Positron tomographic assessment of androgen receptors in prostatic carcinoma

  • Farrokh Dehdashti
  • Joel Picus
  • Jeff M. Michalski
  • Carmen S. Dence
  • Barry A. Siegel
  • John A. Katzenellenbogen
  • Michael J. Welch
Molecular Imaging

Abstract

Purpose

The purpose of this study was to evaluate the feasibility of androgen receptor (AR) imaging with 16β-[18F]fluoro-5α-dihydrotestosterone (FDHT) by positron emission tomography (PET) and to assess the binding selectivity of FDHT to AR in patients with prostate cancer.

Methods

Twenty men (age range 56–87 years) with advanced prostate cancer were studied. All except one had metastatic disease confirmed by biopsy and/or radiological studies. One patient who had radiological findings suggesting a single hepatic metastasis was found to have focal fatty infiltration on biopsy obtained after FDHT-PET and was excluded from further data analysis. FDHT uptake was assessed semiquantitatively by determination of the standardized uptake value (SUV) and tumor-to-muscle ratio (T/M). Additionally, to assess the AR binding selectivity of FDHT, patients with one or more foci of abnormally increased FDHT accumulation were studied after administration of an AR antagonist (flutamide).

Results

Conventional imaging demonstrated innumerable lesions in two patients and 43 lesions in the remaining 17 patients with advanced prostate cancer. FDHT-PET was positive in 12 of 19 patients (sensitivity of 63%), including the two patients with innumerable lesions. FDHT-PET detected 24 of 28 known lesions (86%) in the remaining ten patients. In addition, FDHT-PET detected 17 unsuspected lesions in five of these ten patients. All 12 patients with positive FDHT-PET underwent a repeat PET study after receiving flutamide for 1 day (250 mg t.i.d.). In all of these patients, there was a decrease in tumor FDHT uptake after flutamide; the mean (± standard deviation) SUV and T/M decreased from 7.0±4.7 and 6.9±3.9, respectively, to 3.0±1.5 and 3.0±1.6, respectively (p=0.002). The mean PSA in patients with positive FDHT-PET was significantly higher than that in patients with negative FDHT-PET (p=0.006).

Conclusion

Our results document the feasibility of PET imaging of prostate cancer with FDHT and suggest that tumor uptake of FDHT is a receptor-mediated process. Positive PET studies were associated with higher PSA levels and thus, presumably, with greater tumor burden.

