The Koschmann lab is studying the molecular mechanisms by which mutations in pediatric High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG) can be therapeutically targeted. The Koschmann Lab’s work in precision medicine pushes the boundaries of targeted therapies and precision diagnostics for children diagnosed with these brain tumors. Through highly collaborative basic, translational, and clinical research, the Koschmann Lab strives towards improving outcomes and providing hope for children fighting these devastating diseases.
Targeted Therapies for DMG and DIPG
The Koschmann lab is working to develop and understand new molecularly targeted therapies for children and young adults with DMG and DIPG, based on selection of drugs with the highest likelihood of crossing the highly selective blood brain barrier.
Their work is currently heavily focused on optimization of use and combination of the imipridone ONC201 in this patient population.
Precision Medicine for Pediatric Brain Tumors
In contrast to adult tumors, recent surveys of pediatric tumors have shown that most are driven by relatively few mutational events, many of which may be targetable with personalized clinically available agents. In collaboration with the U of M MiOncoseq Study (Dr Arul Chinnaiyan and Rajen Mody, PIs), we have an ongoing clinical sequencing study to better understand the role of personalized genomic characterization and precision oncology in the management of children with high-risk brain tumors. We discuss these results in a multi-disciplinary and multi-institutional brain tumor precision medicine conference, with a special emphasis on discussion of the CNS penetration of potential targeted agents.
Our work thus far has revealed a potentially actionable germline or tumor alteration in two-thirds of children with high-risk brain tumors which has resulted in an impact on treatment or change of diagnosis in over half of enrolled patients (Koschmann et al, JCO Precision Oncology, 2018). Ongoing collaborative work with the Koschmann lab and the MiOncoseq program is exploring tying tumor sequencing results to spinal fluid tumor DNA analysis.
Central Nervous System Targeted Agent Prediction (CNS TAP)
The number of targeted therapies utilized in precision medicine is rapidly increasing. Neuro-oncology offers a unique challenge due to the varying blood brain barrier (BBB) penetration of each agent. We have established a translational pipeline for scoring relevant targeted agents by applying multiple variables (pre-clinical data, clinical data, BBB permeability) to patient specific genomic information and clinical trial availability (Linzey et al, J Neuro Oncology, 2017). The CNS TAP is now a formalized algorithm to assist clinicians in selecting the optimal targeted therapy for neuro-oncology patients. Ongoing work in the Koschmann lab is looking at integrating the pharmacologic and BBB attributes of the most frequently used 50 agents through further in vitro and in vivo analysis of the most promising agents in neuro oncology precision medicine.
