatectomy at the Walter Reed Army Medical Center (WRAMC). Gene expression
clusters predictive of “aggressive” or “non-aggressive”
form of the disease were evaluated based on a multidimensional scaling
(MDS) method. MDS plots were generated for 18 tumor-versus-normal sample
pairs, as well as for the “aggressive” versus “non-aggressive”
CaP patients. 200 genes were selected as a basis for separation of the
groups on each MDS plot. A subset of the genes that strongly separate
the “aggressive” and “non-aggressive” CaP patients
represent genes associated with oncogenic activity, apoptosis and cell
growth regulation, and antioxidant activity. Genes commonly over- or under-expressed
in CaP that were also noted in our study included AMACR, NPY, PAP, PSP94.
Expression of selected genes was verified by real time RT-PCR (TaqMan)
in matched tumor and normal LCM-RNAs. The most promising genes are being
further validated on a larger cohort of CaP patients.
Highly promising accomplishments of our multidisciplinary team thus far
include:
Carefully optimized the experimental conditions for GeneChip evaluation of small quantities of RNA derived from laser microdissected epithelial and stromal cell
Defined gene expression clusters classifying aggressive and non-aggressive CaP by MDS analysis
Identified a subset of these classifier genes that are associated with oncogenic activity, regulation of apoptosis and cell growth, and antioxidant activity
Validation of promising genes is in progress
With the assistance of the NIH funding, Dr. Srivastava and his team propose to identify CaP-associated epithelial cell specific gene expression patterns in aggressive and non-aggressive CaP; identify CaP-associated stromal cell-specific gene expression patterns in aggressive and non-aggressive CaP. The long-term goal of these studies is to identify prostate-specific biomarkers and therapeutic targets.
The CPDR mission is fulfilled primarily through its three principal programs – the Clinical Research Center, the Basic Science Research Program and the National Multicenter Prostate Cancer Database– and through a robust education and training program that operates out of its Headquarters location, the Clinical Research Center, and the original laboratories at USUHS. CPDR is also committed to patient outreach, primarily through its affiliation with the WRAMC US TOO! organization and through a heavy schedule of health fairs in which it participates.
