| AR |
Androgen receptor (AR), nuclear transcription factor mediates steroid hormones and stromal cell growth. AR activation in luminal cells surpresses growth 3. |
Stimulates early PCa growth, found in 30% androgen independent (AI) tumours 4. Vorinostat a histone deactylase inhibitor may reduce AR expression and act synergistically with bicaltamide (AR antagonist) to inhibit PCa 5. |
Therapeutic & Prognostic |
| AKT & PTEN |
Prostate specific phosphatase/tensin homologue, PTEN loss of function induces AKT & p53 senescence, inhibits apoptosis 4, 6. |
PTEN null mice develop high grade PCa/metastasis 7. PTEN alteration seen in 10% PCa, > 30% metastases. AKT may cause tubule regeneration with prostatic intraepithelial neoplasia (PIN) 6. Possible gene vector 8. |
Therapeutic & Prognostic |
| Bcl-2 |
B-cell CLL/lymphoma 2, Anti-apoptotic protein found in basal cells and stem cells 6. Loss of expression associated with PIN, progression and androgen independence 2. |
Antisene oligonucleotides (Oblimersen) against Bcl-2 delay progression, improve chemo-sensitivity. Docetaxel combination trial underway (NCT00085228) 9, 10. |
Therapeutic & Prognostic |
| c-MYC |
Oncogene transcription factor linked to cellular proliferation and apoptosis 11. Chromosome 8q24. High levels linked to androgen independence. |
c-MYC RNA increased in PCa, variable reports, linked to PIN 4. Antisene oligonucleotides against c-MYC, decreased PCa growth in vivo/vitro
12, 13. |
Therapeutic |
| Calcitriol receptor |
Vitamin D cellular modulator of growth/differentiation, reduced calcitriol level may allow malignant transformation/metastases in vitro & in vivo
14. |
Randomized double blind trial of high dose calcitriol with docetaxel improved overall survival (P = 0.035 univarate analysis) 15. Phase III ASCENT trial with Docetaxel and calcitriol stopped due to increase death rate. |
Therapeutic |
| Endothelin-1 (ET-1) |
Secreted by PCa cells, autocrine/paracrine activity promoting tumour growth/osteoblastic metastasis 16. ET-1 increase and loss of ETA endothelin receptor may inhibit apoptosis in PCa 10. |
Altrasentan (ET-1 antagonist) variable results, may delay progression in metastatic hormone-resistant Pca (HRPC) 17. Possible role in bone metastasis 15. Phase III trial with Docetaxel, Zolendronic acid underway (SWOG 0421). |
Therapeutic |
| EGFR (Erb B1 Her-2/Neu (Erb 2) |
Epidermal growth factor receptor. associated with proliferation, malignant transformation, relapse, progression and AI 4. |
Higher levels in PCa than BPH 18. Monoclonal antibodies directed against specific binding domains anti-EGFR eg: cetuximab, anti-HER2 eg: trastuzumab 19. Lack significant role in PCa 9. |
Therapeutic & Prognostic |
| HDAC |
Histone deacetylase by acetylation inhibitors can activate tumour suppressor genes 10. Histones are nuclear proteins that organize DNA regulating gene expression by reversible acetylation. |
Early inhibitor phenylbutyrate (PB) resulted in cell-cycle arrest, apoptosis and reduction in DNA synthesis with fragmentation. Multiple HDACs may have additive effect. PB, 13-cis-retinoic acid (CRA) and pacitaxel shown to inhibit PCa growth in vivo. Newer agents trials underway (Vorinostat) 10. |
Therapeutic |
| KLK3/PSA |
Encodes prostate-specific antigen (PSA) a kalikrein (serine protease subgroup) on chromosome 19 9. |
Combination rV-PSA and fowl pox primed rF-PSA vaccines trialled. Median time to PSA progression increased from 9.2 to 18.2 months (Study ECOG7897). Phase III PARADIGM trial underway 9. |
Therapeutic & Prognostic |
| LMTK2 |
Encodes neuronal cyclin dependent kinase 5 (cdk5)/p53-regulated kinase 20. |
|
Therapeutic |
| MSR1 (SR-A) |
