ABSTRACT
Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma - DIPG), is the primary cause of brain tumor-related death in pediatric patients. DIPG is characterized by a median survival of <12 months from diagnosis, harboring the worst 5-year survival rate of any cancer. Corticosteroids and radiation are the mainstay of therapy; however, they only provide transient relief from the devastating neurological symptoms. Numerous therapies have been investigated for DIPG, but the majority have been unsuccessful in demonstrating a survival benefit beyond radiation alone. Although many barriers hinder brain drug delivery in DIPG, one of the most significant challenges is the blood-brain barrier (BBB). Therapeutic compounds must possess specific properties to enable efficient passage across the BBB. In brain cancer, the BBB is referred to as the blood-brain tumor barrier (BBTB), where tumors disrupt the structure and function of the BBB, which may provide opportunities for drug delivery. However, the biological characteristics of the brainstem's BBB/BBTB, both under normal physiological conditions and in response to DIPG, are poorly understood, which further complicates treatment. Better characterization of the changes that occur in the BBB/BBTB of DIPG patients is essential, as this informs future treatment strategies. Many novel drug delivery technologies have been investigated to bypass or disrupt the BBB/BBTB, including convection enhanced delivery, focused ultrasound, nanoparticle-mediated delivery, and intranasal delivery, all of which are yet to be clinically established for the treatment of DIPG. Herein, we review what is known about the BBB/BBTB and discuss the current status, limitations, and advances of conventional and novel treatments to improving brain drug delivery in DIPG.
Subject(s)
Antineoplastic Agents , Blood-Brain Barrier , Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Drug Delivery Systems , Humans , Brain Stem Neoplasms/drug therapy , Animals , Diffuse Intrinsic Pontine Glioma/drug therapy , Drug Delivery Systems/methods , Blood-Brain Barrier/metabolism , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacokinetics , Glioma/drug therapyABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is a childhood malignancy of the brainstem with a dismal prognosis. Despite recent advances in its understanding at the molecular level, the prognosis of DIPG has remained unchanged. This article aims to review the current understanding of the genetic pathophysiology of DIPG and to highlight promising therapeutic targets. Various DIPG treatment strategies have been investigated in pre-clinical studies, several of which have shown promise and have been subsequently translated into ongoing clinical trials. Ultimately, a multifaceted therapeutic approach that targets cell-intrinsic alterations, the micro-environment, and augments the immune system will likely be necessary to eradicate DIPG.
Subject(s)
Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Humans , Diffuse Intrinsic Pontine Glioma/genetics , Diffuse Intrinsic Pontine Glioma/therapy , Diffuse Intrinsic Pontine Glioma/pathology , Diffuse Intrinsic Pontine Glioma/drug therapy , Brain Stem Neoplasms/genetics , Brain Stem Neoplasms/therapy , Brain Stem Neoplasms/pathology , Brain Stem Neoplasms/drug therapy , Prognosis , Tumor Microenvironment , Molecular Targeted Therapy/methodsABSTRACT
PURPOSE: Pediatric diffuse intrinsic pontine glioma (DIPG) is a fatal disease associated with a median survival of < 1 year despite aggressive treatments. This retrospective study analyzed the treatment outcomes of patients aged < 18 years who were diagnosed with DIPG between 2012 and 2022 and who received different chemotherapy regimens. METHODS: After radiotherapy, patients with DIPG received nimotuzumab-vinorelbine combination or temozolomide-containing therapy. When nimotuzumab was unavailable, it was replaced by vincristine, etoposide, and carboplatin/cyclophosphamide (VECC). Temozolomide was administered as a single agent or a part of the combination chemotherapy comprising temozolomide, irinotecan, and bevacizumab. Furthermore, 1- and 3-year overall survival (OS), progression-free survival (PFS), and median OS and PFS were analyzed. RESULTS: The median age of 40 patients with DIPG was 97 ± 46.93 (23-213) months; the median follow-up time was 12 months. One and 3-year OS were 35.0% and 7.5%, respectively. Median OS was 12 months in all patients (n = 40), and it was 16, 10, and 11 months in those who received first-line nimotuzumab-vinorelbine combination (n = 13), temozolomide-based (n = 14), and VECC (n = 6) chemotherapy regimens, respectively (p = 0.360). One patient who received gefitinib survived for 16 months. Conversely, patients who never received radiotherapy and any antineoplastic medicamentous therapy (n = 6) had a median OS of 4 months. CONCLUSION: Nimotuzumab-vinorelbine combination therapy prolonged OS by 6 months compared with temozolomide-containing chemotherapy, although the difference was not statistically significant.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Humans , Female , Child , Male , Brain Stem Neoplasms/drug therapy , Child, Preschool , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Adolescent , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Diffuse Intrinsic Pontine Glioma/drug therapy , Temozolomide/therapeutic use , Temozolomide/administration & dosage , Vinblastine/administration & dosage , Vinblastine/therapeutic use , Vinblastine/analogs & derivatives , Infant , Treatment OutcomeABSTRACT
Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy.
