The principal investigator for this Small Research Grant is a pediatric neurosurgeon with specific interest in improving the neurological and functional outcomes (e.g. quality of life, school performance, activities of daily living) for children afflicted with Adamantinomatous Craniopharyngioma (ACP). This neurologically devastating tumor, forces children and their families to face a lifetime of chronic and profound disability. As an early stage investigator, the PI established North America's only consortium dedicated to the study of pediatric ACP, Advancing Treatment for Pediatric Craniopharyngioma (ATPC). This award will determine whether a systemically delivered monoclonal antibody reaches ACP tumor in vivo. As large molecules, these drugs would not be expected to reach brain tumors, which lie behind the blood-brain barrier. However, work by Dr. Hankinson's group and others indicates that ACP may be unique in this regard, making it accessible to these agents. If this is true, a multitude of novel agents may be used with therapeutic intent. Cytokine expression in ACP indicates a unique proinflammatory profile, raising the possibility that FDA approved medications targeting IL-6/IL-6 receptor, could control ACP growth and/or invasion. We have considerable clinical experience with the IL-6R inhibitor, Tocilizumab. Presently, there is no available assay to detect Tocilizumab in human tissue. Through collaboration between the Hankinson and Reisdorph laboratories, we derived pilot data indicating that mass spectrometric techniques will allow us to establish such an assay. This collaboration demonstrates that Drs. Hankinson, Hoffman and Reisdorph work in an environment that is ideal for the completion of the work detailed in Aim 1. In addition to Dr. Hankinson's appointment in the Skaggs School of Pharmacy, he and Dr. Hoffman work closely in the clinical management and laboratory investigation of pediatric CNS tumors. Children's Hospital Colorado has a considerable clinical research infrastructure and a record of successful study recruitment, facilitating Aim 2. Our key personnel are experts in the methods required for this award, and our infrastructure is exceptional. Tissue specimens for Aim 1 have already been obtained; we have years of expertise in mass spectrometry; and we are one of the largest clinical pediatric neuro-oncology programs in the country. Dr. Hankinson has built collaborative relationships with international leaders in ACP research, such as Dr. Juan Pedro Martinez-Barbera, who has established the only animal models of ACP. If this project does not identify Tocilizumab within ACP in vivo, we will proceed with animal studies regarding the efficacy of IL-6 blockade to determine whether these drugs offer adequate promise to merit study using more invasive delivery methods, such as intrathecal or direct intracystic delivery. If the results of this work indicate that Tocilizumab does have access to ACP tissue in vivo, then we will proceed with clinical trials to determine the efficacy of Tocilizumab, and potentially other targeted monoclonal antibodies (e.g. Siltuximab) against ACP.
Before clinical trials of Tocilizumab (an FDA approved monoclonal antibody) for patients with Adamantinomatous Craniopharyngioma (ACP) can be pursued, we must know if this drug reaches ACP in vivo. This focused proposal answers this question by: 1) establishing a reliable assay for Tocilizumab using tissue already collected through our 14-member consortium and 2) undertaking a small Phase 0 study (n=5) to assay for the presence of Tocilizumab in tissue immediately following resection by the Principal Investigator. The results may massively impact therapy for ACP by demonstrating that an entire class of large molecules can be expected to reach ACP in vivo following systemic delivery.