FY27 ABL and Pediatric Glioma

ABSTRACT Brain cancer is the leading cause of death in US children, and the incidence and mortality is even greater in Kentucky children. Historically, pediatric gliomas were treated with surgery and/or radiation; however, with the recent advent of molecular sequencing, newer targeted therapies are being developed. A subset of low-grade pediatric gliomas (pLGG) and high-grade gliomas (pHGGs) are driven by activation of the MAPK pathway, which occurs via oncogenic mutation of BRAF, loss of function of NF1, or activation of receptor tyrosine kinases (RTKs). While BRAFi and BRAFi/MEKi have been FDA-approved for decades for treating metastatic melanoma, application of these drugs to glioma has only recently been initiated due to a delay in identification of key drivers. Recently, BRAF and MEK inhibitors (BRAFi, MEKi; MAPKi) were FDA-approved for treating pLLG, and show promise for pHGG. While tolerated better than cytotoxic drugs, BRAFi and MEKi are cytostatic, and thus, not curative. Moreover, some patients do not respond due to intrinsic resistance and others develop resistance. Thus, it is important to identify factors driving drug insensitivity in order to develop cytotoxic combinations that induce a durable response. The ABL family of tyrosine kinases (ABL1, ABL2) is most known for driving the development of human leukemia, FDA-approved, targeted drugs are used to treat these diseases. However, we and others showed that ABL kinases also play critical roles in solid tumors. For example, ABL kinases are activated in melanomas that develop resistance to BRAFi and BRAFi/MEKi, and ABL1/2 inhibition not only reverses resistance but also prevents resistance from developing in the first place, in vivo. Since pediatric gliomas are now being treated with BRAFi and BRAFi/MEKi, we tested whether ABL1/2 mediate MAPKi insensitivity in pediatric gliomas. Indeed, ABL1/2 inhibition with nilotinib, reduces glioma viability and cooperates with MAPKi. Moreover, a highly specific ABL1/2 allosteric inhibitor, GNF-5 also kills glioma cells on its own and is even more effective when combined with BRAFi/MEKi or DDR1i (another target of nilotinib). Importantly, ABL1/2 inhibition also is remarkably effective in glioma cells that have acquired BRAFi or BRAFi/MEKi resistance. Based on these exciting findings, we hypothesize that ABL1/2 are activated in pediatric gliomas driven by MAPK signaling, and serve as key nodes in intrinsic/acquired MAPKi resistance pathways. Thus, targeting ABL1/2 in combination with BRAFi and/or MEKi, may be an effective treatment strategy. To test this hypothesis, we will: 1) Identify the contexts leading to ABL1/2 activation in pediatric glioma (Aim 1); 2) Define signaling pathways utilized by ABL1/2 to drive MAPKi insensitivity (Aim 2); and 3) Test the efficacy of targeting ABL1/2, in vivo (Aim 3). This proposal is collaboration between a basic scientist with decades experience studying tyrosine kinases, neuro-oncologists that treat children with brain cancer, a neuropathologist that diagnoses glioma, and a neuroscientist experienced with intracranial injections. If successful, this project will further examine the efficacy of targeting ABL1/2 in pediatric glioma with the long-term goal of clinical testing.