Subject(s)
Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Glioma , Metformin , Humans , Mice , Animals , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/genetics , Phosphatidylinositol 3-Kinases/genetics , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/genetics , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , TOR Serine-Threonine Kinases/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Glucose , Metformin/pharmacology , Tumor MicroenvironmentABSTRACT
Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. On the basis of these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Because radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of Ataxia Telangiectasia Mutated to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.
Subject(s)
Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Humans , Child , Mice , Animals , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/genetics , Diffuse Intrinsic Pontine Glioma/metabolism , Neoplasm Recurrence, Local , DNA Repair , Signal Transduction , DNA/therapeutic use , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/genetics , Brain Stem Neoplasms/pathologyABSTRACT
Diffuse intrinsic pontine gliomas (DIPG) are an aggressive type of pediatric brain tumor with a very high mortality rate. Surgery has a limited role given the tumor's location. Palliative radiation therapy alleviates symptoms and prolongs survival, but median survival remains less than 1 year. There is no clear role for chemotherapy in DIPGs as trials adding chemotherapy to palliative radiation therapy have failed to improve survival compared to radiation alone. Thus, there is a critical need to identify tissue-specific radiosensitizers to improve clinical outcomes for patients with DIPGs. Pharmacologic (high dose) ascorbate (P-AscH-) is a promising anticancer therapy that sensitizes human tumors, including adult high-grade gliomas, to radiation by acting selectively as a generator of hydrogen peroxide (H2O2) in cancer cells. In this study we demonstrate that in contrast to adult glioma models, P-AscH- does not radiosensitize DIPG. DIPG cells were sensitive to bolus of H2O2 but have faster H2O2 removal rates than GBM models which are radiosensitized by P-AscH-. These data support the hypothesis that P-AscH- does not enhance DIPG radiosensitivity, likely due to a robust capacity to detoxify and remove hydroperoxides.
Subject(s)
Antineoplastic Agents , Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Glioma , Child , Adult , Humans , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/pathology , Brain Stem Neoplasms/radiotherapy , Brain Stem Neoplasms/pathology , Peroxides/therapeutic use , Hydrogen Peroxide/pharmacology , Hydrogen Peroxide/therapeutic use , Glioma/radiotherapy , Glioma/pathology , Antineoplastic Agents/therapeutic useABSTRACT
Diffuse intrinsic pontine gliomas (DIPG) are an incurable childhood brain cancer for which novel treatments are needed. DIPGs are characterized by a mutation in the H3 histone (H3K27M), resulting in loss of H3K27 methylation and global gene dysregulation. TRX-E-009-1 is a novel anticancer agent with preclinical activity demonstrated against a range of cancers. We examined the antitumor activity of TRX-E-009-1 against DIPG neurosphere cultures and observed tumor-specific activity with IC50s ranging from 20 to 100 nmol/L, whereas no activity was observed against normal human astrocyte cells. TRX-E-009-1 exerted its anti-proliferative effect through the induction of apoptotic pathways, with marked increases in cleaved caspase 3 and cleaved PARP levels, while also restoring histone H3K27me3 methylation. Co-administration of TRX-E-009-1 and the histone deacetylase (HDAC) inhibitor SAHA extended survival in DIPG orthotopic animal models. This antitumor effect was further enhanced with irradiation. Our findings indicate that TRX-E-009-1, combined with HDAC inhibition, represents a novel, potent therapy for children with DIPG.
