panobinostat and Brain-Stem-Neoplasms

The objective of this study was to determine the safety, tolerability, and distribution of MTX110 (aqueous panobinostat) delivered by convection-enhanced delivery (CED) in patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) who completed focal radiation therapy (RT).. Patients with DIPG (2-21 years) were enrolled after RT. CED of MTX110 combined with gadoteridol was completed across 7 dose levels (DL) (30-90 µM; volumes ranging from 3 mL to 2 consecutive doses of 6 mL). An accelerated dose escalation design was used. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4-8 weeks. Quality-of-life (QoL) assessments were obtained at baseline, every 3 months on therapy, and end of therapy.. Between May 2018 and March 2020, 7 patients who received a total of 48 CED infusions, were enrolled (median age 8 years, range 5-21). Three patients experienced dose-limited toxicities. Four grade 3 treatment-related adverse events were observed. Most toxicities were transient new or worsening neurologic function. Median overall survival (OS) was 26.1 months (95% confidence interval: 14.8-not reached). Progression-free survival was 4-14 months (median, 7). Cumulative percentage of tumor coverage for combined CED infusions per patient ranged from 35.6% to 81.0%. Increased CED infusions were negatively associated with self-reported QoL assessments.. Repeat CED of MTX110 with real-time imaging with gadoteridol is tolerable for patients with DIPG. Median OS of 26.1 months compares favorably with historical data for children with DIPG. The results support further investigation of this strategy in a larger cohort.

Topics: Adolescent; Adult; Antineoplastic Agents; Brain Stem Neoplasms; Child; Child, Preschool; Convection; Diffuse Intrinsic Pontine Glioma; Glioma; Histone Deacetylase Inhibitors; Humans; Panobinostat; Quality of Life; Young Adult

Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain tumor. Mutation of p53-induced protein phosphatase 1 (PPM1D) in DIPG cells promotes tumor cell proliferation, and inhibition of PPM1D expression in DIPG cells with PPM1D mutation effectively reduces the proliferation activity of tumor cells. Panobinostat effectively kills DIPG tumor cells, but its systemic toxicity and low blood-brain barrier (BBB) permeability limits its application. In this paper, a nano drug delivery system based on functionalized macrophage exosomes with panobinostat and PPM1D-siRNA for targeted therapy of DIPG with PPM1D mutation is prepared. The nano drug delivery system has higher drug delivery efficiency and better therapeutic effect than free drugs. In vivo and in vitro experimental results show that the nano drug delivery system can deliver panobinostat and siRNA across the BBB and achieve a targeted killing effect of DIPG tumor cells, resulting in the prolonged survival of orthotopic DIPG mice. This study provides new ideas for the delivery of small molecule drugs and gene drugs for DIPG therapy.

Topics: Animals; Astrocytoma; Brain Stem Neoplasms; Diffuse Intrinsic Pontine Glioma; Exosomes; Glioma; Humans; Macrophages; Mice; Panobinostat; Protein Phosphatase 2C; RNA, Small Interfering

Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), have a dismal prognosis, with less than 2% surviving 5 years postdiagnosis. The majority of DIPGs and all DMGs harbor mutations altering the epigenetic regulatory histone tail (H3 K27M). Investigations addressing DMG epigenetics have identified a few promising drugs, including the HDAC inhibitor (HDACi) panobinostat. Here, we use clinically relevant DMG models to identify and validate other effective HDACi and their biomarkers of response.. HDAC inhibitors were tested across biopsy-derived treatment-naïve in vitro and in vivo DMG models with biologically relevant radiation resistance. RNA sequencing was performed to define and compare drug efficacy and to map predictive biomarkers of response.. Quisinostat and romidepsin showed efficacy with low nanomolar half-maximal inhibitory concentration (IC50) values (~50 and ~5 nM, respectively). Comparative transcriptome analyses across quisinostat, romidepsin, and panobinostat showed a greater degree of shared biological effects between quisinostat and panobinostat, and less overlap with romidepsin. However, some transcriptional changes were consistent across all 3 drugs at similar biologically effective doses, such as overexpression of troponin T1 slow skeletal type (TNNT1) and downregulation of collagen type 20 alpha 1 chain (COL20A1), identifying these as potential vulnerabilities or on-target biomarkers in DMG. Quisinostat and romidepsin significantly (P < 0.0001) inhibited in vivo tumor growth.. Our data highlight the utility of treatment-naïve biopsy-derived models; establishes quisinostat and romidepsin as effective in vivo; illuminates potential mechanisms and/or biomarkers of DMG cell lethality due to HDAC inhibition; and emphasizes the need for brain tumor-penetrant versions of potentially efficacious agents.

