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BY THERAPEUTIC AREA
BY RESEARCH STAGE
06 June 2018
It is well established that cancer is tightly linked to development; something that becomes particularly relevant when studying childhood cancers.
We at ZeClinics carry out preclinical research with juvenile animals, thus enabling us to monitor multiple genetic factors still at play during early developmental stages. Dr. Genevieve Kendall from the University of Texas Southwestern Medical Center is of a similar mindset: She and her team resorted to zebrafish larvae in order to study different factors at once... and came out with some interesting results.
Learn more after the break.
By: Cathy Frisinger
Image credit: Dr. Genevieve Kendall
"Representative overlay of images from co-injections of mCherry-HES3 and GFP-PAX3FOXO1 from the same embryo at 24 and 72 hr post-fertilization".
Muscle precursor cells called myoblasts are formed during normal fetal development and mature to become the skeletal muscles of the body. Rarely, a genetic error in which pieces of two chromosomes fuse together occurs in a cell related to this process and triggers those cells to multiply and behave abnormally. A particularly aggressive form of the muscle cancer rhabdomyosarcoma results.
The fused genes create an abnormal protein called PAX3-FOXO1, which blocks the normal maturation of muscle cells by inappropriately turning hundreds if not thousands of genes on and off. The exact mechanism by which PAX3-FOXO1 does this is not known.
Cancer researchers at UT Southwestern Medical Center developed a zebrafish model for the childhood cancer. To do this, Dr. James Amatruda's lab inserted the human PAX3-FOXO1 gene into the DNA of zebrafish. Using this new transgenic zebrafish, the researchers showed that the fused-gene DNA causes rhabdomyosarcoma that is similar to the human disease. They found it does this by turning on another gene, HES3, which leads to overproduction of the skeletal muscle precursor cells and allows for PAX3-FOXO1+ cells to survive during development instead of dying.
"There is a lot of interest in understanding the PAX3-FOXO1 block and in identifying treatments that overcome this block," said Dr. Amatruda, Associate Professor of Pediatrics, Internal Medicine, and Molecular Biology. "Such treatments could potentially cause the tumor to 'mature' and slow its growth without exposing the patient's normal tissue to the side effects of chemotherapy and radiation."
Efforts to directly counter the effects of PAX3-FOXO1 have been unsuccessful, so the HES3 gene provides a potential back door for targeted treatment for this cancer.
Current treatments for rhabdomyosarcoma include surgery, chemotherapy, and radiation. Finding a drug that specifically targets part of the pathway initiated by the PAX3-FOXO1 gene fusion could improve survival rates as well as make treatments more tolerable for young patients.
The zebrafish model of rhabdomyosarcoma the researchers developed is particularly useful because few other options are available. "Gene fusions that function as transcription factors are notoriously difficult to model in animals, hence the limited availability of vertebrate animal models for this disease. Zebrafish are powerful models because their use provides insight into how cancer genes function during development and the fish are a platform for drug discovery efforts," said Dr. Genevieve Kendall, postdoctoral researcher and first author on the study.
The long-term goal of their work is to identify potential drugs for the most aggressive type of rhabdomyosarcoma tumor and to test these treatments in the zebrafish model. The new findings open the possibility of finding drugs that block HES3 or its downstream targets as a therapy for this cancer.
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