Subject(s)
Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Glioma , Child , Animals , Humans , Histones/metabolism , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/genetics , Diffuse Intrinsic Pontine Glioma/pathology , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/genetics , Brain Stem Neoplasms/pathology , Glioma/drug therapy , Glioma/genetics , Glioma/metabolism , Histone Deacetylases/genetics , Cell Line, Tumor , Mutation , Microtubules/metabolismABSTRACT
Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and confers a poor prognosis. While therapeutic histone deacetylase (HDAC) inhibition of diffuse intrinsic pontine glioma (DIPG) has been reported; here, we use a clinically relevant biopsy-derived hypermutant DIPG model (PBT-24FH) and a CRISPR-Cas9 induced genetic model to evaluate the efficacy of HDAC inhibition against hypermutant DIPG. We screened PBT-24FH cells for sensitivity to a panel of HDAC inhibitors (HDACis) in vitro, identifying two HDACis associated with low nanomolar IC50s, quisinostat (27 nM) and romidepsin (2 nM). In vivo, quisinostat proved more efficacious, inducing near-complete tumor regression in a PBT-24FH flank model. RNA sequencing revealed significant quisinostat-driven changes in gene expression, including upregulation of neural and pro-inflammatory genes. To validate the observed potency of quisinostat in vivo against additional hypermutant DIPG models, we tested quisinostat in genetically-induced mismatch repair (MMR)-deficient DIPG flank tumors, demonstrating that loss of MMR function increases sensitivity to quisinostat in vivo. Here, we establish the preclinical efficacy of quisinostat against hypermutant DIPG, supporting further investigation of epigenetic targeting of hypermutant pediatric cancers with the potential for clinical translation. These findings support further investigation of HDAC inhibitors against pontine high-grade gliomas, beyond only those with histone mutations, as well as against other hypermutant central nervous system tumors.
Subject(s)
Diffuse Intrinsic Pontine Glioma , Glioma , Humans , Child , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/genetics , Histone Deacetylase Inhibitors/pharmacology , Histones , Hydroxamic Acids , Glioma/drug therapy , Glioma/geneticsABSTRACT
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat is an oral multihistone deacetylase inhibitor with preclinical activity in DIPG models. Study objectives were to determine safety, tolerability, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of panobinostat in children with DIPG. PATIENTS AND METHODS: In stratum 1, panobinostat was administered 3 days per week for 3 weeks on, 1 week off to children with progressive DIPG, with dose escalation following a two-stage continual reassessment method. After this MTD was determined, the study was amended to evaluate the MTD in children with nonprogressive DIPG/Diffuse midline glioma (DMG) (stratum 2) on an alternate schedule, 3 days a week every other week in an effort to escalate the dose. RESULTS: For stratum 1, 19 subjects enrolled with 17/19 evaluable for dose-finding. The MTD was 10 mg/m2/dose. Dose-limiting toxicities included thrombocytopenia and neutropenia. Posterior reversible encephalopathy syndrome was reported in 1 patient. For stratum 2, 34 eligible subjects enrolled with 29/34 evaluable for dose finding. The MTD on this schedule was 22 mg/m2/dose. DLTs included thrombocytopenia, neutropenia, neutropenia with grade 4 thrombocytopenia, prolonged intolerable nausea, and increased ALT. CONCLUSIONS: The MTD of panobinostat is 10 mg/m2/dose administered 3 times per week for 3 weeks on/1 week off in children with progressive DIPG/DMG and 22 mg/m2/dose administered 3 times per week for 1 week on/1 week off when administered in a similar population preprogression. The most common toxicity for both schedules was myelosuppression.
