NCT04454151: FAP

Azithromycin Treatment for Readthrough of APC Gene Stop Codon Mutations in Familial Adenomatous Polyposis

Status unknown Phase 4 Last updated 1 July 2020

What this trial tests

Phase 4 trial testing Azithromycin Tablets in Familial Adenomatous Polyposis in 10 participants. Status unknown.

Timeline

1 August 2020

Primary endpoint
1 January 2022

1 April 2022

Quick facts

Lead sponsor	Tel-Aviv Sourasky Medical Center
Phase	Phase 4
Status	Status unknown
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	10
Start date	1 August 2020
Primary completion	1 January 2022
Estimated completion	1 April 2022
Sites	1 location across Israel

Drugs / interventions tested

• Azithromycin Tablets — full drug profile →

Conditions studied

• Familial Adenomatous Polyposis — all drugs for Familial Adenomatous Polyposis →

Sponsor

Tel-Aviv Sourasky Medical Center

Who can join

Adults 18 to 120, any sex, with Familial Adenomatous Polyposis. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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-Azithromycin 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 the investigators will select FAP patients which carry APC nonsense mutations, treat them with Azithromycin 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 non-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 Azithromycin to read-through APC nonsense mutation in FAP patients. The read-through effect of Azithromycin 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 Azithromycin 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 4 month and will be conducted in parallel.

Publications & conference data

5 peer-reviewed publications reference this trial (live from Europe PMC):

1. Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer.
   Al-Bari MAA, Ito Y, Ahmed S, Radwan N, et al · · 2021 · cited 34× · PMID 34575981 · DOI 10.3390/ijms22189807
2. <i>Adenomatous polyposis</i> coli in cancer and therapeutic implications.
   Noe O, Filipiak L, Royfman R, Campbell A, et al · · 2021 · cited 24× · PMID 34267890 · DOI 10.4081/oncol.2021.534
3. Wnt Pathway-Targeted Therapy in Gastrointestinal Cancers: Integrating Benchside Insights with Bedside Applications.
   Nayak A, Streiff H, Gonzalez I, Adekoya OO, et al · · 2025 · cited 6× · PMID 39936971 · DOI 10.3390/cells14030178
4. Current trends and future prospects of drug repositioning in gastrointestinal oncology.
   Fatemi N, Karimpour M, Bahrami H, Zali MR, et al · · 2023 · cited 4× · PMID 38239190 · DOI 10.3389/fphar.2023.1329244
5. Metabolic vulnerability of cancer stem cells and their niche.
   Marrone L, Romano S, Malasomma C, Di Giacomo V, et al · · 2024 · cited 3× · PMID 38659591 · DOI 10.3389/fphar.2024.1375993