Macrophage scavenger-1 gene, Ch 8p22. Binds variety of antigens including gram-negative bacteria lipopolysaccharides 21. |
May have role in prostate carcinogenesis 21
|
Prevention |
| Osteocalcin (OC) |
Androgen independent bone specific protein associated with metastasis. Offer potential target of bone metastasis. |
OC-E1A virus gene therapy used in mice. PSA dropped to undetectable levels, 40% cured with no evidence of skeletal metastasis at study end 22, 23. Ad-OC-TK (recombinant adenoviral vector carrying an osteocalcin promoter-driven HSV-tk gene) with valacyclovir trialled 24. |
Therapeutic |
| PSMA |
Prostate specific membrane antigen. AI prostatic epithelium transmembrane protein found in PCa/lymph node metastasis 25. |
DCVax-prostate vaccine target. Phase I/II trial underway 9. |
Therapeutic & Prognostic |
| PDGFR |
Platelet derived growth factor is overexpressed in the presence of bone metastasis. Suggested role in osteotropism 26. |
PDGFR inhibited by tyrosine kinase inhibitor, imatinib mesylate. Long-term combination therapy with docetaxel, PSA < 50% in 14/21 patients 27. |
Therapeutic |
| PAP |
Prostate acid phosphatase, glycoprotein more specific to prostatic tissue than PSA 9. |
APC8015 autologous vaccine. Phase I/II trials in HRPC. 31 patients, 38% developed immune response to PAP, 3 had PSA reduction > 50%. Phase III trial improved overall survival by 4.5 months (P = 0.01). Phase III IMPACT trial ongoing 9. |
Diagnostic & Therapeutic |
| p27Kip1 |
Cell cycle inhibitor found in basal compartment. Chromosome 12p12–13.1 2. |
Functional loss linked to Pca progression/androgen independence 4, 28. proliferative inflammatory atrophy (PIA) association 29. Gene therapy use with recombinant adenovirus 2. |
Therapeutic & Prognostic |
| p53 |
Tumour supressor gene allows DNA repair/cell apoptosis in cellular stress conditions 3. |
Less significant in PCa, uncommon mutation in early/localized PCa 30. Frequent in late stage PCa, independent prognositic marker 31. Concomitant homozygous PTEN and p53 inactivation lead to PCa lethality in mice 32. |
Prognostic & Therapeutic |
| Sex hormones & binding-globulin |
Testosterone is essential for prostatic development and maintanence. Ostrogens are associated with low risk of PCa 33. |
High testosterone levels = lower PCa risk (non Gleeson > 7, Stage 4, N+,M+) (P = 0.003). Serum testosterone < 300 ng/100mL predicts PSA failure after radical prostatectomy. High levels SHBG predicts extracapsular extension (P = 0.006) 33. |
Prognostic & Prevention |
| TMPRSS2:ETS |
Transmembrane protease, serine 2 Fusion gene (Ch 21), upregulates ETS target genes modulates cell proliferation, differentiation, apoptosis and transformation 4, 6. |
May be an early marker, as seen in 20% of PIN lesions 34. |
Prognostic & Prevention |
| VEGF/HIF-1μ |
Tissue hypoxia inducible factor, HIF-1μ, normally degraded by von Hippel Lindau E3 ubiquitin ligase. Stabilised by hypoxia and promotes hypoxia responsive genes, angiogenesis (vascular endothelial growth factor [VEGF]), metastasis and reduces chemotherapy sensitivity 35. Implicated as novel mechanism for tumor escape from radiation damage 36. |
Therapeutic targeting VEGF/HIF-1μ, along with anti-androgens may overcome hypoxia. VEGF/HIF-1μ staining density linked to Gleeson score following radical prostatectomy 35. Monoclonal antibodies against VEGF (Bevacizumab), Phase II trial, PSA reduced to < 50% in 65% HRPC patients. Phase III CALGB 90401 enrolling 37. Possible radiosensitiser, and prevention role through DNA repair. PX-478 an oral agent against HIF-1, phase I clinical trial ongoing 38. Combined VEGF/PDGF receptor inhibition shown to reduce required radiation treatment doses to around 20% 36. |
Therapeutic & Prognostic |