Subject(s)
Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Glioma , Neutropenia , Posterior Leukoencephalopathy Syndrome , Thrombocytopenia , Child , Humans , Panobinostat/pharmacokinetics , Diffuse Intrinsic Pontine Glioma/drug therapy , Glioma/drug therapy , Glioma/pathology , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/pathologyABSTRACT
BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Subject(s)
Antineoplastic Agents , Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Glioma , Humans , Child , Child, Preschool , Adolescent , Young Adult , Adult , Panobinostat/therapeutic use , Antineoplastic Agents/therapeutic use , Diffuse Intrinsic Pontine Glioma/drug therapy , Brain Stem Neoplasms/pathology , Quality of Life , Convection , Glioma/pathology , Histone Deacetylase Inhibitors/therapeutic useABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is an aggressive incurable brainstem tumor that targets young children. Complete resection is not possible, and chemotherapy and radiotherapy are currently only palliative. This study aimed to identify potential therapeutic agents using a computational pipeline to perform an in silico screen for novel drugs. We then tested the identified drugs against a panel of patient-derived DIPG cell lines. Using a systematic computational approach with publicly available databases of gene signature in DIPG patients and cancer cell lines treated with a library of clinically available drugs, we identified drug hits with the ability to reverse a DIPG gene signature to one that matches normal tissue background. The biological and molecular effects of drug treatment was analyzed by cell viability assay and RNA sequence. In vivo DIPG mouse model survival studies were also conducted. As a result, two of three identified drugs showed potency against the DIPG cell lines Triptolide and mycophenolate mofetil (MMF) demonstrated significant inhibition of cell viability in DIPG cell lines. Guanosine rescued reduced cell viability induced by MMF. In vivo, MMF treatment significantly inhibited tumor growth in subcutaneous xenograft mice models. In conclusion, we identified clinically available drugs with the ability to reverse DIPG gene signatures and anti-DIPG activity in vitro and in vivo. This novel approach can repurpose drugs and significantly decrease the cost and time normally required in drug discovery.
Subject(s)
Astrocytoma , Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Glioma , Humans , Mice , Animals , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/genetics , Mycophenolic Acid/therapeutic use , Glioma/drug therapy , Glioma/genetics , Glioma/metabolism , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/genetics , Brain Stem Neoplasms/pathology , Gene Expression , Guanosine/therapeutic useABSTRACT
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.
Subject(s)
Diffuse Intrinsic Pontine Glioma , Exosomes , Glioma , Protein Phosphatase 2C , RNA, Small Interfering , Animals , Astrocytoma/drug therapy , Astrocytoma/genetics , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/genetics , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/genetics , Exosomes/chemistry , Exosomes/genetics , Glioma/drug therapy , Glioma/genetics , Humans , Macrophages/chemistry , Macrophages/metabolism , Mice , Panobinostat/therapeutic use , Protein Phosphatase 2C/genetics , Protein Phosphatase 2C/therapeutic use , RNA, Small Interfering/genetics , RNA, Small Interfering/therapeutic useABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor. While there are a number of in vivo rodent models for evaluating tumor biology and response to therapy, these models require significant time and resources. Here, we established the chick-embryo chorioallantoic (CAM) assay as an affordable and time efficient xenograft model for testing a variety of treatment approaches for DIPG. We found that patient-derived DIPG tumors develop in the CAM and maintain the same genetic and epigenetic characteristics of native DIPG tumors. We monitored tumor response to pharmaco- and radiation therapy by 3-D ultrasound volumetric and vasculature analysis. In this study, we established and validated the CAM model as a potential intermediate xenograft model for DIPG and its use for testing novel treatment approaches that include pharmacotherapy or radiation.