Keywords

PET Prostate Cancer Androgen Receptor 

References

  1. 1.
    Huggins C. The effect of castration, of estrogen and of androgen injections on serum phosphatases in metastatic carcinoma of the prostate: studies on prostate cancer. Cancer Res 1941;1:293–7.Google Scholar
  2. 2.
    Buchanan G, Irvine RA, Coetzee GA, Tilley WD. Contribution of the androgen receptor to prostate cancer predisposition and progression. Cancer Metastasis Rev 2001;20:207–23.CrossRefGoogle Scholar
  3. 3.
    Loblaw DA, Mendelson DS, Talcott JA, Virgo KS, Somerfield MR, Ben-Josef E, et al. American Society of Clinical Oncology recommendations for the initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer. J Clin Oncol 2004;22:2927–41.Google Scholar
  4. 4.
    Mintun MA, Welch MJ, Siegel BA, Mathias CJ, Brodack JW, McGuire AH, et al. Breast cancer: PET imaging of estrogen receptors. Radiology 1988;169:45–8.PubMedGoogle Scholar
  5. 5.
    McGuire AH, Dehdashti F, Siegel BA, Lyss AP, Brodack JW, Mathias CJ, et al. Positron tomographic assessment of 16α-[18F]fluoro-17β-estradiol uptake in metastatic breast carcinoma. J Nucl Med 1991;32:1526–31.PubMedGoogle Scholar
  6. 6.
    Dehdashti F, McGuire AH, Van Brocklin HF, Siegel BA, Andriole DP, Griffeth LK, et al. Assessment of 21-[18F]fluoro-16 α-ethyl-19-norprogesterone as a positron-emitting radiopharmaceutical for the detection of progestin receptors in human breast carcinomas. J Nucl Med 1991;32:1532–7.PubMedGoogle Scholar
  7. 7.
    Dehdashti F, Mortimer JE, Siegel BA, Griffeth LK, Bonasera TJ, Fusselman MJ, et al. Positron tomographic assessment of estrogen receptors in breast cancer. Comparison with FDG-PET and in vitro receptor assays. J Nucl Med 1995;36:1766–74.PubMedGoogle Scholar
  8. 8.
    Dehdashti F, Flanagan FL, Mortimer JE, Katzenellenbogen JA, Welch MJ, Siegel BA. PET assessment of “metabolic flare” to predict response of metastatic breast cancer to antiestrogen therapy. Eur J Nucl Med 1999;26:51–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Mortimer JE, Dehdashti F, Siegel BA, Katzenellenbogen JA, Fracasso P, Welch MJ. Positron emission tomography with 2-[18F]fluoro-2-deoxy-d-glucose and 16α-[18F]fluoro-17β-estradiol in breast cancer: correlation with estrogen receptor status and response to systemic therapy. Clin Cancer Res 1996;2:933–9.Google Scholar
  10. 10.
    Bonasera TA, O‘Neil JP, Xu M, Dobkin JA, Cutler PD, Lich LL, et al. Preclinical evaluation of fluorine-18-labeled androgen receptor ligands in baboons. J Nucl Med 1996;37:1009–15.PubMedGoogle Scholar
  11. 11.
    Liu A, Dence CS, Welch MJ, Katzenellenbogen JA. Fluorine-18-labeled androgens: radiochemical synthesis and tissue distribution studies on six fluorine-substituted androgens, potential imaging agents for prostatic cancer. J Nucl Med 1992;33:724–34.PubMedGoogle Scholar
  12. 12.
    Kubota K, Matsuzawa T, Ito M, Ito K, Fujiwara T, Abe Y, et al. Lung tumor imaging by positron emission tomography using C-11 L-methionine. J Nucl Med 1985;26:37–42.Google Scholar
  13. 13.
    Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, et al. Cancer statistics 2005. CA Cancer J Clin 2005;55:10–30.Google Scholar
  14. 14.
    Thenot S, Charpin M, Bonnet S, Cavailles V. Estrogen receptor cofactors expression in breast and endometrial human cancer cells. Mol Cell Endocrinol 1999;156:85–93.CrossRefGoogle Scholar
  15. 15.
    Kozlowski JM, Ellis WJ, Grayhack JT. Advanced prostatic carcinoma. Early versus late endocrine therapy. Urol Clin North Am 1991;18:15–24.Google Scholar
  16. 16.
    Hyytinen ER, Haapala K, Thompson J, Lappalainen I, Roiha M, Rantala I, et al. Pattern of somatic androgen receptor gene mutations in patients with hormone-refractory prostate cancer. Lab Invest 2002;82:1591–8.Google Scholar
  17. 17.
    Wong CI, Zhou ZX, Sar M, Wilson EM. Steroid requirement for androgen receptor dimerization and DNA binding. Modulation by intramolecular interactions between the NH2-terminal and steroid-binding domains. J Biol Chem 1993;268:19004–12.Google Scholar
  18. 18.
    Culig Z, Hobisch A, Hittmair A, Peterziel H, Cato AC, Bartsch G, et al. Expression, structure, and function of androgen receptor in advanced prostatic carcinoma. Prostate 1998;35:63–70.CrossRefGoogle Scholar
  19. 19.
    Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T. Amplification and over expression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 2001;61:3550–5.Google Scholar
  20. 20.
    Yeh S, Lin HK, Kang HY, Thin TH, Lin MF, Chang C. From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci U S A 1999;96:5458–63.CrossRefGoogle Scholar
  21. 21.
    Bentel JM, Tilley WD. Androgen receptors in prostate cancer. J Endocrinol 1996;151:1–11.CrossRefGoogle Scholar
  22. 22.
    Sadar MD, Hussain M, Bruchovsky N. Prostate cancer: molecular biology of early progression to androgen independence. Endocr Relat Cancer 1999;6:487–502.CrossRefGoogle Scholar
  23. 23.
    Jenster G. The role of the androgen receptor in the development and progression of prostate cancer. Semin Oncol 1999;26:407–21.Google Scholar
  24. 24.
    Larson SM, Morris M, Gunther I, Beattie B, Humm JL, Akhurst TA, et al. Tumor localization of 16β-18F-fluoro-5α-dihydrotestosterone versus 18F-FDG in patients with progressive, metastatic prostate cancer. J Nucl Med 2004;45:366–73.Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Farrokh Dehdashti
    • 1
    • 4
  • Joel Picus
    • 1
    • 2
  • Jeff M. Michalski
    • 1
    • 3
  • Carmen S. Dence
    • 4
  • Barry A. Siegel
    • 1
    • 4
  • John A. Katzenellenbogen
    • 5
  • Michael J. Welch
    • 1
    • 4
  1. 1.The Alvin J. Siteman Cancer CenterWashington University School of MedicineSt. LouisUSA
  2. 2.Department of Internal MedicineWashington University School of MedicineSt. LouisUSA
  3. 3.Department of Radiation OncologyWashington University School of MedicineSt. LouisUSA
  4. 4.Edward Mallinckrodt Institute of RadiologyWashington University School of MedicineSt. LouisUSA
  5. 5.Department of ChemistryUniversity of IllinoisUrbanaUSA

Personalised recommendations