Does oral simvastatin at standard doses alter BMP pathway signalling in colorectal cancer specimens in humans?
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
A tissue microarray (TMA) will be used to semi-quantify the protein expression
levels in the resection specimens of treated and nontreated patients. The TMA
will be analysed by immunohistochemistry for levels of BMP2 and 4, pSMAD1,
SMAD4 and ID-2. We will also analyse markers of apoptosis (cleaved caspase 3)
proliferation (Ki-67) and angiogenesis (VEGF and CD31). Staining will be scored
in a semiquantitative fashion by 3 independent investigators with no patient
information.
Tumour samples taken before initiation of Simvastatin treatment will be
compared to tumour samples taken after therapy. We will use
immunohistochemistry for elements of the BMP pathway as well as Elisa (BMP2)
and qRT-PCR using the frozen tissue where RNA and protein will be isolated from
samples that consist of more that 70% tumour cells as analysed by frozen
section.
Secondary outcome
Not applicable
Background summary
In 2005 a large epidemiological study found that the use of statins was
associated with a 50% reduced risk of the development of CRC. This has excited
widespread interest in statins as chemopreventative agents in CRC and has lead
several authors to suggest large prospective trials of statins.
Statins are powerful modulators of the BMP pathway. A screen of 30,000
molecules identified Lovostatin as the most potent upregulator of BMP2
production in bone cells. We have shown that BMP2 has proapoptotic effects in
CRC cells and we hypothesised that the actions of the statins in CRC are due to
actions on the BMP pathway. Our preliminary experiments confirm that statins
induce apoptosis in CRC cells by inducing the BMP pathway. We are able to block
the effects of statins with the specific BMP antagonist Noggin.
Study objective
Does oral simvastatin at standard doses alter BMP pathway signalling in
colorectal cancer specimens in humans?
Study design
30 patients with colorectal cancer will be randomised to either receive 40mg
simvastatin per day from their inclusion in the trial up to their operation
date, or to receive no simvastatin.
6 extra biopsies from the tumour will be taken at the time of the initial
colonoscopy and tumour material not needed for pathological diagosis will be
taken from the resection specimen by the pathologist at the time of operation.
Tumour samples will be analysed for expression of BMPs and activity of the BMP
pathway using RT-PCR, western blotting and immunohisochemistry.
Intervention
40mg simvastatin per day from the point of inclusion in the trial until the
operation.
Study burden and risks
The risks are limited to the risk of the extra 6 biopsies of the tumour ( no
risk) and the risks of taking Simvastatin 40mg per day until the operation (
0,01 - 0,1% risk of side-effects according to the pharmacotherapeutic kompas)
Postbus 9600
2300 RC Leiden
NL
Postbus 9600
2300 RC Leiden
NL
Listed location countries
Age
Inclusion criteria
>18 years
histologically confirmed colorectal cancer
Eligible for surgical resection
Exclusion criteria
Current use of cholesterol lowering drugs or NSAIDs.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2007-001179-13-NL |
| CCMO | NL16891.058.07 |