Expression of the platelet-derived growth factor receptor in prostate cancer and treatment implications with tyrosine kinase inhibitors.
The platelet-derived growth factor receptor (PDGFR) is a receptor tyrosine kinase overexpressed in a subset of solid tumors and therefore is the target of drugs inhibiting this function such as imatinib mesylate (Gleevec). Thus far, drug therapy has played a limited role in the treatment of localized prostate cancer (PCa). This study characterizes PDGFR-beta expression in a wide spectrum of PCa samples to provide empirical data as part of a rational treatment strategy. A survey of five published prostate expression array studies, including 100 clinically localized PCa, did not identify tumors with increased PDGFR-beta expression level. Protein expression of PDGFR-beta, as determined by immunohistochemistry, revealed 5% of clinically localized PCa and 16% of metastatic PCa cases to show moderate or strong expression. To develop a strategy to detect patients most likely to profit from Gleevec treatment, we analyzed cDNA expression array data from 10,000 transcripts for PDGFR-beta expression and divided tumors in groups based on PDGFR-beta expression level. Performing a supervised analysis to identify potential comarkers of PDGFR-beta in PCa, we identified a set of genes whose expression was associated with PDGFR-beta status including early growth response 1 (Egr1), an upstream effector of PDGF (4.2-fold upregulation), alpha-methylacyl-CoA racemase, as well as v-Maf and neuroblastoma suppressor of tumorigenicity (both with a 2.2-fold downregulation). Taken together, this study suggests that only a small subset of PCas may be amenable to tyrosine kinase inhibitors specific for PDGFR.
Hofer
Matthias D
MD
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Fecko
Alice
A
Shen
Ronglai
R
Setlur
Sunita R
SR
Pienta
Kenneth G
KG
Tomlins
Scott A
SA
Chinnaiyan
Arul M
AM
Rubin
Mark A
MA
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta