Research And Grants

Characterizing and Targeting ABL1 and ABL2 in Medulloblastoma Leptomeningeal Dissemination.

The molecular mechanisms that drive dissemination throughout the central nervous system (leptomeningeal dissemination) in patients with medulloblastoma (MB) are not well characterized, resulting in a nearly 100% mortality in children with recurrent leptomeningeal MB. Additionally, the presence of LD at diagnosis of MB, the most common malignant pediatric brain tumor, is an independent risk factor for poor overall survival (OS). There is currently a fundamental lack of understanding of the drivers of MB LD and thus, a lack of therapies to prevent and treat LD. For LD to occur, tumor cells must be able to proliferate in the leptomeningeal compartment.

The Abelson (ABL) family of tyrosine kinases were initially identified as genes that cause cancer in human leukemia. Our group has recently discovered ABL1 and 2 are putative drivers of MB LD. We have found that elevated ABL1 and ABL2 levels are associated with significantly worse OS in a group of 763 patients with MB. ABL1 and ABL2 are significantly elevated in patients with LD compared to patients without LD. We have also found that ABL1/2 expression is greatest in Group 3 and Group 4 MB, the MB subgroups with the highest rates of LD.

Pharmacologic inhibition of ABL1/2 results in potent cell death and decreased c-myc expression, a key driver of MB tumor development and cell proliferation in medulloblastoma cell culture. Genetic ABL1/2 knockdown also results in decreased c-myc expression. Importantly, ABL1/2 double knockdown significantly decreased proliferation, resulting in decreased LD and improved OS in mouse models. ABL1/2 inhibition with nilotinib monotherapy in vivo resulted in modest survival benefit in LD mice models. Combination therapy of specific ABL1/2 inhibition plus other multi-tyrosine kinase inhibition (nilotinib) in cell culture resulted in significantly decreased cell viability compared to either agent alone, suggesting combination therapy may further improve OS in mouse models. Notably, evaluation of the ability of ABL1 allosteric inhibitors to penetrate the BBB have not previously been undertaken.

Our overall objectives in this application are to 1) determine if genetic overexpression of ABL1 and ABL2 results in increased MB LD and 2) optimize pharmacologic inhibition of ABL1 and ABL2 in rodent models of MB LD. The long term goal is to use knowledge gained from this project to execute a Phase I clinical trial to target ABL1 and ABL2 to treat MB LD and prevent MB LD recurrence. Our central hypothesis is that 1) overexpression of ABL1 and ABL2 drive cellular proliferation in MB LD and 2) combination therapies and or direct delivery of ABL inhibitors to the central nervous system will significantly improve OS in MB LD.

At this project’s completion, our expected outcomes are to have further defined ABL1 and ABL2 as key drivers of MB and identify the most efficacious means to therapeutically inhibit ABL1 and ABL2. This data will lay the foundation for a Phase I clinical trial to prevent and treat MB LD in children.