Margaret G. House

Prostate cancer prevention: strategies for agent development.

Purpose of review This article provides an update of clinical research supported by the National Cancer Institutes Phase I/II prostate cancer chemoprevention agent development program. Recent findings Numerous clinical trials of pharmacologic interventions to delay, prevent or reverse carcinogenesis (‘chemoprevention’) with the ultimate goal of reducing cancer incidence have been conducted over the past decade. These trials range from relatively small, short-duration studies with biomarker endpoints to very large, long-term, general population trials with definitive cancer endpoints. Two large, population-based, Phase III prostate cancer prevention trials have shown a significant benefit for 5-&agr;-reductase inhibitors. However, this class of agents was also associated with increased detection of high-grade prostate cancer. Another large, Phase III prostate cancer prevention trial showed no benefit for either selenium or vitamin E, given individually or in combination; in fact, a significant increase in prostate cancer was observed among men randomized to the vitamin E alone arm. Summary A number of early phase trials and three definitive Phase III trials have been conducted in the field of prostate cancer prevention over the past decade. Although a great deal has been learned from these studies, significant work remains to be done to fully realize the potential of chemoprevention in this disease.

BCAN Think Tank session 3: Prevention of bladder cancer

The Bladder Cancer Think Tank III brought together a multidisciplinary group of clinician scientists, patient advocates, representatives from the National Cancer Institute, and Industry leaders to discuss the current state of the field in urothelial cancer and to develop strategies to move forward. This paper summarizes the session devoted to prevention. Experts sought to define primary, secondary, and tertiary prevention and discussed clinical trials performed to date testing retinoids, difluoromethylornithine, celecoxib, and other oral agents in a tertiary prevention setting following transurethral resection with or without intravesical therapy. Urologists practice tertiary prevention in the form of intravesical therapy, and strategies were discussed to identify biomarkers, including urinary cytokines and pathway single nucleotide polymorphism analysis associated with response to treatment. Optimizing delivery of intravesical chemotherapy to the target tissue with simple pharmacologic manipulations or packaging drugs in nanoparticles may improve treatment outcome. Defining a premalignant lesion should be a focus of future research as a strategy for early detection and secondary prevention. Cigarette smoking is the most prevalent risk factor for urothelial cancer, and emphasis was placed on smoking cessation as a powerful tool to reduce the burden of urothelial cancer, and the central role physicians must play in educating patients and providing resources. There is a strong need for research to develop markers of disease initiation and progression. These markers, combined with histories of environmental exposure to bladder carcinogens, may provide a tool to identify patients who will benefit from primary prevention.

A Phase II Randomized, Double-blind, Presurgical Trial of Polyphenon E in Bladder Cancer Patients to Evaluate Pharmacodynamics and Bladder Tissue Biomarkers

We performed a phase II pharmacodynamic prevention trial of Polyphenon E [a green tea polyphenol formulation primarily consisting of epigallocatechin gallate (EGCG)] in patients prior to bladder cancer surgery. Patients with a bladder tumor were randomized to receive Polyphenon E containing either 800 or 1,200 mg of EGCG or placebo for 14 to 28 days prior to transurethral resection of bladder tumor or cystectomy. The primary objective was to compare the postintervention EGCG tissue levels in patients receiving Polyphenon E as compared with placebo. Secondary objectives included assessments of tissue expression of PCNA, MMP2, clusterin, VEGF, p27, IGF-1, IGFBP-3; correlation of tissue, plasma, and urine levels of EGCG; and EGCG metabolism by catechol-O-methyltransferase and UDP-glucuronosyltransferase pharmacogenomic mutations. Thirty-one patients (male:female, 26:5; mean age, 67.2 years) were randomized and 29 (94%) completed the study. There was not an observed significant difference (P = 0.12) in EGCG tissue levels between two Polyphenon E dosage groups combined versus placebo. However, a dose–response relationship for EGCG levels was observed in both normal (P = 0.046) and malignant bladder tissue (P = 0.005) across the three study arms. In addition, EGCG levels in plasma (P < 0.001) and urine (P < 0.001) increased and PCNA (P = 0.016) and clusterin (P = 0.008) were downregulated in a dose-dependent fashion. No pharmacogenomic relationship was observed. EGCG levels in plasma, urine, and bladder tissue followed a dose–response relationship, as did modulation of tissue biomarkers of proliferation and apoptosis. Despite the limitations of this pilot study, the observed pharmacodynamics and desirable biologic activity warrant further clinical studies of this agent in bladder cancer prevention. Cancer Prev Res; 10(5); 298–307. ©2017 AACR.

