PBroC: Chemoprevention of Prostate Cancer, HDAC Inhibition and DNA Methylation
Study Details
Study Description
Brief Summary
The objective of the study is to identify mechanisms by which compounds found in cruciferous vegetables alter gene expression via epigenetic modifications (changes in gene expression) and may prevent prostate cancer development.
The investigators have found that sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, inhibits histone deacetylase (HDAC) activity in human colorectal and prostate cancer cells.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
Prostate cancer is the most frequently diagnosed non-cutaneous cancer and is the second leading cause of cancer death in American men. The precise etiologic factors that initiate and enhance the progression of prostate cancer remain unknown, but epigenetic alterations and diet/lifestyle factors have come forth as significant contributing factors. Epidemiologic studies suggest that cruciferous vegetable intake decreases the risk for prostate cancer. The long-term goal of this proposal is to identify mechanisms by which dietary compounds, such as those found in cruciferous vegetables decrease prostate cancer risk. The objective of the study is to identify mechanisms by which compounds found in cruciferous vegetables alter gene expression via epigenetic modifications and may prevent prostate cancer development.
The investigators have found that SFN, an isothiocyanate found in cruciferous vegetables, inhibits HDAC activity in human colorectal and prostate cancer cells.
Targeting the epigenome, including the use of HDAC and DNA methyltransferase (DNMT) inhibitors, is an evolving strategy for cancer chemoprevention and both have shown promise in cancer clinical trials.
This Randomized, Double Blind, Clinical Trial will address the following objectives:
-
Identify distribution of SFN and its metabolites and HDAC inhibition following supplementation with an SFN-rich broccoli sprout extract in subjects at risk for prostate cancer (Primary Endpoints)
-
Investigate the effects of supplementation with an SFN-rich broccoli sprout extract on DNA methylation status and proliferation markers in a pre-biopsy setting (secondary analysis)
The effects of short-term supplementation with an SFN-rich broccoli sprout extract on benign epithelial tissue will be studied in men characterized as being at risk for prostate cancer in a randomized, placebo-controlled trial. Men scheduled for prostate biopsy will be recruited into the trial.
Following successful completion of the consent, two 10 mL blood specimens for study analyses, a 4 mL specimen for total bilirubin assessment will be drawn and the subject will provide a urine sample. The study coordinator will explain the Diet History questionnaires (DHQ) and administer the risk factor and adverse event (AE) questionnaires in order to obtain data on potential confounding dietary variables and gain subjects' baseline symptoms.
The study coordinator will provide the subject with a month' supply of either an SFN-rich broccoli sprout extract (BSE) capsule which consist of 200µmol of sulforaphane (SFN) or matching placebo, as dispensed by the Research Pharmacy. The matching placebo for the BSE consists of a gelatin capsule containing microcrystalline cellulose.
Around every 2 weeks, study coordinator will call to complete AE reporting and any changes in medications or supplements and complete brief cruciferous vegetable intake checklist. Subjects will return any unused study "drug" to the study coordinator at the time of biopsy (or at the 4 week visit if subject's prostate biopsy is delayed).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: SFN-rich broccoli sprout extract capsules Four weeks SFN-rich broccoli sprout extract (BSE) capsules: 200µmol of sulforaphane (SFN) daily, 2 capsules (1 capsule B.I.D.) daily |
Drug: SFN-rich broccoli sprout extract capsules
Four weeks SFN-rich broccoli sprout extract (BSE) capsules: 200µmol of SFN, 2 capsules (1 capsule B.I.D.) daily
Other Names:
|
| Placebo Comparator: Placebo capsules Four weeks placebo capsules: 2 capsules (1 capsule B.I.D.) daily |
Dietary Supplement: Gelatin capsule containing microcrystalline cellulose.
Four weeks placebo capsules: 2 capsules (1 capsule B.I.D.) daily
|
Outcome Measures
Primary Outcome Measures
- Change of Total Urine SFN (Sulforaphane) Metabolites [Baseline and 4-8 weeks following intervention]
Collection of blood and urine specimens occurred at pre-intervention and post-intervention. Change = post-intervention level minus pre-intervention level
- Change of Total Plasma SFN (Sulforaphane) Metabolites Level [Baseline and 4-8 weeks following intervention]
In subjects at risk for prostate cancer, presence of SFN was analyzed in plasma. Collection of blood specimens occurred at pre-intervention and post-intervention. The Change = post-intervention level minus pre-intervention level
- Percentage of Ki67 Positive Cells up to 8 Weeks Post-randomization [Baseline and 4-8 weeks following intervention; prostate biopsy were collected post-intervention when clinically-indicated]
Ki67 is a biomarker of disease progression. Immunohistochemical (IHC) analysis of Ki67 was performed using research only prostate biopsy specimens collected post-intervention at the time of the clinically-indicated prostate biopsy.