Topics: Biopsy; Brain Stem Neoplasms; Glioma; Histones; Humans; Mutation; Panobinostat

Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.

Topics: Acetylation; Animals; Antineoplastic Agents; Brain Stem Neoplasms; Carbazoles; Cell Cycle Proteins; Cell Line, Tumor; Child; Chromatin; Diffuse Intrinsic Pontine Glioma; DNA-Binding Proteins; Drug Synergism; E2F1 Transcription Factor; Epigenesis, Genetic; Epigenome; High Mobility Group Proteins; Histones; Humans; Methylation; Mice; Neuroglia; Panobinostat; Primary Cell Culture; Retinoblastoma Protein; Signal Transduction; Survival Analysis; Transcription Factors; Transcriptional Elongation Factors; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Diffuse intrinsic pontine glioma (DIPG) is one of the deadliest forms of childhood cancers. To date, no effective treatment options have been developed. Recent drug screening studies identified the HDAC inhibitor panobinostat as an active agent against DIPG cells lines and animal models. To guide in the clinical development of panobinostat, we evaluated the CNS pharmacokinetics of panobinostat using CSF as a surrogate to CNS tissue penetration in a pre-clinical nonhuman primate (NHP) model after oral administration.. CSF penetration of panobinostat after systemic delivery was low, with levels detectable in only two subjects.. The CSF penetration of panobinostat was low following oral administration in this pre-clinical NHP model predictive of human PK.

Topics: Animals; Antineoplastic Agents; Brain Stem Neoplasms; Diffuse Intrinsic Pontine Glioma; Humans; Macaca mulatta; Male; Panobinostat; Tissue Distribution

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain cancer whose median survival time is under one year. The possible roles of the two most common DIPG associated cytoplasmic ACVR1 receptor kinase domain mutants, G328V and R206H, are reexamined in the context of new biochemical results regarding their intrinsic relative ATPase activities. At 37 °C, the G328V mutant displays a 1.8-fold increase in intrinsic kinase activity over wild-type, whereas the R206H mutant shows similar activity. The higher G328V mutant intrinsic kinase activity is consistent with the statistically significant longer overall survival times of DIPG patients harboring ACVR1 G328V tumors. Based on the potential cross-talk between ACVR1 and TβRI pathways and known and predicted off-targets of ACVR1 inhibitors, we further validated the inhibition effects of several TβRI inhibitors on ACVR1 wild-type and G328V mutant patient tumor derived DIPG cell lines at 20-50 µM doses. SU-DIPG-IV cells harboring the histone H3.1K27M and activating ACVR1 G328V mutations appeared to be less susceptible to TβRI inhibition than SF8628 cells harboring the H3.3K27M mutation and wild-type ACVR1. Thus, inhibition of hidden oncogenic signaling pathways in DIPG such as TβRI that are not limited to ACVR1 itself may provide alternative entry points for DIPG therapeutics.

Topics: Activin Receptors, Type I; Benzazepines; Brain Stem Neoplasms; Cell Line, Tumor; Diffuse Intrinsic Pontine Glioma; Dose-Response Relationship, Drug; Humans; Imidazoles; Mutation; Panobinostat; Phosphotransferases; Prognosis; Protein Conformation; Pyrimidines; Quinoxalines; Receptor Cross-Talk; Receptors, Transforming Growth Factor beta

We report the synthesis of two novel platinum(ii) complexes which incorporate histone deacetylase (HDAC) inhibitors: [Pt

Topics: Antineoplastic Agents; Brain Stem Neoplasms; Cell Line, Tumor; Diffuse Intrinsic Pontine Glioma; Humans; Organoplatinum Compounds; Oxaliplatin; Panobinostat

Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD

Topics: Animals; Brain Neoplasms; Brain Stem Neoplasms; Cell Death; Cell Line, Tumor; Drug Evaluation, Preclinical; Drug Synergism; Female; Glioma; High-Throughput Screening Assays; Humans; Lactones; Male; Metabolomics; Mice; Panobinostat; Pyrroles; Reproducibility of Results; Sequence Analysis, RNA; Transcription, Genetic; Xenograft Model Antitumor Assays

OBJECTIVE The pan-histone deacetylase inhibitor panobinostat has preclinical efficacy against diffuse intrinsic pontine glioma (DIPG), and the oral formulation has entered a Phase I clinical trial. However, panobinostat does not cross the blood-brain barrier in humans. Convection-enhanced delivery (CED) is a novel neurosurgical drug delivery technique that bypasses the blood-brain barrier and is of considerable clinical interest in the treatment of DIPG. METHODS The authors investigated the toxicity, distribution, and clearance of a water-soluble formulation of panobinostat (MTX110) in a small- and large-animal model of CED. Juvenile male Wistar rats (n = 24) received panobinostat administered to the pons by CED at increasing concentrations and findings were compared to those in animals that received vehicle alone (n = 12). Clinical observation continued for 2 weeks. Animals were sacrificed at 72 hours or 2 weeks following treatment, and the brains were subjected to neuropathological analysis. A further 8 animals received panobinostat by CED to the striatum and were sacrificed 0, 2, 6, or 24 hours after infusion, and their brains explanted and snap-frozen. Tissue-drug concentration was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). Large-animal toxicity was investigated using a clinically relevant MRI-guided translational porcine model of CED in which a drug delivery system designed for humans was used. Panobinostat was administered at 30 μM to the ventral pons of 2 juvenile Large White-Landrace cross pigs. The animals were subjected to clinical and neuropathological analysis, and findings were compared to those obtained in controls after either 1 or 2 weeks. Drug distribution was determined by LC-MS/MS in porcine white and gray matter immediately after CED. RESULTS There were no clinical or neuropathological signs of toxicity up to an infused concentration of 30 μM in both small- and large-animal models. The half-life of panobinostat in rat brain after CED was 2.9 hours, and the drug was observed to be distributed in porcine white and gray matter with a volume infusion/distribution ratio of 2 and 3, respectively. CONCLUSIONS CED of water-soluble panobinostat, up to a concentration of 30 μM, was not toxic and was distributed effectively in normal brain. CED of panobinostat warrants clinical investigation in patients with DIPG.

Topics: Animals; Antineoplastic Agents; Brain Stem Neoplasms; Calcium-Binding Proteins; Chromatography, Liquid; Convection; Disease Models, Animal; Dose-Response Relationship, Drug; Glial Fibrillary Acidic Protein; Glioma; Magnetic Resonance Imaging; Male; Microfilament Proteins; Panobinostat; Phosphopyruvate Hydratase; Rats; Rats, Wistar; Swine; Tandem Mass Spectrometry; Time Factors; Tissue Distribution; Xenograft Model Antitumor Assays

Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Azepines; Brain Stem Neoplasms; Cell Cycle Proteins; Cell Proliferation; Chromatin Assembly and Disassembly; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Glioma; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Indoles; Male; Mice, Inbred NOD; Mice, SCID; Mutation; Nuclear Proteins; Panobinostat; Phenylenediamines; Primary Cell Culture; Protein Kinase Inhibitors; Pyrimidines; Receptors, Eph Family; RNA Interference; Signal Transduction; Time Factors; Transcription Factors; Transcription, Genetic; Transfection; Triazoles; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG.. A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo.. In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice.. Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.

Topics: Acetylation; Animals; Apoptosis; Brain Stem Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cerebral Cortex; Clone Cells; Genetic Engineering; Glioma; Histones; Humans; Hydroxamic Acids; Indoles; Inhibitory Concentration 50; Mice, Inbred C57BL; Panobinostat; Treatment Outcome; Xenograft Model Antitumor Assays

Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.

Topics: Animals; Benzazepines; Brain Stem Neoplasms; Disease Models, Animal; Drug Synergism; Glioma; Humans; Hydroxamic Acids; Indoles; Panobinostat; Pyrimidines; Sequence Analysis, RNA; Xenograft Model Antitumor Assays

Topics: Brain Stem Neoplasms; Child; Child, Preschool; Glioma; Humans; Hydroxamic Acids; Indoles; Panobinostat