FAP-Familial Adenomatous Polyposis Clinical Trial
Official title:
Erythromycin as a Novel Therapy Against Familial Adenomatous Polyposis and Sporadic Colorectal Cancer by APC Nonsense Mutation Readthrough.
Colorectal cancer (CRC) is a leading cause for cancer related mortality in the western world
with a lifetime risk of 6%. Etiology is complex, while genetic background significantly
affects the risk. Around one third of all genetic disorders as well as most cases of
Familial Adenomatous Polyposis (FAP) and a large proportion of all sporadic CRC cases occur
as a result of premature nonsense mutations (creating a stop codon) in an individual's
adenomatous polyposis coli (APC) gene. Nonsense mutations are single-point alterations in
the DNA that prematurely halt the protein translation process, producing a shortened,
nonfunctional protein. In many of these cases, if the cell can be 'persuaded' to ignore the
premature stop codon signal, the resulting protein may be able to ameliorate or stop the
disease.
Recently, members of the aminoglycoside family of antibiotics have been found to induce
ribosomal read-through of nonsense mutations, leading to expression of a full length,
functional protein. Investigators have recently shown that members of the aminoglycoside and
macrolide antibiotic families can induce read-through of the nonsense mutations in the APC
gene and lead to reduced oncogenic phenotypes in CRC cells and in different mice models.
The aim of this project is to determine the ability of the macrolide antibiotic-erythromycin
to induce read-through of the nonsense mutations in the APC gene and to induce expression of
a full length, functional APC protein in patients suffering from FAP and to tests its effect
on adenoma number and size and on desmoid tumors in these patients. The future goal is to
maximize the effect of stop-codon suppressors on APC while minimizing side effects.
In this study investigators will select FAP patients which carry APC nonsense mutations,
treat them with erythromycin PO for 4-6 months and examine colonic and duodenal adenomas as
well as abdominal desmoid tumors, that will be documented before during and after treatment.
In parallel, investigators will test polyp, adenoma and desmoid tissue samples as well as
blood samples from these patients for changes in expression levels of the APC protein and
related oncogenic markers.
Suppression of nonsense mutations within the APC gene should be of benefit for patients
suffering from FAP, attenuated FAP or multiple adenomas and for patients with advanced or
diffuse CRC. Furthermore, given the rapid progress being made in the identification of
different nonsense mutations in human genes that lead to mostly un-curable disease, the
identification of clinically approved compounds that suppress nonsense mutations and that
can be administered long-term without significant side effects would open new venues in the
treatment of genetic human diseases that arise from pre-mature stop codons in important
coding sequences.
Immediate goal: establish the ability of erythromycin to read-through APC nonsense mutation
in FAP patients. The read-through effect of erythromycin will be clinically tested by
counting and measuring the number and size of both colonic and duodenal adenomas before and
over treatment and by measuring the size of known desmoid tumors. Samples of the adenomas
and desmoid tumors will be tested by western blot, immunofluorescence and
immunohistochemistry for restoration of APC expression and changes in oncogenic markers.
These experiments should be conducted within 6 month.
Long term objective:
1. Determine the lowest dose of erythromycin that can inhibit growth of colonic neoplasia
and CRC in patients expressing a truncated APC protein due to nonsense mutations.
2. Examine the ability of a panel of additional macrolide antibiotics to induce APC
nonsense mutation suppression using in-vitro methods. Investigators will focus on
macrolide antibiotics that are currently in clinical use and are administrated for long
terms. These objectives should take around 6 month and will be conducted in parallel.
n/a
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Not yet recruiting |
NCT02354560 -
Erythromycin Treatment for Readthrough of APC Gene Stop Codon Mutation in Familial Adenomatous Polyposis-minors' Adjusted Version
|
Phase 4 |