FUS Etoposide for DMG

Inclusion Criteria:

* Ages 4 - 21 years
* Radiological diagnosis of Diffuse Midline Glioma with tumor involving the pons (intrinsic, pontine based infiltrative lesion; hypointense on T1 weighted images (T1WIs) and hyperintense in T2 sequences, with mass effect on the adjacent structures and occupying at least 50% of the pons), thalami, and/or histological confirmation of H3K27M mutation of pontine or thalamic glioma. Subjects must have evidence of clinical and/or radiographic progression of disease.
* Lansky performance status score of at least 60 for subjects 16 years of age or younger.
* Karnofsky performance status of at least 60 for subjects greater than 16 years of age
* Organ Function:

  * Adequate hematologic function defined as:

    * Peripheral absolute neutrophil count ≥ 1,500/µL
    * Platelet count ≥ 100,000/µL
    * Partial thromboplastin time (PTT) and activated partial thromboplastin time (APTT): within normal institutional limits
  * Adequate renal function defined as:

    * Potassium and magnesium levels within institutional limits
    * Serum creatinine below the institutional upper limit of normal (ULN) for age and gender, or creatinine clearance: ≥ 60 mL/min/1.73m2
  * Adequate hepatic function defined as:

    * Total bilirubin below the institutional ULN for age
    * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × institutional ULN
* Prior Therapy:

  * Subjects must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment.
  * Cytotoxic chemotherapy or anti-cancer agents known to be myelosuppressive: at least 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy.
  * Anti-cancer agents not known to be myelosuppressive: at least 7 days must have elapsed from last dose of agent.
  * Antibodies: at least 21 days must have elapsed from infusion of last dose of antibody.
  * Interleukins, interferons, and cytokines: at least 21 days must have elapsed since the completion of interleukins, interferon, or cytokines.
  * Stem cell infusions: at least 42 days must have elapsed after completion of an autologous stem cell infusion, and at least 84 days must have elapsed after completion of an allogeneic stem cell infusion.
  * Cellular therapy: at least 42 days must have elapsed since the completion of any type of cellular therapy
  * Radiotherapy (XRT): at least 1 month must have elapsed after local XRT.
  * Subjects must be on a stable or decreasing dose of steroids, as well as stable dose of anti-seizure medication for at least 1 week.
* Subject able to give consent

Exclusion Criteria:

* Subjects that have previously received etoposide therapy
* Subjects unable to tolerate study procedures and/or anesthesia based on the opinion of the principal investigator
* Uncontrolled seizure disorder
* Pregnancy or Breast-Feeding: pregnant or breast-feeding women will not be entered on this study, since there is yet no available information regarding human fetal or teratogenic toxicities; a pregnancy test must be obtained in girls who are post-menarchal. Males with female partners of reproductive potential or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control- including a medically accepted barrier method of contraception (e.g., a male or female condom) for the entire period in which they are receiving protocol therapy and for at least 1 month following their last study treatment requirement. Abstinence is an acceptable method of birth control. Women of childbearing potential will be provided a routine quantitative beta-human chorionic gonadotropin (B-hCG) test during the pre-study phase, prior to enrollment and each cycle.
* Concomitant medications: subjects who are currently receiving another investigational drug or other anti-cancer agents are not eligible.
* Screening EKG with a QTc \> 450 msec.
* Subjects with evidence of active systemic infection
* Subjects with a documented allergy to compounds of similar chemical or biologic composition to etoposide or gadolinium compounds
* Subjects with implanted metallic or electrical devices
* Subjects with uncontrollable hypertension
* Subjects with a documented bleeding disorder
* Subjects with history of structural cardiac anomalies or arrhythmias
* Subjects with history of unprovoked stroke or signs of stroke in the area of FUS target
* Subjects with SARS-CoV-2 infection requiring hospitalization in the past month and requires anticoagulation as per the Columbia University Irving Medical Center (CUIMC) institutional "Anticoagulation for COVID-19 Positive Pediatric Inpatients" guidelines (See Appendix B)
* Subjects with coagulopathy or under anticoagulant therapy.
* Subjects with signs of impending herniation or an acute or previous intratumoral hemorrhage
* Subjects with spinal cord diffuse midline glioma
* Subjects receiving a drug where CNS toxicity is reasonably suspected