Scientist Seeks to Understand Neuroblastoma Gene Mutation

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One Year Research Update:

Shizhen (Jane) Zhu, MD, PhD at Mayo Clinic has a CureSearch Young Investigator award to study the influence of the mutation and over expression of a gene called SHP2 on the growth of neuroblastoma tumors. SHP2 is known to be mutationally activated (hyperactive) and over expressed in cells when a patient has neuroblastoma and Dr. Zhu is studying whether abnormal SHP2 can create neuroblastoma.

In her first year of work, Dr. Zhu compared tumor growth in zebrafish with over-expressed mutant SHP2 and zebrafish with over-expressed mutant SHP2 and another gene, MYCN. Her work revealed that the combination of these two genes over-expressing cooperate in the development of neuroblastoma and ganglioneuroma tumors.

In addition, Dr. Zhu developed zebrafish models that over express another gene called GAB2. The GAB2 gene is a known activator of SHP2 and over expressed in neuroblastoma patients with SHP2 overexpression. She investigated whether GAB2 is important for SHP2–mediated neuroblastoma formation.

In the next phase of her research, Dr. Zhu will continue to study the relationship between SHP2 and MYCN and will treat the zebrafish with neuroblastoma with a compound and monobody that she hopes will inhibit the hyper-activation of SHP2 and therefore stop the growth of tumors.

Shizhen (Jane) Zhu, MD, PhD at Mayo Clinic was recently awarded a CureSearch for Children’s Cancer Young Investigator’s Grant to study the influence of the mutation and over expression of a gene called SHP2 on the growth of neuroblastoma tumors.

Dr Zhu
  • Shizhen Zhu, MD, PhD
  • Mayo Clinic

Neuroblastoma is a cancer of the sympathetic nervous system occurring primarily in young children and accounting for approximately 10% of all deaths in children with cancer. Progress in treating this cancer has been challenging because researchers do not fully understand the mutations, or abnormalities, that occur in the genes that make neuroblastoma. In a recent conversation with Dr. Zhu, CureSearch asked her about the research she plans to conduct and how it might make a difference in treating children with neuroblastoma.

CureSearch: Tell us about what you plan to study with this Grant.

Dr. Zhu: Researchers know that a gene called SHP2 is mutationally activated and over expressed in cells when a patient has neuroblastoma. Mutational activation means the mutations identified in the SHP2 gene cause it to be hyperactive, leading to its downstream pathway. Over expression means there is more of the gene in each cell than there is supposed to be. My hypothesis is that both mutations and over expression of SHP2 create a pathway that leads to tumor development, creating neuroblastoma.

CureSearch:You used the team “pathway.” What does that mean?

Dr. Zhu: A pathway is an exact step-by-step process that leads to something else. Think about baking a cake. There are a certain number of precisely measured ingredients that get put together in order to make the cake. If you add more of one ingredient, the cake would not come out right. In the case of neuroblastoma, I suspect that if there is too much SHP2 and it is activated, then the normal pathway of the cells change, and lead to cancer, thus making SHP2 an oncogene, or one that causes cancer.

CureSearch: You are using Zebrafish to conduct your research. A lot of people will wonder why you are using a fish to study children’s cancer.

Dr. Zhu: It’s important to understand first that the fish do not develop neuroblastoma on their own. We are using a transgenic strategy, which means we are injecting the fish with the mutated or wild-type human SHP2 gene. The human SHP2 gene becomes integrated into the genome of the fish. This is called a “transgenic fish.” Then we can study how cancer develops in the transgenic fish with over expression of the mutated or wild-type SHP2 gene.

This model has been used for some time now because we have proven that pathology of neuroblastoma in Zebrafish is very similar to that of humans, and when the transgenic fish reproduce, the newly born fish carry the mutated or wild-type human SHP2 gene in all the cells. These two factors allow us to conduct studies on lots of fish very inexpensively. And, we can conduct studies that would not be possible on humans.

CureSearch: Why use Zebrafish specifically?

Dr. Zhu: We can see the tumors begin to develop in the fish very easily because Zebrafish are transparent. We begin to see neuroblastoma tumors at about 5 weeks in the fish over expressing both mutated human SHP2 gene and another human gene called MYCN, which is a known neuroblastoma oncogene. That means we can dissect the fish and review their cells before 5 weeks to begin to look for changes in the cells. We hope this will help us understand how these two oncogenes collaborate to cause the tumor formation.

CureSearch: How will this research help children with neuroblastoma?

Dr. Zhu: If we understand how the mutations and overexpression of SHP2 affects the development of neuroblastoma in our zebrafish model and what pathway mediates hyperactive SHP2 signal during these processes, then researchers can try to develop medications that inhibit, or block, the activated SHP2 pathway. Basically, that means that a child could receive a targeted therapy that kills the existing cancer cells and tells the pathway to stop over react.

Dr. Zhu will begin working on this project in early 2013 and is funded for the research by CureSearch for Children’s Cancer for two years. During the course of her grant, Dr. Zhu will provide updates on her research, and CureSearch looks forward to sharing those with you.

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