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Development of Angiogenesis Inhibition as Therapy for Prostate Cancer

Development of Angiogenesis Inhibition as Therapy for Prostate Cancer

ABSTRACT: Angiogenesis is essential to prostate cancer progression. The first study of antiangiogenic therapy in patients with locally advanced prostate cancer at The University of Texas M. D. Anderson Cancer Center showed that preoperative treatment with a fumagillin analog was safe. Microvascular density correlated with Gleason score, but marked intertumoral and intratumoral changes were observed. Clinical experience with thalido-mide (Thalomid), which inhibits angiogenesis induced by both vascular endothelial growth factor and basic fibroblast growth factor, has included observation of "clinical improvement" in patients with androgen-independent prostate cancer and anecdotal responses in patients with metastatic disease refractory to chemotherapy. In an effort to assess the in vivo effect of thalidomide in prostate carcinoma, we have initiated a study of neoadjuvant thalidomide treatment in patients with locally advanced prostate cancer that is to include serial ultrasonographic and pathologic evaluation, as well as serial collection of serum/urine markers that may prove useful surrogate markers of antiangiogenic activity. We have also initiated a phase I/II trial of thalidomide, paclitaxel (Taxol), and estramustine (Emcyt) in patients with metastatic androgen-independent prostate cancer progressing after up to two courses of chemotherapy. [ONCOLOGY 14(Suppl 13):21-23, 2000]

Introduction

Angiogenesis is essential to progression of prostate cancer. In 1993, Weidner and colleagues[1] demonstrated a correlation between microvascular density and stage of prostate cancer. A number of studies over the next several years showed a correlation between microvessel count and disease stage or risk of disease recurrence after local therapy.[2-6]

A program for antiangiogenesis trials was started at M. D. Anderson Cancer Center on the basis of these data. One of the major questions at this time is how best to measure the activity of putative antiangiogenesis drugs in prostate cancer in light of the fact that the target is the host (endothelial cell) rather than the epithelial malignant compartment per se (prostate cancer cell), and that markers of biologic activity of angiogenesis inhibitors might be different than tumor markers (ie, prostate-specific antigen [PSA]). The availability of soluble, surrogate markers of antiangiogenic activity would accelerate assessment of drug activity and development of novel therapies; however, it remains unknown which soluble markers might be relevant to prediction of clinical effect. Further, methods such as positron-emission tomography (PET) scanning or new technologies for measuring tumor blood flow have not been clinically validated in this setting. We therefore hypothesized that assessment of the in vivo effect of the antiangiogenesis treatment on endothelial cells/vessels and malignant compartment (comparison of tissue samples prior to and after treatment with putative angiogenesis inhibitors) would constitute the optimal approach to assessment of drug effect.

Initial Studies of Angiogenesis Inhibition in Prostate Cancer

Initial studies have included patients with locally advanced prostate cancer defined as clinical stage T1c/T2 (Gleason score of ³ 7 and PSA level > 10 ng/dL) or stage T3; such patients are categorized as ‘potentially resectable’ but not ‘highly curable’ with local therapies alone.

Studies have shown that 50% to 97% of patients with stage T1c/T2 disease and a Gleason grade ³ 8, and 73% of those with T2 disease and Gleason grade ³ 7 and PSA level > 10 ng/dL, have extracapsular extension of disease at surgery.[7] Positive surgical margins range between 22% and 33% for patients with high-grade T1/T2 disease and 50% for those with T3 disease.[8] Ten-year and 15-year survival rates varying from 12% to 60% and 20% to 28% for patients with stage T3 disease were observed. The addition of androgen ablation to radiation therapy shows improvement in disease-free survival, but no clear improvement in overall survival for patients with locally advanced prostate cancer. The European Organization for Research and Treatment of Cancer (EORTC) trial[9] indicated improved disease-free and overall survival while the Radiation Therapy Oncology Group (RTOG) trial[10] showed improvement only in disease-free survival.

