Diffuse intrinsic pontine glioma (DIPG) is a universally fatal brainstem tumor with survival <1 year despite multimodal therapy. Similarly, other childhood high-grade gliomas (HGG) have a very poor prognosis with 3-year overall survival (OS) of 10-22%. Recent studies have delineated molecularly-distinct subgroups of pediatric HGG, including DIPGs, based on genomic/epigenomic features with clinical and prognostic implications. Despite these strides, radiotherapy remains the only standard therapy in pediatric HGG and DIPG, as no chemotherapeutic regimens have proven effective. This underscores an urgent need for novel therapies to improve outcome in this population. The B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) protein, widely overexpressed in many cancers, has been implicated in self-renewal of normal and cancer cells and in DNA-damage signaling. We have shown that BMI1 is highly expressed in DIPG, (regardless of molecular subtype) compared to matched normal tissue and that BMI1 downregulation leads to inhibition of i) DIPG patient-derived neurosphere cell proliferation, ii) cell- cycle signaling, iii) self-renewal, and v) DIPG cell migration. Our studies demonstrate that targeted inhibition of BMI1 sensitizes DIPG cells to radiomimetic drug-induced DNA damage. Similarly, BMI1 is highly expressed in pediatric glioblastoma (GBM) and its inhibition in in vitro and in vivo models leads to growth inhibition and cell death. Collectively, our data identify BMI1 as a potential therapeutic target for children with DIPG and HGG, setting the stage for clinical testing of BMI1 modulators such as PTC596. Pre-clinical studies from our group and others have demonstrated in vitro and in vivo efficacy of BMI1 inhibitors, PTC209 and PTC596, in HGG, and DIPG, alone and with radiomimetic agents. We propose to build on our pre-clinical studies to investigate the molecular activity and therapeutic potential of BMI1 inhibition in children with newly-diagnosed DIPG and HGG. The primary aims of this proposal are a) to determine the recommended phase II dose (RP2D) of PTC596 given concurrently with radiotherapy in children with newly- diagnosed HGG and DIPG, characterize its pharmacokinetics (PK); b) at the RP2D, to assess PTC596 intratumoral PK and its ability to inhibit BMI1 activity in tumor in newly-diagnosed DIPG/HGG children who receive PTC596 pre-resection/biopsy in a surgical molecular biology study. This study will assess BMI1 activity and PTC596 PK in tumor and cerebrospinal fluid among children with HGG and DIPG. The trial is being conducted through the Collaborative Network of Neuro-oncology Clinical Trials (CONNECT). These data will be used in the rational design of potential combination studies to improve outcome in children with DIPG and HGG.

Public Health Relevance

Pediatric high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG) are rare, have a dismal prognosis, underscoring the urgent need to develop novel therapeutic strategies to improve the outcome in children with these malignancies. The proposed phase I and surgical molecular biology study of the BMI-1 inhibitor, PTC596, will be conducted through the Collaborative Network for Neuro-oncology Clinical Trials (CONNECT). The ultimate goal is to use the data derived from this study to optimally design larger frontline studies using PTC596 in combination with radiotherapy and/or other cytotoxic or targeted therapies to improve the overall outcome in these particularly vulnerable groups of patients.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1)
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Reese, James
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Cincinnati Children's Hospital Medical Center
United States
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