Strategies for the Chemoprevention of Prostate Cancer

Carcinogenesis is a multistep process driven by genetic and epigenetic alterations that disrupt the regulatory pathways controlling cellular proliferation, programmed cell death (apoptosis), angiogenesis, and differentiation (1–3). The age-dependent incidence of most cancers and the recognition that precursor lesions, representing intermediate stages between normal and malignant cells, may precede invasive cancer by 20 yr or more, suggests that malignant transformation generally occurs over decades (4–10) (Fig. 1). The protracted nature of this process provides an opportunity to intervene before the malignant phenotype is established. This may be done with life-style changes such as diet and exercise, or by chemoprevention, the administration of natural or synthetic agents to reverse, inhibit, slow, or prevent the development of cancer (11).

Phase Ib placebo-controlled, tissue biomarker trial of diindolylmethane (BR-DIMNG) in patients with prostate cancer who are undergoing prostatectomy.

Epidemiologic, preclinical, and early phase I studies of the cruciferous vegetable bioactive metabolite, 3,3′-diindolylmethane (DIM), support its potential prostate cancer chemopreventive ability. We performed a multicenter, double-blind, placebo-controlled trial of DIM in patients diagnosed with prostate cancer and scheduled for radical prostatectomy. A total of 45 patients with organ-confined prostate cancer were randomized to 21–28 days of an absorption-enhanced formulation of DIM (BR-DIMNG) at doses of 100 or 200 mg per os twice daily or to placebo twice daily. Prostate tissue levels of DIM were the primary endpoint, with selected secondary biomarker endpoints including blood levels of DIM, total prostate-specific antigen, testosterone, and the insulin-like growth factor-1: insulin-like growth factor binding protein-3 ratio and the urinary 2-hydroxyestrone/16-hydroxyestrone ratio, obtained at baseline, at day 15, and before surgery, as well as tissue expression of androgen receptor, prostate-specific antigen, Ki67, caspase 3 with cytochrome p450 mRNA expression and genotyping (polymorphisms). DIM was well tolerated with excellent study compliance and relatively rapid accrual of all 45 patients within 1 year. DIM levels were detected in only seven of 28 prostate tissue specimens. There was a statistically significant difference in the change in the urinary 2-hydroxyestrone/16-hydroxyestrone ratio from baseline until before surgery between the placebo and 400 mg DIM groups, with otherwise statistically nonsignificant changes in plasma biomarker expression. The administration of BR-DIMNG to prostate cancer patients before prostatectomy yields detectable plasma levels but without consistent or significant tissue accumulation or biomarker modulation. This study demonstrates the feasibility of biologic evaluation of relatively nontoxic preventive agents in the preprostatectomy setting with the potential for rapid accrual.

Prostate cancer prevention: agent development strategies.

Despite advances in surgery, radiation, and medical therapy over the past decade and the widespread adoption of PSA screening, prostate cancer continues to be the second leading cause of cancer death in men in the United States. Invasive cancer is the end result of carcinogenesis, a chronic process occurring over many years driven by genetic and epigenetic alterations. The protracted nature of this transformation to the malignant phenotype provides an opportunity to intervene pharmacologically to prevent, reverse, or delay carcinogenesis, i.e. chemoprevention. Herein, we describe the unique features of cancer prevention, as opposed to cancer treatment, agent development clinical trials, and provide a summary of the ongoing research in this field being supported by the National Cancer Institute.

Prostate Cancer Chemoprevention Strategies

Carcinogenesis is the multistep process by which normal cells undergo malignant transformation. The clinical expression of cancer may be prevented or delayed either by risk factor modification, such as quitting smoking, or by the administration of drugs to prevent or delay the clinical expression of the malignant phenotype. This chapter focuses on the latter approach, often referred to as “chemoprevention.” Specifically, it addresses the two key issues distinguishing cancer prevention from cancer treatment agent development: selection of study endpoints and patient cohorts. In addition, a comprehensive update is provided of recently completed and ongoing phase 1, 2, and 3 prostate cancer prevention clinical trials conducted under the auspices of the Division of Cancer Prevention, NCI.

Soy food frequency questionnaire does not correlate with baseline isoflavone levels in patients with bladder cancer