We have offered patients with locally advanced prostate cancer, good performance status, and extended life expectancy participation in clinical studies of preoperative investigational treatments, including antiangiogenesis therapy. The safety of preoperative treatment with another angiogenesis inhibitor (fumagillin analog) has been established in a previous trial,[11] although the results may not be comparable because of the different mechanism of action and much longer half-life of thalidomide (Thalomid). As with other studies, it was observed that microvascular density correlated with the Gleason score. We observed marked intertumoral and intratumoral changes in microvascular density, which mandates careful assessment of consecutive, matched, pre- and posttreatment biopsies and correlation with putative serum/urine markers.

Thalidomide in Prostate Cancer

Thalidomide is a promising candidate for antiangiogenic treatment in prostate cancer. It inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis and basic fibroblast growth factor (bFGF)-induced angiogenesis, both of which are implicated in prostate cancer progression[12-14]; it also down-regulates interleukin-6,[15] an autocrine and paracrine growth factor in prostate carcinoma,[11,16,17] and suppresses production of tumor necrosis factor-alpha, a cachexia factor that is elevated in advanced prostate cancer.[18] Thalidomide has shown some evidence of "clinical benefit" in patients with androgen-independent prostate cancer enrolled in National Cancer Institute (NCI) phase II trials.[19]

Neoadjuvant Thalidomide Trial

Angiogenesis is tumor site-specific[20]; it remains uncertain whether beneficial effects of antiangiogenic treatment would be observed at both primary and metastatic tumor sites. This question will be addressed in an ongoing neoadjuvant trial of thalidomide. The rationale for the trial is based on the hypothesis that thalidomide may reduce postoperative disease recurrence and that neoadjuvant angiogenesis inhibition, assessed by consecutive prostate biopsies, may constitute a useful strategy for identifying intermediate markers of antiangiogenic and antitumor activity.

Objectives of the trial are (1) to assess safety of treatment, (2) to determine efficacy of preoperative thalidomide treatment through assessment of tumor size and PSA levels, and (3) to obtain qualitative measurements of the in vivo effects of thalidomide on endothelial cells—consisting of measurement of microvascular density, bFGF, VEGF, E-selectin, thrombomodulin, and tumor blood flow—and on the epithelial compartment, including assessment of apoptosis and proliferation of prostatic carcinoma cells. The study design is shown in Figure 1.

Patients and Methods

Patients are to undergo transrectal ultrasound and needle biopsy prior to initiating thalidomide treatment at 200 mg/d; the thalidomide dose is to be increased to 600 mg/d over the initial 6 weeks of administration, during which urine and serum markers are to be assessed. After ultrasound and biopsy are repeated, patients with stable disease are to receive 6 additional weeks of thalidomide (600 mg/d) before undergoing prostatectomy, with urine and serum markers being assessed at the start of the second phase and prior to and after prostatectomy. It is hoped that the findings of this trial and other neoadjuvant studies will help in the development of optimal combination therapy strategies.

Phase I/II Trial of Thalidomide, Paclitaxel, and Estramustine

Chemotherapy is active in metastatic androgen-independent prostate cancer. Synergistic effects of antiangiogenic agents and chemotherapy have been observed in preclinical investigations. Thalidomide has been associated with "clinical improvement" in some patients with metastatic androgen-independent prostate cancer. We have anecdotal experience with thalidomide in some patients with metastatic androgen-independent prostate cancer refractory to chemotherapy. We observed clinical improvement (pain relief) as well as PSA reduction using thalidomide combined with the previous chemotherapy that had resulted in progression of disease for these patients (personal communication, C. Logothetis, 2000).

Based on such clinical experience, we have initiated a phase I/II trial of thalidomide, paclitaxel (Taxol), and estramustine (Emcyt) in patients with metastatic androgen-independent prostate cancer progressing after prior chemotherapy. In addition to determining the maximum tolerated dose of thalidomide in this setting, the study will evaluate the safety of the regimen and assess effects on analgesic consumption, nausea, mental status, time to disease progression, and overall survival.

