By: Anna C. Greene, PhD
Fusion proteins have been identified as major drivers of many childhood cancers. Fusion proteins arise when a piece of chromosome breaks off and combines with another chromosome. Chromosomal rearrangements such as this can form new genes, fusion genes, that when expressed produce a fusion protein. Sometimes these fusion proteins lead to cancer by reprogramming activities in the cell that cause uncontrolled growth of cells.
You might be wondering that if fusion oncoproteins can lead to cancer, why can’t we simply target them with a drug? Many of the fusion oncoproteins in childhood cancers involve transcription factors, which are critical proteins that help regulate the expression of genes. Unlike other targetable proteins, transcription factors often lack a binding pocket for a drug, making them incredibly challenging to target. Many childhood cancer researchers are searching for a breakthrough in targeting these transcription factor-involved fusion oncoproteins.
One example of a well-known fusion oncoprotein is EWS-FLI1 which drives the majority of Ewing sarcoma cases. While it is known that EWS-FLI1 reprograms cellular activity leading to Ewing sarcoma, researchers still don’t have a thorough understanding of how it does so and how this oncoprotein can successfully be drugged. One researcher, Dr. Heinrich Kovar, is using his Crazy 8 grant to find out which cells in the body are suspectable to EWS-FLI1.
At Alex’s Lemonade Stand Foundation, we recognize the crucial problem fusion oncoproteins cause for childhood cancer and continue to support breakthrough research to find a cure.
Here’s everything you need to know about fusion oncoproteins:
How do fusion oncoproteins work?
When two new genes fuse together to create a fusion gene and later a fusion protein, it can be difficult to know how it will function because it’s a new protein with an unknown behavior. Sometimes these fusion proteins lead to cancer by substantially changing how cells function so that it proliferates to form a tumor.
When were fusion oncoproteins discovered?
The first fusion gene discovered was the BCR-ABL fusion, known as the Philadelphia chromosome, in 1960. This fusion is found in more than 95% of individuals with chronic myeloid leukemia.
What are common types of fusion oncoproteins?
With the invention of next-generation sequencing technologies, it has become easier to find fusion genes that lead to fusion oncoproteins. Many childhood cancers are driven by a fusion oncoprotein. Examples include:
- EWS-FLI1 in Ewing sarcoma
- SS18-SSX in synovial sarcoma
- PAX3/7-FOXO1 in alveolar rhabdomyosarcoma
- C11orf95-RELA in supratentorial ependymoma
- CALM-AF10 in acute leukemia
What is the fusion oncoprotein that drives Ewing sarcoma?
EWS-FLI1 drives more than 85% of Ewing sarcoma cases. The chromosomal translocation was discovered in 1984 and is the only recurrent genetic alteration found in Ewing sarcoma, illustrating that it is the key driver of this disease. Understanding how this fusion propagates disease is critical to finding a cure.
Do all childhood cancers have fusion oncoproteins?
No, not all childhood cancers are driven by fusion oncoproteins.
What is the challenge in treating cancers with fusion oncoproteins involving transcription factors?
Transcription factors help control the expression of genes. If they become uncontrolled, cells can grow unchecked, leading to cancer. Unfortunately, transcription factors are difficult to drug because they do not have a binding pocket in which a drug could dock and destroy the transcription factor. Imagine a transcription factor as a door lock without a hole for the key.
Can two different kinds of cancer have the same fusion oncoprotein?
Yes, there are different types of leukemia that have the same fusion oncoprotein.
Are there any successful treatments that target fusion oncoproteins?
The first drug targeting a fusion protein, the BCR-ABL fusion, was imatinib (Gleevec), approved in 2001 by the FDA. More recently, larotrectinib (approved in 2018) and entrectinib (approved in 2019) were approved to target NTRK fusions. These drugs were approved as some of the first tissue-agnostic therapies, meaning that they are prescribed based on the NTRK fusion status as opposed to the tissue of origin. These drugs are able to target a kinase, which has a drug binding pocket, unlike fusions involving transcription factors. To date, there are no approved drugs to target a fusion oncoprotein involving a transcription factor.
Building on its history as a leading funder in pediatric cancer research, Alex's Lemonade Stand Foundation established the Crazy 8 Initiative to harness collaborative spirit across global institutions to go after the most pressing pediatric cancer research roadblocks. ALSF focused the program to address the eight most challenging aspects of pediatric oncology: embryonal brain cancers; high-grade gliomas; fusion-positive sarcomas; fusion-negative sarcomas; leukemias; neuroblastoma; big data; and catalyzing clinical trials.
While work on the first awarded Crazy 8 Initiative grants is underway, a second Crazy 8 Initiative request for applications has been issued, bringing the total commitment to $25 million. To learn more visit the Crazy 8 page.