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MUC1 glycoprotein that is overexpressed in aberrant forms in epithelial cancers has been used for diagnosis, staging and therapy. As normal prostate and prostate cancer tissues express MUC1, it represents a potential target, but MUC1 epitopes specific to prostate cancer have not been well characterized. In order to assess MUC1 epitopes in prostate cancer, and their correlation with Gleason grades, binding of 7 well-characterized anti-MUC1 monoclonal antibodies (MAbs) (BrE-3, SM3, BC2, EMA, B27.29, HMFG-1 and NCL MUC1 core), were studied on a prostate tissue microarray. This microarray contained 197 prostate tissue cores representing: i) normal/benign prostate; ii) prostatic intraepithelial neoplasia and Gleason grades 1 and 2; and iii) Gleason grades 3-5. These MAbs bind the MUC1 extracellular domain, but have variable sensitivity to MUC1 glycosylation. To further characterize the effect of glycosylation on their binding, MAb reactivities with unglycosylated MUC1 core peptide and breast and prostate cancer cell lysates were compared. These studies demonstrated strong binding of BrE-3, BC2 and EMA to the peptide core and recognition by BrE-3, SM3, BC2 and EMA of hypoglycosylated MUC1. The results for the microarray indicated that higher Gleason grades were associated with markedly increased cellular staining by MAbs that preferentially recognize less glycosylated MUC1 (BrE-3, p<0.001; SM3, p<0.004; EMA, p=0.009; and BC2, p<0.001). Staining by MAbs that bind preferentially to hyperglycosylated MUC1 (B27.29, p=0.33; HMFG-1, p=0.89; and NCL MUC1 core, p=0.96) did not correlate with Gleason grade. These results demonstrated that hypoglycosylated MUC1 expression increased with Gleason grade, thus supporting the targeting of hypoglycosylated MUC1 epitopes in prostate cancer for more specific imaging and therapy applications.

Prostate cancer continues to be a significant source of morbidity and mortality among older men. One possible means of reducing its impact on overall health and vitality is via cancer chemoprevention, both in the population that is unaffected but at some risk and in those who have undergone some form of curative therapy after the onset of the disease. Chemoprevention holds significant promise, but large phase III clinical trials evaluating chemopreventive agents in prostate cancer can require vast numbers of enrollees and require the commitment of significant financial resources and time before any therapeutic benefit may become apparent. One technique to shorten the time required for chemoprevention clinical trials is to use surrogate endpoint biomarkers in place of the currently used actual endpoints of cancer incidence or survival. The validation of such surrogate endpoint biomarkers will require small, well-designed phase I and/or II trials to accumulate data on the modulation of the surrogate biomarkers and the endpoints of cancer incidence or survival by the chemopreventive agent. Careful statistical correlation and clinical validation of the data will then allow us to justify the use such surrogates in place of the actual endpoint in large, randomized trials, potentially shortening trial duration, improving financial efficiency, and accelerating approval of the chemopreventive agent. To that end, we first review the theoretical construct of cancer chemoprevention trials with particular reference to prostate cancer. We thereafter describe the design of a small, randomized, double-blinded, placebo-controlled phase I/II clinical trial of an analogue of vitamin D, vitamin D5, which we believe could serve as a model for data accumulation on surrogate biomarkers and correlation with other clinical endpoints.

Objective: To determine the frequency and predictive value of p53 mutations in localized prostate cancer, comparing the accuracy of detection using immunohistochemistry (IHC) with a modified yeast assay, on archival tissue samples., Materials and Methods: Prostate cancer tissue was obtained from 98 patients who had >/= 2 years of clinical follow-up after radical prostatectomy. DNA sequencing was used to verify the presence of p53 mutations in samples that were immunopositive or that gave evidence for p53 alterations using the yeast assay. The IHC and yeast findings were compared with patient outcome to determine the predictive value of these two test types., Results: Fifty-five tumours (57%) were immunopositive, and 58 (59%) were positive using the yeast assay. Sequence-confirmed p53 mutations occurred in 44 (45%) cases. The IHC protocol generated 49% (27/55) false-positive and 36% (15/42) false-negative results, and was 65% sensitive and 50% specific, with an overall accuracy of 57%. The yeast assay resulted in 24% (14/58) false-positive results with a specificity of 74% and an accuracy of 86%. When the p53 status of these patients was correlated with their clinical outcome, patients who had sequence-confirmed p53 mutations had a 2.6-fold greater failure rate (P = 0.026) and a 2.5-fold greater risk of dying from prostate cancer (P = 0.05). Notably, mutations in exon 6 predicted a six-fold increase in treatment failure (P = 0.043) and a 5.3-fold increase in the chance of dying from prostate cancer (P = 0.009). Abnormal yeast-assay findings gave similar predictive results to those obtained for DNA sequencing, while immunopositivity did not correspond to patient outcome., Conclusions: Mutations of p53 occurred in 45% of localized prostate cancers. These alterations have important prognostic implications. The yeast assay was more accurate for detecting p53 mutations than the IHC protocol used and, unlike IHC, the results of the yeast assay were predictive of patient outcome.