Conclusion

Angiogenesis is important for prostate cancer progression. The development of the clinical methodology to assess the in vivo effect of angiogenesis inhibitors will expedite the assessment of their efficacy and their clincal applications. The clinical trials described here will provide insight into the clinical activity of thalidomide, a potent angiogenesis inhibitor, in early as well as advanced prostate cancer.

References

1. Weidner N, Carroll PR, Flax J, et al: Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143:401-409, 1993.

2. Bigler SA, Deering RE, Brawer MK: Comparison of microscopic vascularity in benign and malignant prostate tissue. Hum Pathol 24:220-226, 1993.

3. Brawer MK, Deering RE, Brown M, et al: Predictors of pathologic stage in prostatic carcinoma. The role of neovascularity. Cancer 73(3):678-687, 1994.

4. Siegal JA, Yu E, Brawer MK: Topography of neovascularity in human prostate carcinoma. Cancer 75:2545-2551, 1995.

5. Bostwick DG, Wheeler TM, Blute M, et al: Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies. Urology 48:47-57, 1996.

6. Silberman MA, Partin AW, Veltri RW, et al: Tumor angiogenesis correlates with progression after radical prostatectomy but not with pathologic stage in Gleason sum 5 to 7 adenocarcinoma of the prostate. Cancer 79:772-779, 1997.

7. Partin AW, Yoo J, Carter B, et al: The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 150:110-114, 1993.

8. Stamey TA, McNeal JE: Adenocarcinoma of the prostate, in Walsh PC, Retik AB, Stamey MA, et al (eds): Campbell’s Urology, 6th ed, pp 1159-1221. Philadelphia, Saunders, 1992.

9. Bolla M, Gonzales D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337:295-300, 1997.

10. Pipelich MV, Caplan R, Byhardt RW, et al: Phase III trial of androgen suppression using goserelin in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy: Report of Radiation Therapy Oncology Group Protocol 85-31. J Clin Oncol 15:1013-1021, 1997.

11. Daliani D, Finn L, Hodges S, et al: Interleukin-6 (IL-6): a marker of androgen-independent (AI) growth in prostatic carcinoma (PC) (abstract 1183). Proc Am Soc Clin Oncol 16:331a, 1997.

12. Greene GF, Kitadai Y, Pettaway CA, et al: Correlation of metastasis-related gene expression with metastatic potential in human prostate carcinoma cells implanted in nude mice using an in situ messenger RNA hybridization technique. Am J Pathol 150:1571-1582, 1997.

13. Ferrer FA, Miller LJ, Andrawis RI, et al: Vascular endothelial growth factor (VEGF) expression in human prostate cancer: In situ and in vitro expression of VEGF by human prostate cancer cells. J Urol 157:2329-2333, 1997.

14. Melnyk O, Zimmerman M, Kim KJ, et al: Neutralizing anti-vascular endothelial growth factor antibody inhibits further growth of established prostate cancer and metastases in a pre-clinical model. J Urol 161:960-963, 1999.

15. Rowland TL, McHugh SM, Deighton J, et al: differential regulation by thalidomide and dexamethasone of cytokine expression in human peripheral blood mononuclear cells. Immunopharmacol 40:11-20, 1998.

16. Hoosein N, Abdul M, McCabe R, et al: Clinical significance of elevation in neuroendocrine factors and interleukin-6 in metastatic prostate cancer. J Urol Oncol 1:246, 1995.

17. Drachenberg DE, Elgamal AA, Rowbotham R, et al: Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 41:127-133, 1999.

18. Sampaio EP, Sarno EN, Galilly R, et al: Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 173:699-703, 1991.

19. Figg WD: in press.

20. Singh RK, Fidler IJ: Regulation of tumor angiogenesis by organ-specific cytokines. Curr Top Microbiol Immunol 213(Pt 2):1-11, 1996.

 
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