Frank Szulzewsky, PhD

Research Statement

The research of our lab is focused on the functions of oncogenic drivers found in several types of both pediatric and adult brain tumors, including Glioma, Meningioma, and Supratentorial (ST) Ependymoma. Pediatric and adult tumors can differ dramatically in their genetic markup and their underlying mutations. While adult cancers frequently harbor a highly aberrant genome with gains and losses of entire chromosomal regions, the genomes of pediatric cancers are oftentimes relatively more stable and are enriched for more defined mutations, such as gene fusions. Pediatric cancers that harbor targetable gene fusions are ideal candidates for targeted therapies. However, even though clinical trials targeting gene fusions have achieved promising initial responses (such as Larotrectinib in NTRK fusion positive tumors), these effects are usually only partial, and the tumors ultimately recur due to the occurrence of resistance mutations. Our lab utilizes genetically-engineered mouse models in order to study how specific oncogenes (such as gene fusions) drive tumor development, how these tumors respond to targeted therapies in vivo, and what mechanisms of resistance lead to treatment failure and tumor recurrence in order to develop novel adjuvant therapies that can increase treatment success and survival.

YAP1 gene fusions

YAP1 gene fusions frequently occur in rare cancers (often pediatric cancers) or subtypes of more common cancers. Our work was able to show that these fusions are strong oncogenic drivers and can induce the formation of tumors that resemble the human disease when expressed in mice. Different YAP1 fusions all exert strong YAP activity that is resistant to negative inhibition by the Hippo signaling pathway (a tumor suppressive protein cascade that inhibits the activity of wild type YAP1), and thereby constitute activating YAP mutations (Szulzewsky et al, 2020, Genes & Development; Szulzewsky et al, 2022, Genes & Development). In a subsequent project, we could show that the TFE3 domains and activity significantly contributes to the oncogenic functions of YAP1::TFE3 (Cimino et al, 2025, Scientific Reports).

YAP/TAZ activity in meningioma

We are investigating the role of oncogenic YAP/TAZ activity in low-grade versus high-grade NF2 mutant meningiomas. Around half of all meningiomas harbor mutations that result in the functional loss of NF2/Merlin, resulting in the deregulation of oncogenic YAP signaling. While low-grade NF2 mutant meningiomas harbor few recurrent additional mutations, high-grade tumors exhibit a highly aberrant genome with multiple concurrent mutations, as well as gains and losses of chromosomal regions. We could recently show that high-grade NF2 mutant meningiomas actively down-regulate oncogenic YAP activity, in part by overexpressing the YAP1 antagonist VGLL4 (Parrish et al, 2024, Neuro-Oncology Advances). We are aiming to understand why aggressive meningiomas downregulate YAP1 activity and what implications this has for the treatment of these tumors.

NTRK & ALK gene fusions in pediatric glioma

Gene fusions involving receptor tyrosine kinase genes (such as NTRK and ALK) are enriched in pediatric and infantile cancers, including pediatric glioma. Similar to other gene fusion-driven tumors, these cancers harbor few additional mutations (at least in treatment naïve tumors) and are mainly driven by the oncogenic activity induced by the gene fusion. Clinical trials with targeted agents directed at these gene fusions (such as Larotrectinib and Entrectinib against NTRK fusions) show high initial overall response rates, but ultimately fail due to the occurrence of resistant tumor cells. Using the RCAS/tv-a system for somatic cell gene transfer, we have developed several NTRK and ALK gene fusion-driven glioma mouse models (Schmid et al, 2024, Cell Reports). Treatment with tyrosine kinase inhibitors induces a rapid regression of these tumors, however, similar to the human disease, therapy-resistant persister cells ultimately lead to tumor recurrence. Several factors may contribute to therapy resistance, such as low drug penetration into the brain, tumor-microenvironment interactions, and the presence of drug efflux transporters. We are currently using these models to study the biology of these tumors and their response to targeted therapy, in order to ultimately overcome treatment resistance.