Subject(s)
Antineoplastic Agents/pharmacology , Brain Stem Neoplasms/genetics , Chorioallantoic Membrane/drug effects , Chorioallantoic Membrane/radiation effects , Diffuse Intrinsic Pontine Glioma/genetics , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/pathology , Brain Stem Neoplasms/radiotherapy , Cell Line, Tumor , Chick Embryo , Chorioallantoic Membrane/pathology , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/pathology , Diffuse Intrinsic Pontine Glioma/radiotherapy , Humans , Rats , Ultrasonography , Xenograft Model Antitumor AssaysABSTRACT
PURPOSE: Crizotinib, a potent oral tyrosine kinase inhibitor, was evaluated in combination with dasatinib in a phase 1 trial (NCT01644773) in children with progressive or recurrent high-grade and diffuse intrinsic pontine gliomas (HGG and DIPG). This study aimed to characterize the pharmacokinetics of crizotinib in this population and identify significant covariates. METHODS: Patients (N = 36, age range 2.9-21.3 years) were treated orally once or twice-daily with 100-215 mg/m2 crizotinib and 50-65 mg/m2 dasatinib. Pharmacokinetic studies were performed for crizotinib alone after the first dose and at steady state, and for the drug combination at steady state. Crizotinib plasma concentrations were measured using a validated LC-MS/MS method. Population modeling was performed (Monolix) and the impact of factors including patient demographics and co-medications were investigated on crizotinib pharmacokinetics. RESULTS: Crizotinib concentrations were described with a linear two-compartment model and absorption lag time. Concomitant dasatinib and overweight/obese status significantly influenced crizotinib pharmacokinetics, resulting in clinically relevant impact (> 20%) on drug exposure. Crizotinib mean apparent clearance (CL/F) was 66.7 L/h/m2 after single-dose and decreased to 26.5 L/h/m2 at steady state when given alone, but not when combined with dasatinib (mean 60.8 L/h/m2). Overweight/obese patients exhibited lower crizotinib CL/F and apparent volume V1/F (mean 46.2 L/h/m2 and 73.3 L/m2) compared to other patients (mean 75.5 L/h/m2 and 119.3 L/m2, p < 0.001). CONCLUSION: A potential pharmacokinetic interaction was observed between crizotinib and dasatinib in children with HGG and DIPG. Further, crizotinib exposure was significantly higher in overweight/obese patients, who may require a dosing adjustment.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Brain Stem Neoplasms/drug therapy , Crizotinib/pharmacokinetics , Diffuse Intrinsic Pontine Glioma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adolescent , Adult , Antineoplastic Agents/administration & dosage , Brain Stem Neoplasms/metabolism , Brain Stem Neoplasms/pathology , Child , Child, Preschool , Crizotinib/administration & dosage , Diffuse Intrinsic Pontine Glioma/metabolism , Diffuse Intrinsic Pontine Glioma/pathology , Female , Follow-Up Studies , Humans , Male , Maximum Tolerated Dose , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Prognosis , Tissue Distribution , Young AdultABSTRACT
OBJECTIVE: Delivery of drugs intraarterially to brain tumors has been demonstrated in adults. In this study, the authors initiated a phase I trial of superselective intraarterial cerebral infusion (SIACI) of bevacizumab and cetuximab in pediatric patients with refractory high-grade glioma (diffuse intrinsic pontine glioma [DIPG] and glioblastoma) to determine the safety and efficacy in this population. METHODS: SIACI was used to deliver mannitol (12.5 ml of 20% mannitol) to disrupt the blood-brain barrier (BBB), followed by bevacizumab (15 mg/kg) and cetuximab (200 mg/m2) to target VEGF and EGFR, respectively. Patients with brainstem tumors had a balloon inflated in the distal basilar artery during mannitol infusion. RESULTS: Thirteen patients were treated (10 with DIPG and 3 with high-grade glioma). Toxicities included grade I epistaxis (2 patients) and grade I rash (2 patients). There were no dose-limiting toxicities. Of the 10 symptomatic patients, 6 exhibited subjective improvement; 92% showed decreased enhancement on day 1 posttreatment MRI. Of 10 patients who underwent MRI at 1 month, 5 had progressive disease and 5 had stable disease on FLAIR, whereas contrast-enhanced scans demonstrated progressive disease in 4 patients, stable disease in 2, partial response in 2, and complete response in 1. The mean overall survival for the 10 DIPG patients was 519 days (17.3 months), with a mean posttreatment survival of 214.8 days (7.2 months). CONCLUSIONS: SIACI of bevacizumab and cetuximab was well tolerated in all 13 children. The authors' results demonstrate safety of this method and warrant further study to determine efficacy. As molecular targets are clarified, novel means of bypassing the BBB, such as intraarterial therapy and convection-enhanced delivery, become more critical. Clinical trial registration no.: NCT01884740 (clinicaltrials.gov).
