Mostaghel EA, Montgomery B, Nelson PS. Castration-resistant prostate cancer: Targeting androgen metabolic pathways in recurrent disease. Urol Oncol. 2009 May-Jun;27(3):251-7. PubMed PMID: 19414113.
Emerging evidence suggests that despite testicular androgen ablation, residual androgens, likely of adrenal–though potentially of prostatic–origin, play a critical role in the progression of prostate cancer to recurrent “castration-resistant” disease. Thus, a reassessment of the concept of total androgen deprivation is warranted. Current treatment strategies may not only lack optimal efficacy, but may actually contribute to the selection of neoplastic clones adapted to exist and proliferate in a low (but not zero) androgen environment. Moreover, the adequacy of androgen receptor (AR) pathway inhibition cannot be surmised from serum or plasma androgen levels, but must be ascertained at the tissue and molecular level prior to drawing conclusions regarding clinical efficacy or failure. Recent studies by our group and others indicate that prostate cancers undergo an adaptive response to castration that is associated with the up-regulation of transcripts encoding enzymes involved in the biosynthesis of androgens. Targeting these metabolic enzymes either individually or using combinations of agents to inhibit testicular, adrenal, and intracrine sources may provide enhanced clinical responses in the setting of both localized and metastatic disease.
Qian DZ, Huang CY, O’Brien CA, Coleman IM, Garzotto M, True LD, Higano CS, Vessella R, Lange PH, Nelson PS, Beer TM. Prostate cancer-associated gene expression alterations determined from needle biopsies. Clin Cancer Res. 2009 May 1;15(9):3135-42. Epub 2009 Apr 14. PubMed PMID: 19366833.
PURPOSE: To accurately identify gene expression alterations that differentiate neoplastic from normal prostate epithelium using an approach that avoids contamination by unwanted cellular components and is not compromised by acute gene expression changes associated with tumor devascularization and resulting ischemia. EXPERIMENTAL DESIGN: Approximately 3,000 neoplastic and benign prostate epithelial cells were isolated using laser capture microdissection from snap-frozen prostate biopsy specimens provided by 31 patients who subsequently participated in a clinical trial of preoperative chemotherapy. cDNA synthesized from amplified total RNA was hybridized to custom-made microarrays composed of 6,200 clones derived from the Prostate Expression Database. Expression differences for selected genes were verified using quantitative reverse transcription-PCR. RESULTS: Comparative analyses identified 954 transcript alterations associated with cancer (q < 0.01%), including 149 differentially expressed genes with no known functional roles. Gene expression changes associated with ischemia and surgical removal of the prostate gland were absent. Genes up-regulated in prostate cancer were statistically enriched in categories related to cellular metabolism, energy use, signal transduction, and molecular transport. Genes down-regulated in prostate cancers were enriched in categories related to immune response, cellular responses to pathogens, and apoptosis. A heterogeneous pattern of androgen receptor expression changes was noted. In exploratory analyses, androgen receptor down-regulation was associated with a lower probability of cancer relapse after neoadjuvant chemotherapy followed by radical prostatectomy. CONCLUSIONS: Assessments of tumor phenotypes based on gene expression for treatment stratification and drug targeting of oncogenic alterations may best be ascertained using biopsy-based analyses where the effects of ischemia do not complicate interpretation.
Mendiratta P, Mostaghel E, Guinney J, Tewari AK, Porrello A, Barry WT, Nelson PS, Febbo PG. Genomic strategy for targeting therapy in castration-resistant prostate cancer. J Clin Oncol. 2009 Apr 20;27(12):2022-9. Epub 2009 Mar 16. PubMed PMID: 19289629.
PURPOSE: Despite treatments which lower circulating androgens, advanced prostate cancers often maintain androgen receptor (AR) signaling. The variable response to secondary hormonal manipulations in men with castrate-resistant prostate cancer (CRPC) creates a compelling need for strategies to individualize therapy based on the molecular features of each patient’s tumor. METHODS: A transcription-based AR activity signature was developed from an androgen-sensitive prostate cancer cell (LNCaP) and tested on independent data sets of prostate cancer cell lines and human tumors to assess its precision and accuracy in detecting AR activity. The AR signature was applied to multiple sets of prostate specimens to determine how AR activity changes with hormone therapy and progression and oncogenic pathway analysis was used to identify biologic pathways correlating with AR activity. RESULTS: A robust AR signature accurately predicts AR activity in multiple prostate cancer cell lines, has minimal variation between replicate samples, and accurately reflects an individual’s hormone status and intraprostatic dihydrotestosterone levels. The AR signature finds AR activity to be high in local, untreated prostate tumors and decreased in prostate tissue after neoadjuvant hormone therapy and in CRPC. Heterogeneity of AR activity exists along the spectrum of prostate cancer progression and decreasing predicted AR activity correlates with increasing predicted Src activity and sensitivity to dasatinib (Src-targeting kinase inhibitor). CONCLUSION: A transcription-based AR signature can detect AR activity within individual prostate cancer specimens and has the potential to help individualize and improve care for patients with CRPC.
Pritchard C, Mecham B, Dumpit R, Coleman I, Bhattacharjee M, Chen Q, Sikes RA, Nelson PS. Conserved gene expression programs integrate mammalian prostate development and tumorigenesis. Cancer Res. 2009 Mar 1;69(5):1739-47. Epub 2009 Feb 17. PubMed PMID: 19223557.
Studies centered at the intersection of embryogenesis and carcinogenesis have identified striking parallels involving signaling pathways that modulate both developmental and neoplastic processes. In the prostate, reciprocal interactions between epithelium and stroma are known to influence neoplasia and also exert morphogenic effects via the urogenital sinus mesenchyme. In this study, we sought to determine molecular relationships between aspects of normal prostate development and prostate carcinogenesis. We first characterized the gene expression program associated with key points of murine prostate organogenesis spanning the initial in utero induction of prostate budding through maturity. We identified a highly reproducible temporal program of gene expression that partitioned according to the broad developmental stages of prostate induction, branching morphogenesis, and secretory differentiation. Comparisons of gene expression profiles of murine prostate cancers arising in the context of genetically engineered alterations in the Pten tumor suppressor and Myc oncogene identified significant associations between the profile of branching morphogenesis and both cancer models. Further, the expression of genes comprising the branching morphogenesis program, such as PRDX4, SLC43A1, and DNMT3A, was significantly altered in human neoplastic prostate epithelium. These results indicate that components of normal developmental processes are active in prostate neoplasia and provide further rationale for exploiting molecular features of organogenesis to understand cancer phenotypes.