- Expression of Histone Deacetylase 6 (HDAC6) [Baseline and 4-8 weeks following intervention; prostate biopsy were collected post-intervention when clinically-indicated]
Immunohistochemical (IHC) analysis of HDAC6 expression using research-only prostate biopsy tissue collected post-intervention at the time of the clinically-indicated prostate biopsy. A modified Histo-score (H-score) was calculated, which involved semiquantitative assessment of both staining intensity (graded as 1-3 with 1 representing weak staining, 2 moderate, and 3 strong) and percentage of positive cells. H-score ranged from 0 to 300 with 300 the strongest expression.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Men scheduled for a prostate biopsy
-
Age 21 years or older
-
Signed informed subject consent
Exclusion Criteria:
-
Definitive diagnosis with prostate cancer
-
Significant active medical illness which in the opinion of the investigator or clinician would preclude protocol treatment
-
Diagnosis of liver disease as noted on the patient problem list or baseline total bilirubin greater than institutional upper limit of normal
-
Subject reported allergy or sensitivity to cruciferous vegetables
-
Use of oral antibiotics, with the exception of doxycycline, within three months prior to randomization
-
Use of warfarin or need for therapeutic anticoagulation at time of biopsy or at anytime during the course of the trial.
-
Current oral steroid therapy
-
Current therapy with valproate or other pharmacological drugs associated with HDAC inhibition
-
Diagnosed dementia as noted on the patient problem list or other significant mental illness that may impact the subjects' ability to follow instructions or comply with the study protocol
-
Patient may not be a part of another flagged study
-
Patients already taking SFN dietary supplements
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | OHSU Knight Cancer Institute | Portland | Oregon | United States | 97239 |
| 2 | Portland VA Medical Center | Portland | Oregon | United States | 97239 |
Sponsors and Collaborators
- Portland VA Medical Center
- National Cancer Institute (NCI)
- Oregon State University
- OHSU Knight Cancer Institute
Investigators
- Principal Investigator: Jackilen Shannon, PhD, Portland VA Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Portland VA-09-0607
- 2096
- 6232
- 2P01CA090890-06A2
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Supplement | Placebo |
|---|---|---|
| Arm/Group Description | Subjects in this group were administered with broccoli sprout extract. | Subjects in this group were administered with placebo. |
| Period Title: Overall Study | ||
| STARTED | 50 | 48 |
| COMPLETED | 45 | 45 |
| NOT COMPLETED | 5 | 3 |
Baseline Characteristics
| Arm/Group Title | Broccoli Sprout Extract Capsules | Placebo Capsules | Total |
|---|---|---|---|
| Arm/Group Description | Four weeks broccoli sprout extract (BSE) capsules: 200µmol of sulforaphane (SFN) daily, 2 capsules (1 capsule B.I.D.) daily | Four weeks placebo capsules: 2 capsules (1 capsule B.I.D.) daily Dietary Supplement: Gelatin capsule containing microcrystalline cellulose | Total of all reporting groups |
| Overall Participants | 50 | 48 | 98 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
65.7
(5.4)
|
64.9
(5.0)
|
65.3
(5.2)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
0
0%
|
0
0%
|
0
0%
|
| Male |
50
100%
|
48
100%
|
98
100%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
1
2%
|
1
2.1%
|
2
2%
|
| White |
48
96%
|
46
95.8%
|
94
95.9%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
1
2%
|
1
2.1%
|
2
2%
|
| Region of Enrollment (Count of Participants) | |||
| United States |
50
100%
|
48
100%
|
98
100%
|
| BMI (kg/m^2) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [kg/m^2] |
28.9
(7.6)
|
31.1
(6.4)
|
30.0
(7.1)
|
Outcome Measures
| Title | Change of Total Urine SFN (Sulforaphane) Metabolites |
|---|---|
| Description | Collection of blood and urine specimens occurred at pre-intervention and post-intervention. Change = post-intervention level minus pre-intervention level |
| Time Frame | Baseline and 4-8 weeks following intervention |
Outcome Measure Data
| Analysis Population Description |
|---|
| Not all subjects had urine samples for analysis, therefore, the total number of subjects in this urine analysis is different from total number of enrolled subjects. |
| Arm/Group Title | Supplement | Placebo |
|---|---|---|
| Arm/Group Description | Subjects in this group were administered with broccoli sprout extract. | Subjects in this group were administered with placebo. |
