Development of Angiogenesis Inhibition as Therapy for Prostate Cancer

December 2, 2000

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

ABSTRACT: Angiogenesis is essential to prostate cancer progression. Thefirst study of antiangiogenic therapy in patients with locally advanced prostatecancer at The University of Texas M. D. Anderson Cancer Center showed thatpreoperative treatment with a fumagillin analog was safe. Microvascular densitycorrelated with Gleason score, but marked intertumoral and intratumoral changeswere observed. Clinical experience with thalido-mide (Thalomid), which inhibitsangiogenesis induced by both vascular endothelial growth factor and basicfibroblast growth factor, has included observation of "clinicalimprovement" in patients with androgen-independent prostate cancer andanecdotal responses in patients with metastatic disease refractory tochemotherapy. In an effort to assess the in vivo effect of thalidomide inprostate carcinoma, we have initiated a study of neoadjuvant thalidomidetreatment in patients with locally advanced prostate cancer that is to includeserial ultrasonographic and pathologic evaluation, as well as serial collectionof serum/urine markers that may prove useful surrogate markers of antiangiogenicactivity. We have also initiated a phase I/II trial of thalidomide, paclitaxel(Taxol), and estramustine (Emcyt) in patients with metastaticandrogen-independent prostate cancer progressing after up to two courses ofchemotherapy. [ONCOLOGY14(Suppl 13):21-23, 2000]

Introduction

Angiogenesis is essential to progression of prostate cancer. In1993, Weidner and colleagues[1] demonstrated a correlation between microvasculardensity and stage of prostate cancer. A number of studies over the next severalyears showed a correlation between microvessel count and disease stage or riskof 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 atthis time is how best to measure the activity of putative antiangiogenesis drugsin prostate cancer in light of the fact that the target is the host (endothelialcell) rather than the epithelial malignant compartment per se (prostate cancercell), and that markers of biologic activity of angiogenesis inhibitors might bedifferent than tumor markers (ie, prostate-specific antigen [PSA]). Theavailability of soluble, surrogate markers of antiangiogenic activity wouldaccelerate assessment of drug activity and development of novel therapies;however, it remains unknown which soluble markers might be relevant toprediction of clinical effect. Further, methods such as positron-emissiontomography (PET) scanning or new technologies for measuring tumor blood flowhave not been clinically validated in this setting. We therefore hypothesizedthat assessment of the in vivo effect of the antiangiogenesis treatment onendothelial cells/vessels and malignant compartment (comparison of tissuesamples 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 advancedprostate cancer defined as clinical stage T1c/T2 (Gleason score of ³7 and PSA level > 10 ng/dL) or stage T3; such patients are categorized as ‘potentiallyresectable’ but not ‘highly curable’ with local therapies alone.

Studies have shown that 50% to 97% of patients with stage T1c/T2disease and a Gleason grade ³ 8, and 73% of those with T2 disease and Gleasongrade ³ 7 and PSA level > 10 ng/dL, haveextracapsular extension of disease at surgery.[7] Positive surgical marginsrange between 22% and 33% for patients with high-grade T1/T2 disease and 50% forthose 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. Theaddition of androgen ablation to radiation therapy shows improvement indisease-free survival, but no clear improvement in overall survival for patientswith locally advanced prostate cancer. The European Organization for Researchand Treatment of Cancer (EORTC) trial[9] indicated improved disease-free andoverall 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 clinicalstudies of preoperative investigational treatments, including antiangiogenesistherapy. The safety of preoperative treatment with another angiogenesisinhibitor (fumagillin analog) has been established in a previous trial,[11]although the results may not be comparable because of the different mechanism ofaction and much longer half-life of thalidomide (Thalomid). As with otherstudies, it was observed that microvascular density correlated with the Gleasonscore. We observed marked intertumoral and intratumoral changes in microvasculardensity, which mandates careful assessment of consecutive, matched, pre- andposttreatment biopsies and correlation with putative serum/urine markers.

Thalidomide in Prostate Cancer

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

Neoadjuvant Thalidomide Trial

Angiogenesis is tumor site-specific[20]; it remains uncertainwhether beneficial effects of antiangiogenic treatment would be observed at bothprimary and metastatic tumor sites. This question will be addressed in anongoing neoadjuvant trial of thalidomide. The rationale for the trial is basedon the hypothesis that thalidomide may reduce postoperative disease recurrenceand that neoadjuvant angiogenesis inhibition, assessed by consecutive prostatebiopsies, may constitute a useful strategy for identifying intermediate markersof antiangiogenic and antitumor activity.

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

Patients and Methods

Patients are to undergo transrectal ultrasound and needle biopsyprior to initiating thalidomide treatment at 200 mg/d; the thalidomide dose isto be increased to 600 mg/d over the initial 6 weeks of administration, duringwhich urine and serum markers are to be assessed. After ultrasound and biopsyare repeated, patients with stable disease are to receive 6 additional weeks ofthalidomide (600 mg/d) before undergoing prostatectomy, with urine and serummarkers being assessed at the start of the second phase and prior to and afterprostatectomy. It is hoped that the findings of this trial and other neoadjuvantstudies 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-independentprostate cancer. Synergistic effects of antiangiogenic agents and chemotherapyhave been observed in preclinical investigations. Thalidomide has beenassociated with "clinical improvement" in some patients withmetastatic androgen-independent prostate cancer. We have anecdotal experiencewith thalidomide in some patients with metastatic androgen-independent prostatecancer refractory to chemotherapy. We observed clinical improvement (painrelief) as well as PSA reduction using thalidomide combined with the previouschemotherapy that had resulted in progression of disease for these patients(personal communication, C. Logothetis, 2000).

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

Conclusion

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

References:

1. Weidner N, Carroll PR, Flax J, et al: Tumor angiogenesiscorrelates with metastasis in invasive prostate carcinoma. Am J Pathol143:401-409, 1993.

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

3. Brawer MK, Deering RE, Brown M, et al: Predictors ofpathologic stage in prostatic carcinoma. The role of neovascularity. Cancer73(3):678-687, 1994.

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

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

6. Silberman MA, Partin AW, Veltri RW, et al: Tumor angiogenesiscorrelates with progression after radical prostatectomy but not with pathologicstage 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 prostatespecific antigen, clinical stage and Gleason score to predict pathological stagein men with localized prostate cancer. J Urol 150:110-114, 1993.

8. Stamey TA, McNeal JE: Adenocarcinoma of the prostate, inWalsh PC, Retik AB, Stamey MA, et al (eds): Campbell’s Urology, 6th ed, pp1159-1221. Philadelphia, Saunders, 1992.

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

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

11. Daliani D, Finn L, Hodges S, et al: Interleukin-6 (IL-6): amarker of androgen-independent (AI) growth in prostatic carcinoma (PC) (abstract1183). Proc Am Soc Clin Oncol 16:331a, 1997.

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

13. Ferrer FA, Miller LJ, Andrawis RI, et al: Vascularendothelial growth factor (VEGF) expression in human prostate cancer: In situand in vitro expression of VEGF by human prostate cancer cells. J Urol157:2329-2333, 1997.

14. Melnyk O, Zimmerman M, Kim KJ, et al: Neutralizinganti-vascular endothelial growth factor antibody inhibits further growth ofestablished prostate cancer and metastases in a pre-clinical model. J Urol161:960-963, 1999.

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

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

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

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

19. Figg WD: in press.

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