Background The isoflavone genistein, a natural soy product with receptor tyrosine kinase-inhibiting activity, as well as phytoestrogenic and other potential anticarcinogenic effects, is being studied as an anticancer agent. Since isoflavones are commonly consumed in food products containing soy proteins, a method to control for baseline isoflavone consumption is needed. Methods HPLC was used to evaluate baseline plasma and urine concentrations of isoflavone in fifty-four participants with bladder cancer enrolled on a phase II chemoprevention study of G-2535. The soy food frequency questionnaire was used to assess participant’s baseline soy intake. The association between baseline isoflavone concentrations and intakes for genistein and daidzein was assessed by the Spearman’s rank correlation coefficient. Results The majority of participants had no detectable genistein or daidzein in plasma at baseline. The median and range of values were 0 (0–1480) nmol/L for genistein, and 0 (0–1260) nmol/L for daidzein. In urine, the median and range of values were 91.0 (0–9030) nmol/L for genistein and 623 (0–100,000) nmol/L for daidzein. The median and range of weekly estimated genistein intake was 0 (0–236) mg/wk; the median and range of weekly estimated daidzein intake was 0 (0–114) mg/wk. There was no relationship to soy intake as measured by the food frequency questionnaire and baseline isoflavone levels in plasma or urine and the Spearman’s rank correlation coefficients were not significant. Conclusion The soy food frequency questionnaire did not correlate with plasma or urine concentrations of either isoflavone. Impact Alternative methods for controlling for soy consumption, including measuring plasma and urine concentrations, in isoflavone chemoprevention trials should be considered.

Abstract A20: A phase II randomized, presurgical placebo-controlled trial of polyphenon E in bladder cancer patients to evaluate bladder tissue levels of EGCG and biomarkers of growth and apoptosis

Introduction: Bladder cancer patients are faced with significant morbidity and mortality due to tumor recurrence and progression and therefore would benefit from an effective chemopreventive strategy. Green tea consumption has been associated with a reduction in bladder cancer risk. Polyphenon E is a green tea polyphenol formulation primarily consisting of epigallocatechin gallate (EGCG) which has been shown in preclinical studies to inhibit growth of bladder cancer. We evaluated the tolerability, tissue accumulation, and biologic effects of polyphenon E in a randomized, double-blind, placebo-controlled phase II preoperative study in patients with bladder cancer. Methods: Patients who had an initial diagnosis or recurring bladder tumor found on diagnostic cystoscopy were randomized in a 1:1:1 ratio to receive 800 mg, 1200 mg or placebo polyphenon E prior to undergoing TURBT or radical cystectomy. The primary objective of the study was to assess the nonmalignant bladder tissue levels of EGCG. Secondary objectives included comparison of EGCG levels in nonmalignant versus malignant tissue within treatment arms; examination of the dose-dependent modulation of surrogate endpoint biomarkers (PCNA, MMP2, Clusterin, VEGF, p27, IGF-1, IGFBP-3) in malignant and nonmalignant bladder tissue; correlation of plasma, urine and tissue levels of EGCG; examination of the levels of other catechins (epicatechin, epicatechin gallate, and epigallocatechin) in plasma, tissue, and urine; metabolism of EGCG in plasma, urine and tissue by COMT and UGT in relation to pharmacogenomic mutations. Results: 31 patients (84% male, 16% female) were randomized with a mean age of 67.2 years. Four patients (13%) were non-compliant and drug administration was interrupted in one other patient (3%), whereas the remainder of patients for which we have reports completed study agent administration (n=24, 77%). The worst adverse event severity was severe (grade 3) for one (3%) patient, moderate for five patients (16%), and mild for eight (26%) patients, whereas no adverse event occurred in 17 (55%) of the patients. Although we found a low rate of detectability in tissue (4/25 with detectable values), tissue levels of EGCG were identified in a dose-dependent fashion in both normal (0.00, 0.50, 1.72 ng/ml, p=0.046) and malignant (0.00, 0.00, 2.54 ng/ml p=0.005) bladder tissue for the placebo, low dose and high dose polyphenon E arms respectively. Plasma EGCG levels (2.94, 78.09, 87.52 ng/ml, p=0.001) and urine EGCG levels (0.00, 2.60, 4.32 ng/ml, p Conclusions: We demonstrate in a phase II pilot study tissue accumulation of EGCG in benign and malignant bladder urothelium which follows both plasma and urine levels in a dose-dependent fashion. Furthermore, tissue endpoint biomarkers of proliferation (PCNA) and apoptosis (clusterin) were reduced in a statistically significant dose-dependent fashion. Acknowledging the limitations of this pilot study, we feel these findings indicate polyphenon E administration results in definable tissue accumulation and more importantly desirable biologic activity which warrant further clinical studies assessing the effect of polyphenon E on actual bladder tumor recurrence/progression. Citation Format: Jason R. Gee, Daniel R. Saltzstein, KyungMann Kim, Jill Kolesar, Wei Huang, Tom Havighurst, Barbara W. Wollmer, Jeanne Stublaski, Tracy Downs, Hasan Mukhtar, Margaret House, Howard Parnes, Howard Bailey. A phase II randomized, presurgical placebo-controlled trial of polyphenon E in bladder cancer patients to evaluate bladder tissue levels of EGCG and biomarkers of growth and apoptosis. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A20.