Highlight @ VECR
Even though it was primarily virtual I had an amazing time at the Fred Hutch Virtual Explores Cancer Research program as I got to meet new people and learn with scientists and doctors about cancer research. One of the most interesting things we did was a discussion panel with Dr. Keith Eaton about cancer treatments and research. It was very interesting to hear about his journey through surviving leukemia and an experimental CAR T-Cell clinical trial that destroyed his cancer. I learned a lot about the science behind many kinds of cancer treatments as well as his research on improving healthcare accessibility. Dr. Eaton explained the amazing feeling of satisfaction you get when you are helping people destroy their cancer cells so that they can continue their daily life and I found that very inspiring as I hope to do the same someday.
From Hutch News Story: New study shows cancer-causing ‘Frankengene’ mutation could be target for new drugs
This gene is fused to many partner genes in different tumors. Now, scientists know it causes cancer — and how they might intervene.
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. Sometimes the DNA changes that drive cancer are small, but sometimes DNA undergoes bigger changes. One such "Franken gene" that is widely seen is YAP gene, a growth-promoting gene found fused to another gene in many different cancer types. In new work published in the journal Genes & Development, scientists at Fred Hutchinson Cancer Research Center show that YAP gene fusions cause cancer. One of the YAP protein’s main function is to promote cell growth. In a healthy, growing cell, active YAP travels to the nucleus, and turns on genes that help the cell grow. When the cell needs to stop growing, it activates molecules that modify YAP to keep it out of the nucleus and break it down into amino acids. A mutation in the YAP gene is not the main cause for cancer, instead when YAP is mutated in cancer it’s almost always stuck to a different gene. The scientists tested the effect of each of four different YAP fusions in mouse brain cells and found that tumors developed in the presence of each fusion. By comparing the different YAP gene fusions, they were able to narrow down the key functions of the YAP gene that trigger cancer and figure out how its gene fusions avoid molecular controls that normally limit YAP activity. In lab dishes, drugs that block these common traits slowed growth of cancer cells with YAP fusions. YAP gene fusions are rare in any given cancer, they are found in many kinds of tumors. Even though YAP has many different fusions the fact that they all appear to cause cancer in the same way suggests that anti-YAP therapy may work against many different YAP fusions. The scientists are continuing to pursue potential new drugs with anti-YAP activity. They are also experimenting to see if any of the other genes turned on by YAP could be therapeutic targets by seeking drugs that could synergize with anti-YAP drugs to be even more beneficial. The study, funded by NIH and The Ivy Foundation, was done by Dr. Frank Szulzewsky at Holland Lab, led by Dr. Eric Holland, who directs the Hutch’s Human Biology Division. Dr. Frank Szulzewsky is investigating the biology of different gene fusions, foremost the family of YAP1 fusion genes that have been detected in several pediatric and adult cancers and testing anti-YAP drugs.
Figure 2: YAP pathways in Pancreatic Cancer (From: Rozengurt, E., Sinnett-Smith, J. & Eibl, G. Yes-associated protein (YAP) in pancreatic cancer: at the epicenter of a targetable signaling network associated with patient survival. Sig Transduct Target Ther3, 11 (2018). https://doi.org/10.1038/s41392-017-0005-2)
I choose this study because I have heard of many treatments(that are in use and that are still being studied) which uses radioactive chemicals such as chemotherapy to destroy cancer cells but these comes with serious side effects and more health problems. This study is focuses on finding new anti-cancer drugs that could potentially help people with cancers hopefully with less side effects compared with radioactive materials.
Q and A with Dr. Frank Szulzewsky
Figure 3: Dr. Frank Szulzewskyn (From: Robert Hood / Fred Hutch News Service)
How does the YAP gene fuse with other genes?
You can see an explanation here https://en.wikipedia.org/wiki/Fusion_gene The DNA of chromosomes can sometimes break, and be rearranged with DNA parts from other chromosomes or other regions. This can lead to two different genes fuse together. The YAP1 gene can be fused to several different other genes, such as MAMLD1, TFE3, SS18. Some studies have identified YAP1-MAMLD1 and YAP1-TFE3.
How can drugs (such as verteporfin) be used as anti-YAP to treat cancers?
YAP1 is a transcriptional activator that is involved in the regulation of a multitude of genes, by enhancing or inhibiting their expression (meaning how often a gene is transcribed, or how active a gene is). The genes that are activated by YAP1 lead to more cell division (proliferation) and ultimately to cancer formation.
Because YAP1 does not bind DNA itself, it needs to interact with other proteins to regulate the expression of its target genes. The main interaction partner is a transcription factor called TEAD (there are four different versions, TEAD1, TEAD2, TEAD3, TEAD4). This interaction between YAP1 and TEAD can be blocked by small molecule inhibitors, such as Verteporfin, which basically renders YAP1 “inactive” and it cannot perform its function anymore. I added links to two papers describing the function of Verteporfin in the context of YAP1 inhibition.
Are there any side effects to these drugs?
We don’t know yet. Since YAP1 has lots of functions in the normal body, inhibiting YAP1 function will probably also have side effects. We hope that the cancer cells are more sensitive to Verteporfin, so that at a specific dose it might kill the cancer cells, but the side effects will (hopefully) be manageable.
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