Subject(s)
Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/therapeutic use , Bevacizumab/administration & dosage , Bevacizumab/therapeutic use , Blood-Brain Barrier/drug effects , Brain Stem Neoplasms/drug therapy , Cetuximab/administration & dosage , Cetuximab/therapeutic use , Diffuse Intrinsic Pontine Glioma/drug therapy , Adolescent , Antineoplastic Agents, Immunological/adverse effects , Bevacizumab/adverse effects , Brain Stem Neoplasms/diagnostic imaging , Cetuximab/adverse effects , Child , Child, Preschool , Diffuse Intrinsic Pontine Glioma/diagnostic imaging , Drug Delivery Systems , Female , Glioblastoma/drug therapy , Humans , Injections, Intra-Arterial , Magnetic Resonance Imaging , Male , Survival Analysis , Treatment OutcomeABSTRACT
Diffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, afflicts approximately 350 new patients each year in the United States. DIPG is noted for its lethality, as fewer than 1% of patients survive to five years. Multiple clinical trials involving chemotherapy, radiotherapy, and/or targeted therapy have all failed to improve clinical outcomes. Recently, high-throughput sequencing of a cohort of DIPG samples identified potential therapeutic targets, including interleukin 13 receptor subunit alpha 2 (IL13Rα2) which was expressed in multiple tumor samples and comparably absent in normal brain tissue, identifying IL13Rα2 as a potential therapeutic target in DIPG. In this work, we investigated the role of IL13Rα2 signaling in progression and invasion of DIPG and viability of IL13Rα2 as a therapeutic target through the use of immunoconjugate agents. We discovered that IL13Rα2 stimulation via canonical ligands demonstrates minimal impact on both the cellular proliferation and cellular invasion of DIPG cells, suggesting IL13Rα2 signaling is non-essential for DIPG progression in vitro. However, exposure to an anti-IL13Rα2 antibody-drug conjugate demonstrated potent pharmacological response in DIPG cell models both in vitro and ex ovo in a manner strongly associated with IL13Rα2 expression, supporting the potential use of targeting IL13Rα2 as a DIPG therapy. However, the tested ADC was effective in most but not all cell models, thus selection of the optimal payload will be essential for clinical translation of an anti-IL13Rα2 ADC for DIPG.
Subject(s)
Brain Stem Neoplasms/metabolism , Diffuse Intrinsic Pontine Glioma/metabolism , Drug Design , Immunoconjugates/administration & dosage , Immunoconjugates/metabolism , Interleukin-13 Receptor alpha2 Subunit/metabolism , Animals , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/pathology , Cell Proliferation/drug effects , Cell Proliferation/physiology , Coturnix , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/pathology , Dose-Response Relationship, Drug , Humans , Interleukin-13/administration & dosage , Interleukin-13/metabolism , Interleukin-13 Receptor alpha2 Subunit/antagonists & inhibitors , Neoplasm Invasiveness/pathology , Tumor Cells, CulturedABSTRACT
INTRODUCTION: This study investigates the safety, tolerability, and preliminary efficacy of combined treatment with VEGF inhibitor bevacizumab, topoisomerase I inhibitor irinotecan, and EGFR inhibitor erlotinib in children with progressive diffuse intrinsic pontine glioma (DIPG). METHODS: Biweekly bevacizumab (10 mg/kg) and irinotecan (125 mg/m2) were combined with daily erlotinib. Two cohorts received increasing doses of erlotinib (65 and 85 mg/m2) following a 3 + 3 dose-escalation schedule, until disease progression with a maximum of one year. Dose-limiting toxicities (DLT) were monitored biweekly. Secondary progression free survival (sPFS) and overall survival (OS) were determined based on clinical and radiological response measurements. Quality of life (QoL) during treatment was also assessed. RESULTS: Between November 2011 and March 2018, nine patients with disease progression after initial radiotherapy were enrolled. Median PFS at start of the study was 7.3 months (range 3.5-10.0). In the first dose cohort, one patient experienced a DLT (grade III acute diarrhea), resulting in enrollment of three additional patients in this cohort. No additional DLTs were observed in consecutive patients receiving up to a maximum dose of 85 mg/m2. Median sPFS was 3.2 months (range 1.0-10.9), and median OS was 13.8 months (range 9.3-33.0). Overall QoL was stable during treatment. CONCLUSIONS: Daily erlotinib is safe and well tolerated in doses up to 85 mg/m2 when combined with biweekly bevacizumab and irinotecan in children with progressive DIPG. Median OS of the study patients was longer than known form literature.
