Macrolid Induced Correction of Premature Stop Codons: A novel Treatment for Colorectal Cancer

Technology

An antibiotic of the Macrolid family was demonstrated as a new treatment for colorectal cancer and other genetic human diseases that arise from pre-mature stop codons in important coding sequences.

The Need

Around one third of all genetic disorders as well as most cases of sporadic and hereditary colorectal cancer occur as a result of premature stop codons (termed nonsense mutations) in an individual’s DNA. For a significant proportion 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.

Colorectal cancer (CRC) is the third most common cancer in men and women with over 1,000,000 people diagnosed each year. Around 85% of all people suffering from colorectal adenomas or carcinomas show loss of adenomatous polyposis coli (APC) protein function due to nonsense or frameshift mutations.

Using in-vitro and in vivo experimants we have results showing that antibiotic of the macrolid family, can read-through mutations of the APC gene and reduce the oncogenic properties of CRC cells. The Macrolid, that is used in vetenerian medicine is absorbed well when orally administrated, it reaches the colon and does not appear to have toxic effects.

Potential Applications

Potential applications include colorectal cancer, gastric, prostate and breast cancers, and a large number of other common genetic diseases (over 1,800) that are caused by premature stop codons in important genes.

Advantages

1.

A well tolerated, oral available drug.

2.

Novel treatment for early stage genetic changes in the colorectal tumor progression.

3.

Read-through mutations in the APC gene that are involved in both the initiation and the progression of CRC.

Stage of development

We have provided in vitro evidence showing that treating colorectal cancer cells with a member of the Macrolid family result in read-through of APC stop codon mutations, and lead to differences in expression of Wnt target genes, such as LEF1 and COX-1 that are well known Wnt target gene.

In vivo experiments demonstrated the ability of the Macrolid to read-through the mutated APC gene in colorectal cell lines HT-29 and SW1417 injected into nude mice. This treatment results in reduced tumor size (around 50%) due to tumor cell death. Experiments were also conducted on APCmin mice. These mice develop intestinal adenomas due to a stop codon introduced into the APC gene and are frequently used for studying CRC development and progression. Our results clearly demonstrate that treatment of APCmin mice with the Macrolid results in reduced tumor size and number and leads to elevated red blood cell count.

Patents

WO 2007/144876, granted in Europe

Project manager

Adi Elkeles
BD Manager

Project researchers

Rina Rosin-Arbesfeld
T.A.U Tel Aviv University, Medicine-Sackler Faculty
Anathomy and Anthropology