One of our newest faculty members, Frank Szulzewsky, PhD, is a neuro-oncologist currently studying the driving biology and mechanisms of common brain tumor types found in children and adults, including meningiomas and gliomas. Dr. Szulzewsky and his team study how different types of oncogenes, genes that have the potential to cause cancer, drive tumor formation and progression in several cancer types.
One such oncogene is YAP1, a protein that promotes stemness and proliferation of cells. YAP1 affects the formation and growth of pediatric-type meningiomas and other brain tumors. In childhood tumors YAP1 is sometimes fused to other genes. When fused with specific genes, YAP1 can become dysregulated and
promote the transformation of healthy cells into cancerous cells. Dr. Szulzewsky, alongside an international team, cloned the coding sequences of several different YAP1 gene fusions (occurring in meningiomas, ependymomas, and angiosarcoma) and found that all four were capable of promoting tumor formation when expressed in mice. He was also able to determine more of the function and mechanisms behind these different YAP1 gene fusions and identified a potential therapeutic approach.
In other tumor types, such as adult-type meningiomas, YAP1 is also important but is often dysregulated through other mechanisms (e.g., through the loss of NF2, a suppressor of YAP1). Meningiomas are frequently benign but can recur, making them difficult to treat, especially when they are found near critical blood vessels or nerves that make complete resection difficult. Dr. Szulzewsky said, “Our understanding of the genetic mutations driving tumor growth of different meningioma subgroups has advanced, but especially for aggressive tumors there is little progress for effective chemotherapies. We’re beginning to put the pieces together to create a full picture of what is driving tumor growth, how we can slow it down, and, eventually, how we can stop it entirely.”
In the course of their work, Dr. Szulzewsky and his team found a link between the genetic makeup of a specific meningioma sample and the patient’s outcome, including recurrence. The team used Oncoscape, a web-based interactive tool that allows researchers to visualize and analyze large-scale tumor sequencing data to identify activated oncogenic pathways in specific meningioma subgroups.
NF2 mutations (that lead to dysregulation of YAP1) are present in about half of all meningioma and occur in both benign and aggressive tumors. Dr. Szulzewsky analyzed the levels of YAP1 activity in benign and aggressive NF2 mutant meningiomas and observed that aggressive tumors actively down-regulate YAP1. They are now studying how this finding may impact the efficacy of therapies targeting the YAP1 protein.
Although much of Dr. Szulzewsky’s work to date centers around meningiomas, he is interested in pediatric-type gliomas, which are also frequently driven by oncogenic gene fusions. In a recent study, the team modeled pediatric-type gliomas to see how they responded to targeted therapies. The therapies were promising and slowed the growth of tumors but didn't eradicate them, allowing them to recur when the treatment was stopped.
“We really want to know what else is keeping the tumors alive, and how we can target these drivers to both slow the growth and eradicate these tumors so they do not recur,” Dr. Szulzewsky shared. His goal is to identify whether it will be possible to find a common treatment strategy for all tumors with these gene fusions, or if it will be necessary to specifically tailor treatments to the individual tumors.
We’re thrilled to have Dr. Szulzewsky as part of our team, and welcome the opportunity to join with him in bringing this research to light.