Objectives: To determine whether supplemental amounts of soy isoflavone (genistein-rich extract) would lower prostate-specific antigen (PSA) levels more than 50% in patients with prostate cancer (CaP)., Methods: A total of 62 men (mean age 73.6 years, range 61.4 to 89.3) with histologically proven CaP who had two consecutive elevated PSA readings were accrued during a 13-month period. An open-label pilot study was conducted for 6 months in which the patients took capsules containing the genistein-rich extract three times daily by mouth. The subjects were in one of five groups: after radical retropubic prostatectomy (n = 9), after radiotherapy (n = 17), after both radical retropubic prostatectomy and radiotherapy (n = 6), off-cycle during hormonal therapy (intermittent hormones; n = 14), or active surveillance (n = 16). The primary endpoint for the trial was a 50% reduction in the PSA level at 6 months compared with before treatment., Results: Of the 62 men enrolled, 52 were available for evaluation at 6 months. Three patients discontinued because of adverse events (diarrhea) and seven because of personal choice. One of 52 patients had a more than 50% reduction in the PSA level (1.9% response, 95% confidence interval 0.1% to 10.3%). An additional 7 patients had PSA reductions that were less than 50%. All 8 patients with lower PSA levels at 6 months were in the active surveillance (watchful waiting) treatment subgroup. Repeated measure regression models allowing for correlation between initial levels and change also indicated a decline in PSA in this group compared with other groups: 0 of 52 had a complete response, 9 (17%) had a partial response, 8 (15%) had stable disease, and 35 (67%) had disease progression. In the 9 patients with a partial response, 6 had pathologic findings that were moderately differentiated, 2 had well-differentiated findings, and 1 had poorly differentiated findings. Therefore, the response in this group of patients did not appear to be driven by the Gleason score. The total testosterone level was lowered in one of the patients responding, but it was higher in five others., Conclusions: A genistein-rich extract as the sole treatment for CaP did not reduce PSA levels by 50% or more in 51 of 52 subjects. Thus, it does not appear to be an effective treatment for CaP when given alone. However, 8 of 13 evaluated patients in the active surveillance group had either no rise or a decline in PSA levels of less than 50%. More study is warranted for those choosing active surveillance.

Objectives: To determine whether supplemental amounts of a polysaccharide/oligosaccharide complex obtained from a shiitake mushroom extract (SME) would lower the prostate-specific antigen (PSA) level in patients with prostate cancer., Methods: A total of 62 men (mean age 73.2 years, range 53.6 to 85.5) with histologically proven prostate cancer who had two consecutive elevated PSA readings were accrued to the study during a 3-month period. This was an open-label study in which the patients received oral administration of capsules containing SME given three times daily for 6 months. The endpoint for the trial was the lowering of the PSA levels., Results: Of the 62 men enrolled in the study, 61 were assessable. At 4 months, 1 patient withdrew because of unrelated surgery and 7 withdrew because of disease progression; none had responded with a decrease of greater than 50% in the PSA level. By 6 months, a total of 23 patients had progression and none had responded. Thirty-eight patients had stable PSA levels after 6 months. Although not the primary endpoint of the study, in other studies these patients could have been included as responders. When the patients' rates of PSA rise before study entry were analyzed, 4 (7%) had stabilized disease while taking SME. Thus, the final results for our study patients were 0 with a complete response, 0 with a partial response, 4 (7%) with stable disease, and 23 of 61 with progression while taking SME., Conclusions: SME alone is ineffective in the treatment of clinical prostate cancer.

BackgroundKetoconazole is a well-known CYP17-targeted systemic treatment for castration-resistant prostate cancer (CRPC). However, most of the published data has been in the pre-chemotherapy setting; its efficacy in the post-chemotherapy setting has not been as widely described. Chemotherapy-naïve patients treated with attenuated doses of ketoconazole (200-300 mg three times daily) had PSA response rate (>50% decline) of 21-62%. We hypothesized that low-dose ketoconazole would likewise possess efficacy and tolerability in the CRPC post-chemotherapy state.MethodsMen with CRPC and performance status 0-3, adequate organ function and who had received prior docetaxel were treated with low-dose ketoconazole (200 mg orally three times daily) and hydrocortisone (20 mg PO qAM and 10 mg PO qPM) until disease progression. Primary endpoint was PSA response rate (>50% reduction from baseline) where a rate of 25% was to be considered promising for further study (versus a null rate of 30% from baseline, progression-free survival (PFS), duration of stable disease and evaluation of adverse events (AEs).ResultsThirty patients were accrued with median age of 72 years (range 55-86) and median pre-treatment PSA of 73 ng ml(-1) (range 7-11,420). Twenty-nine patients were evaluable for response and toxicity. PSA response (>50% reduction) was seen in 48% of patients; PSA response (>30% reduction) was seen in 59%. Median PFS was 138 days; median duration of stable disease was 123 days. Twelve patients experienced grade 3 or 4 AEs. Of the 17 grade 3 AEs, only 3 were attributed to treatment. None of the two grade 4 AEs were considered related to treatment.ConclusionsIn docetaxel pre-treated CRPC patients, low-dose ketoconazole and hydrocortisone is a well-tolerated, relatively inexpensive and clinically active treatment option. PSA response to low-dose ketoconazole appears historically comparable to that of abiraterone in this patient context. A prospective, randomized study of available post-chemotherapy options is warranted to assess comparative efficacy.