Packaging of old pharma drugs into new packaging “nanoparticles” is called nano-pharmacology and the products are called nano-based drugs. The inception of nano-pharmacology research and development (R&D) is marked by the approval of the first nano-based drug Doxil® in 1995 by the Food and Drug Administration. However, even after more than two decades, today, there are only ∼20 nano-based drugs in the market to treat cancers and brain diseases. In this article we share the perspectives of nanotechnology scientists, engineers, and clinicians on the roadblocks in nano-pharmacology R&D. Also, we share our opinion on new frontiers in the field of nano-pharmacology R&D that may allow rapid and efficient transfer of nano-pharma technologies from R&D to market.

BACKGROUND Head Start 4 is a randomized clinical trial to determine whether dose-intensive tandem consolidation, compared with a single cycle, with autologous hematopoietic progenitor cell rescue provides a survival benefit in pediatric patients with medulloblastoma or other embryonal tumors. The trial incorporates upfront molecular subgrouping and non-mandatory, prospective blood and cerebrospinal fluid (CSF) collection. This pilot study aimed to identify exosomal non-coding RNAs (exo-ncRNAs) that might serve as novel diagnostic and/or treatment response biomarkers. METHODS CSF(1-2mLs) from 11 controls (non-tumor) and 27 medulloblastoma participants including 23 obtained at baseline, 22 at the end of induction, 3 post-consolidation, and 4 relapse time points, were profiled. Exosome isolation and small RNA-sequencing were performed by System Biosciences. Differential gene expression (DGE) was performed in R (DESeq2). Variations in gene expression profiles between samples were visualized using principal component analysis. RESULTS After limiting to ncRNAs with expression of 2 counts per million in 50% or more of the samples in each comparison, ~9,500 ncRNAs were detected. DGE analyses revealed 118 ncRNAs with log2 fold change(FC) >2 and 1 ncRNA with log2FC< -2 in baseline CSF samples compared to controls. In contrast, 11 ncRNAs(log2FC >2) and 1 ncRNA(log2FC< -2) were detected in end of induction CSF samples compared to controls. Comparing end of induction to baseline CSF samples accounting for paired samples, 0 ncRNAs(log2FC >2) and 52 ncRNAs(log2FC< -2) were detected. CONCLUSIONS Overall, our data indicate that exosomal small RNA-sequencing of limited CSF volumes is feasible. Differential expression and distinct clustering between tumor baseline samples compared to non-tumor controls was observed. CSF-derived exo-ncRNAs at end of induction also demonstrated “normalization” of ncRNA profiles, signifying CSF biomarkers may serve a role in diagnosis and molecular response assessment. A comprehensive analysis including multi-marker predictive model development and molecular subgrouping will be undertaken at completion of study enrollment.

BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults; no effective systemic therapy is available. ONC201, a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 and agonist of the mitochondrial protease ClpP. ONC201 monotherapy demonstrated durable objective responses in adults with recurrent H3 K27M-mutant glioma. This phase 1 trial will evaluate ONC201±radiotherapy (RT) in pediatric patients with H3 K27M-mutant midline glioma DIPG. METHODS This multicenter, open-label, dose escalation and expansion phase 1 study of ONC201 is comprised of eight arms that will evaluate the recommended phase 2 dose (RP2D) of ONC201, biomarkers, and pharmacokinetics (PK) of ONC201±RT in various treatment settings (NCT03416530). Arm G previously defined the RP2D for twice-weekly ONC201 on consecutive days. Arm H, for which enrollment is ongoing, will estimate the influence of tumor location and blood-brain barrier integrity on PK and intratumoral ONC201 exposure in biopsy-eligible pediatric tumors (DIPG or contrast-enhancing thalamic glioma). Patients eligible for Arm H will be aged 2-≤19 years, ≥2 weeks from last RT administration, and have a KPS/LPS ≥50; prior confirmation of H3 K27M mutation is not required. In Arm H, single-agent ONC201 administration will occur twice-weekly on consecutive days during each 21-day cycle at the RP2D defined in Arm G. Arm H has a planned enrollment of 27 patients (DIPG, n=15; thalamic glioma, n=12), with three patients undergoing a single biopsy at each of the following time points: 1-3 h post-first dose, 22-26 h post-second dose, 1-3 h post-first dose, 6-10 h post-second dose, and 22-26 h post-second dose. The 22-26 h post-first dose biopsy in thalamic glioma was previously collected and will not be assessed in this treatment arm. Plasma for PK analysis will be collected from all patients.

BACKGROUND: Meningiomas are rare primary brain tumors in the pediatric population, associated with multiple genetic mutations. Recent description of mutations in the TRAF7gene, a pro-apoptotic E3 ubiquitin ligase, have been found in up to one quarter of non NF-2 tumors. TRAF is downregulated in human keratinocytes after inhibition of the PI3K/AKT/mTOR signaling. Germ-line mutations in this gene are associated with facial, cardiac malformations, variable intellectual deficiency, and musculoskeletal abnormalities. OBJECTIVE: We report a case of meningiomatosis in an adolescent with TRAF 7 mutation. CASE PRESENTATION: A 17 yo female with complex medical history that includes syndactyly of the left foot, small hands and digits, congenital heart disease, overgrowth of the right lower extremity with lipomatous subcutaneous tumors, connective tissue disorder variant mutation of unknown significance in the gene Col11A2, conductive hearing loss developed meningiomas of both optic nerves requiring decompression and unroofing on two separate occasions, with associated blindness. MRI brain showed bilateral optic nerve sheath enhancement, dysplasia of the corpus callosum, mild hemimegalencephaly, inter-hemispheric fissure 1.5 cm meningioma, bilateral enhancement of internal auditory canals as well as trigeminal and glossopharyngeal nerve, consistent with menigiomatosis. Pathology showed a grade I meningioma with a TRAF7 p.G536S detected by performing a 500 genomic panel (UCSF500). She was started on Everolimus and Bevacizumab. CONCLUSION: Recurrent multiple meningiomas represent a treatment challenge for neuro-oncologists. The evolving understanding of the genetics of these tumors has improved our understanding of their pathogenesis as well as treatment. TRAF 7 mutations are associated with non-NF-2 meningiomas, and distinct phenotypic features. Germ-line testing should be considered in patients with associated malformations, as targeted therapy may improve patient outcomes.