Year of Grant: 2015
Colorectal cancer (CRC) is the third most common cancer with over 1 million people diagnosed each year. In the US alone, more than 100,000 people are diagnosed with CRCand over 55,000 people die from the disease each year. Around 85% of all people suffering from a precancerous condition called colorectal adenomas or malignant transformation, called carcinoma, lose the function of a protein called adenomatous polyposis coli (APC).
APC is a classical tumor suppressor protein that shut off the expression of cancer promoting genes. In a subset of colorectal cancer patients, the loss of function of APC occurs due to a mutation, a single base substitution in the individuals’ DNA. This mutation stops the expression of the APC gene leading to expression of cancer promoting genes and the formation of cancer.
The researchers at Tel Aviv University had earlier shown a proof of concept study in mice focusing on an innovative approach to correct this loss of function. Their approach utilizes antibiotics that can cause the human protein translation machinery (the ribosome) to ignore this stop signal, thus translating a full length functional APC protein.
This new clinical trial will recruit patients suffering from familial adenomatous polyposis (FAP), which is an inherited condition in which numerous pre-cancerous polyps form, mainly in the large intestine due to mutations in the APC gene. If these polyps are not treated, they will develop into CRC.
Treatment will include an oral administration of a clinically-approved antibiotic for 4 months, after which the team will examine the presence and properties of colonic and duodenal adenomas and tumors, as well as any additional tumors that these patients may develop. In parallel, they will also test polyp tissue for changes in expression levels of the APC protein and related oncogenic markers.
The study will further optimize the antibiotic effect by testing other antibiotic types. The ultimate goal is to maximize the effect of APC stopcodon suppression while minimizing human side effects. The identification of clinically approved compounds that suppress these mutations may open new avenues for the treatment of other genetic human diseases that arise from such mutations.
TEL AVIV UNIVERSITY: Antibiotics as a cure for colorectal cancer: Erythromycin for readthrough of APC gene stop codon mutations in familial adenomatous polyposis
RTFCCR ACTIVE GRANTS
Cleveland Clinic Foundation, 2017
University of Cambridge, 2015
University of Edinburgh, 2015