The role of Vascular Endothelial Growth Factor in CNS manifestation of pediatric acute lymphoblastic leukemia

• Applicant: Dr. Vera Münch
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535729637

The effective treatment of the central nervous system (CNS) is still the major obstacle in the therapy of acute lymphoblastic leukemia (ALL) patients. Although cure rates for ALL patients reach up to 90%, patients initially diagnosed with CNS involvement and patients relapsing within the CNS show an adverse outcome. At initial diagnosis 3-5% of patients present with CNS disease, though, to prevent CNS relapse, CNS-directed therapy is needed in all patients independent of their initial CNS status. This rigorous CNS-directed treatment strategy comes along with non-ALL related secondary cancers and neurocognitive deficits. To reduce these late sequelae and to develop novel, less toxic CNS-directed treatment strategies the molecular mechanisms leading ALL manifestation within the CNS need to be understood. CNS leukemia is defined as a leptomeningeal disease and the underlining processes of leukemia cell migration towards, entry into, and proliferation within the CNS are unknown. There is limited access to cerebrospinal fluid of CNS-positive patients, which makes patient-derived xenograft (PDX) mouse models valuable systems to be used to preclinically study (CNS) ALL biology. In a previous work I xenotransplanted various PDX samples onto NOD/SCID mice and analyzed gene expression differences between CNS- and bone marrow (BM)-derived ALL cells. Besides a gene expression signature associated to hypoxia and the Vascular Endothelial Growth Factor (VEGF), I identified other genes (ABCA1, ABCG1, CPT1A) associated to lipid- and cholesterol homeostasis of cells to be deregulated in CNS-derived ALL cells. Further, I showed VEGF to be an important mediator in the transmigration of leukemia cells through brain endothelial cells as shown in vitro and in vivo. Importantly, deregulated expression of VEGF and lipid-/cholesterol-regulators in CNS-derived ALL cells was additionally identified in a recent study analyzing the capacity of leukemia cells to metabolically adapt to the nutrient- and oxygen-low CNS microenvironment (Savino et. al, 2020; Cousins et. Al 2022). This emphasizes the role of these genes in CNS disease, though their exact function in supporting leukemia cell transmigration and/or adaptation remains unknown. Within this project the specific role of these genes in CNS disease with particular focus on transmigration into and adaption to the CNS milieu of ALL cells will be studied. First, I will perform in vitro and in vivo analyses to preclinically assess the therapeutic potential in blocking VEGF/VEGFR2 signaling. Further, I will analyze the function of these genes in terms to metabolically adapt to the CNS microenvironment to finally evaluate novel CNS-directed treatment strategies in vivo.

• DFG Programme: Research Grants