| Measure Participants | 42 | 44 |
| Mean (Standard Error) [micromolar (µM) concentrations of urina] |
4.75
(0.64)
|
-0.02
(0.01)
|
| Title | Change of Total Plasma SFN (Sulforaphane) Metabolites Level |
|---|---|
| Description | In subjects at risk for prostate cancer, presence of SFN was analyzed in plasma. Collection of blood specimens occurred at pre-intervention and post-intervention. The Change = post-intervention level minus pre-intervention level |
| Time Frame | Baseline and 4-8 weeks following intervention |
Outcome Measure Data
| Analysis Population Description |
|---|
| We missed blood samples from some subjects, therefore, total number of subjects analyzed for the plasma-based analysis is different from the number of total enrolled subjects. |
| Arm/Group Title | Supplement | Placebo |
|---|---|---|
| Arm/Group Description | Subjects in this group were administered with broccoli sprout extract. | Subjects in this group were administered with placebo. |
| Measure Participants | 42 | 44 |
| Mean (Standard Error) [micromolar (µM)] |
0.12
(0.03)
|
-0.0003
(0.0002)
|
| Title | Percentage of Ki67 Positive Cells up to 8 Weeks Post-randomization |
|---|---|
| Description | Ki67 is a biomarker of disease progression. Immunohistochemical (IHC) analysis of Ki67 was performed using research only prostate biopsy specimens collected post-intervention at the time of the clinically-indicated prostate biopsy. |
| Time Frame | Baseline and 4-8 weeks following intervention; prostate biopsy were collected post-intervention when clinically-indicated |
Outcome Measure Data
| Analysis Population Description |
|---|
| Some subjects did not have post-intervention prostate tissue that can be used for IHC analysis, therefore, the overall number of participants analyzed for IHC analysis is different from the total enrolled subjects. |
| Arm/Group Title | Supplement | Placebo |
|---|---|---|
| Arm/Group Description | Subjects in this group were administered with broccoli sprout extract. | Subjects in this group were administered with placebo. |
| Measure Participants | 41 | 42 |
| Mean (Standard Error) [percent positive] |
1.8
(0.2)
|
1.9
(0.3)
|
| Title | Expression of Histone Deacetylase 6 (HDAC6) |
|---|---|
| Description | Immunohistochemical (IHC) analysis of HDAC6 expression using research-only prostate biopsy tissue collected post-intervention at the time of the clinically-indicated prostate biopsy. A modified Histo-score (H-score) was calculated, which involved semiquantitative assessment of both staining intensity (graded as 1-3 with 1 representing weak staining, 2 moderate, and 3 strong) and percentage of positive cells. H-score ranged from 0 to 300 with 300 the strongest expression. |
| Time Frame | Baseline and 4-8 weeks following intervention; prostate biopsy were collected post-intervention when clinically-indicated |
Outcome Measure Data
| Analysis Population Description |
|---|
| Some subjects did not have post-intervention prostate tissue that can be used for IHC analysis, therefore, the overall number of participants analyzed for IHC analysis is different from the total enrolled subjects. |
| Arm/Group Title | Supplement | Placebo |
|---|---|---|
| Arm/Group Description | Subjects in this group were administered with broccoli sprout extract. | Subjects in this group were administered with placebo. |
| Measure Participants | 41 | 42 |
| Mean (Standard Error) [H-score] |
187
(13)
|
183
(12.5)
|
Adverse Events
| Time Frame | ||||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Supplement | Placebo | ||
| Arm/Group Description | Subjects in this group were administered with broccoli sprout extract. | Subjects in this group were administered with placebo. | ||
All Cause Mortality |
||||
| Supplement | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/50 (0%) | 0/48 (0%) | ||
Serious Adverse Events |
||||
| Supplement | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/50 (0%) | 0/48 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Supplement | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/50 (4%) | 1/48 (2.1%) | ||
| Gastrointestinal disorders | ||||
| Bloating | 1/50 (2%) | 1 | 0/48 (0%) | 0 |
| Nervous system disorders | ||||
| Headache | 1/50 (2%) | 1 | 0/48 (0%) | 0 |
| Taste Alteration | 0/50 (0%) | 0 | 1/48 (2.1%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr.Jackilen Shannon |
|---|---|
| Organization | Oregon Health & Science University |
| Phone | 503-418-9860 |
| shannoja@ohsu.edu |
- Portland VA-09-0607
- 2096
- 6232
- 2P01CA090890-06A2