Diffuse midline gliomas (DMGs) are the most aggressive pediatric high-grade gliomas and are the leading cause of cancer-related deaths in children. At present, there are no effective therapies for DMGs tumors, and over 90% of patients die within 1.5 years of diagnosis. In his lab, Dr. Yadav is leading efforts to understand genetic and epigenetic dependencies and signaling pathways that arise as a consequence of the H3K27M mutation in DMG. His lab performs pre-clinical studies using a novel in utero electroporation (IUE)-derived genetically engineered mouse model to identify promising candidates that can be targeted as therapy for the treatment of DMG.

1-Identifying genomic and epigenetic drivers of pediatric brain tumors with specific genetic alterations (H3K27M or H3G34R/V) using next-generation sequencing and a novel in utero electroporation (IUE) genetically engineered mouse model.

Our Lab mission is to develop more effective treatment options for children with brain tumors.

Current Research Projects:

Project 1: CAR T Cell Immunotherapy for pHGGs: Advancinganti-B7-H3 CAR T cell therapy for (pHGGs), exploring the tumor microenvironment’s influence on CAR T efficacy.

Project Overview:
• CAR T cell therapy offers new potential for treating pediatric high-grade gliomas (pHGGs), including DIPG/DMG and H3G34R/V-mutant diffuse hemispheric glioma (DHG), which currently lack effective treatments. We identified B7-H3 as a consistently overexpressed target in DHG and developed anti-B7-H3 CAR T cells that demonstrated potent, antigen-specific activity in vitro and in orthotopic DHG xenograft models, leading to significant tumor regression and improved survival.
• To further advance this strategy, we established a novel immunocompetent IUE-based mouse model of H3G34R-mutant DHG. Ongoing studies are evaluating monospecific B7-H3 and bispecific B7-H3-GD2 CAR T cells in this model and investigating the influence of the tumor microenvironment and epigenetic regulation on CAR T efficacy using RNA-seq, CUT&RUN-seq, and functional immune assays.
• Our work highlights B7-H3 CAR T therapy as a promising immunotherapeutic approach for DHG and supports its future clinical translation.

Project 2: Targeting ID1-Mediated ONC201 Resistance in H3K27M Diffuse Midline Gliomas Using Cannabidiol Combination Therapy.

Project Overview:
• Our recent studies showed that inhibiting ID1 attenuates DMG cell invasion and migration while improving survival in H3K27M-DMG mouse models. ID1 is a direct downstream target of the ACVR1 pathway and has been identified as a biomarker of ONC201 response, with high ID1 expression correlating with ONC201 resistance. ONC201, a DRD2 antagonist with clinical promise in phase II trials for DMG, induces mitochondrial stress, disrupts OXPHOS, elevates ROS, and promotes apoptosis. However, resistance to ONC201 remains a significant clinical challenge, and the underlying mechanisms remain poorly understood.
• This project aims to establish a clinically translatable therapeutic strategy combining CBD with ONC201 to overcome resistance in H3K27M-DMG. By elucidating resistance mechanisms and testing this combination, our findings will inform future clinical trials and address a critical unmet need in pediatric neuro-oncology.

Project 3: High-Throughput Drug Screening Identifies Novel Combination Therapies Targeting H3K27M-Mutant Diffuse Midline Gliomas.

Project Overview:
• To identify new treatment strategies, we conducted a high-throughput screen of 1,520 FDA-approved drugs in isogenic H3K27M-mutant DMG models, identifying 86 promising candidates. Combination screens revealed that select drugs synergize with ONC201 and enhance radiosensitivity. Using an intrauterine electroporation (IUE)-based H3K27M DMG mouse model, we are validating these combinations in vivo. This work aims to advance novel combination therapies to improve outcomes for children with DMG.

Project 4: Targeting USP1 to Overcome Therapy Resistance and Enhance Radiosensitivity in H3K27M-Mutant Diffuse Midline Gliomas

• Project Overview:
Diffuse midline gliomas (DMGs), driven by H3K27M mutations, are uniformly lethal pediatric brain tumors with limited treatment options and poor outcomes. Our studies identified ubiquitin-specific protease 1 (USP1) as a novel vulnerability in DMG. USP1 is upregulated in H3K27M-mutant tumors, and pharmacologic inhibition of USP1 reduces DMG cell proliferation, induces apoptosis, and downregulates key regulators of stemness and DNA repair. Ongoing work demonstrates that USP1 inhibition sensitizes DMG cells to ionizing radiation. Using our H3K27M DMG mouse model, we are evaluating USP1 inhibitors as radiosensitizers, aiming to develop new combination therapies for this devastating disease.