Subject(s)
Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Astrocytoma , Bevacizumab , Brain Stem Neoplasms/drug therapy , Child , Diffuse Intrinsic Pontine Glioma/drug therapy , Disease Progression , Erlotinib Hydrochloride , Humans , Irinotecan , Quality of LifeABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Brain Stem Neoplasms/drug therapy , DNA-Binding Proteins/genetics , Diffuse Intrinsic Pontine Glioma/drug therapy , Epigenesis, Genetic , High Mobility Group Proteins/genetics , Histones/genetics , Neuroglia/drug effects , Transcriptional Elongation Factors/genetics , Acetylation , Animals , Brain Stem Neoplasms/genetics , Brain Stem Neoplasms/mortality , Brain Stem Neoplasms/pathology , Carbazoles/pharmacology , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Child , Chromatin/chemistry , Chromatin/metabolism , DNA-Binding Proteins/metabolism , Diffuse Intrinsic Pontine Glioma/genetics , Diffuse Intrinsic Pontine Glioma/mortality , Diffuse Intrinsic Pontine Glioma/pathology , Drug Synergism , E2F1 Transcription Factor/genetics , E2F1 Transcription Factor/metabolism , Epigenome , High Mobility Group Proteins/metabolism , Histones/antagonists & inhibitors , Histones/metabolism , Humans , Methylation , Mice , Neuroglia/metabolism , Neuroglia/pathology , Panobinostat/pharmacology , Primary Cell Culture , Retinoblastoma Protein/genetics , Retinoblastoma Protein/metabolism , Signal Transduction , Survival Analysis , Transcription Factors/genetics , Transcription Factors/metabolism , Transcriptional Elongation Factors/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumor, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that are essential for DNA replication, translation and cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine synthesis, is irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show that polyamine synthesis is upregulated in DIPG, leading to sensitivity to DFMO. DIPG cells compensate for ODC1 inhibition by upregulation of the polyamine transporter SLC3A2. Treatment with the polyamine transporter inhibitor AMXT 1501 reduces uptake of polyamines in DIPG cells, and co-administration of AMXT 1501 and DFMO leads to potent in vitro activity, and significant extension of survival in three aggressive DIPG orthotopic animal models. Collectively, these results demonstrate the potential of dual targeting of polyamine synthesis and uptake as a therapeutic strategy for incurable DIPG.
Subject(s)
Biological Transport/drug effects , Brain Stem Neoplasms/drug therapy , Diffuse Intrinsic Pontine Glioma/drug therapy , Polyamines/metabolism , Polyamines/pharmacology , Animals , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Replication/drug effects , Dicarboxylic Acid Transporters , Disease Models, Animal , Eflornithine/pharmacology , Eflornithine/therapeutic use , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Mitochondrial Membrane Transport Proteins , Ornithine Decarboxylase/drug effects , Ornithine Decarboxylase/metabolism , Polyamines/therapeutic useABSTRACT
OBJECTIVE: Diffuse intrinsic pontine glioma (DIPG) is a rare and devastating brainstem glioma that occurs predominately in children. To date, the prognostic impact of radiotherapy (RT) in conjunction with temozolomide (TMZ) in DIPG has not been thoroughly analyzed. The aim of this meta-analysis was to analyze the effectiveness of RT quantitatively and precisely in conjunction with TMZ in improving the prognosis of DIPG. METHODS: A systematic search of 8 electronic databases was conducted. Articles mainly discussing the prognostic impact of RT in conjunction with TMZ in DIPG were selected. The pooled 1- and 2-year overall survival (OS) and progression-free survival (PFS) were calculated. RESULTS: A total of 14 studies fulfilled our inclusion criteria, involving 283 cases of patients with DIPG who were treated with RT in conjunction with TMZ. The pooled 1- and 2-year OS of this treatment was 43% and 11%, respectively. The pooled 1- and 2-year PFS was 20% and 2%, respectively. Subgroup analysis revealed that the heterogeneity remained almost the same in all stratum. Egger's test demonstrated that the possibility of publication bias was low. CONCLUSIONS: Requirements of up-to-date evidence on evaluating the prognostic impact of this therapy are urgent.