A5102719330- Glioma Diagnosis and Treatment
- Neuroblastoma Research and Treatments
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Renal and related cancers
- Pharmacological Effects and Toxicity Studies
- Neurofibromatosis and Schwannoma Cases
- PARP inhibition in cancer therapy
- Cancer Research and Treatments
- Mitochondrial Function and Pathology
- CAR-T cell therapy research
- Nanoplatforms for cancer theranostics
- Cancer, Hypoxia, and Metabolism
- Chromatin Remodeling and Cancer
- Ocular Oncology and Treatments
- Brain Metastases and Treatment
- Cancer Treatment and Pharmacology
- Melanoma and MAPK Pathways
- Kruppel-like factors research
- Pregnancy and Medication Impact
- Neurogenesis and neuroplasticity mechanisms
- Diagnosis and treatment of tuberculosis
- Animal Virus Infections Studies
- Radiation Dose and Imaging
- Cancer Mechanisms and Therapy
Texas Children's Hospital
2013-2024
Baylor College of Medicine
2013-2024
Children's Cancer Center
2010-2024
Dan L Duncan Comprehensive Cancer Center
2023
Gene Therapy Laboratory
2013
First Affiliated Hospital of Harbin Medical University
2013
Sun Yat-sen University
2013
Sun Yat-sen University Cancer Center
2013
Orthopaedic Research Foundation
2013
Harbin Medical University
2013
Abstract BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 ( n = 77) of ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated efficacy oral, selective, central nervous system–penetrant, type II RAF inhibitor tovorafenib (420 mg m − once weekly; 600 maximum) patients with -altered, relapsed/refractory pLGG. 60) is an extension cohort, which provided treatment access for -altered pLGG after arm closure. Based on independent review,...
Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat an oral multihistone deacetylase inhibitor preclinical activity in DIPG models. Study objectives were to determine safety, tolerability, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics panobinostat children DIPG.
Seneca Valley virus (SVV-001) is a nonpathogenic oncolytic that can be systemically administered and pass through the blood-brain barrier. We examined its therapeutic efficacy mechanism of tumor cell infection in pediatric malignant gliomas.In vitro antitumor activities were primary cultures, preformed neurospheres, self-renewing glioma cells derived from 6 patient orthotopic xenograft mouse models (1 anaplastic astrocytoma 5 GBM). In vivo was by systemic treatment xenografts 3 permissive 2...
To study the efficacy and tolerability of valproic acid (VPA) radiation, followed by VPA bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade (HGG).Children 3 to 21 years age received radiation therapy at 15 mg/kg/day dose adjusted maintain a trough range 85 115 μg/mL. was continued post-radiation, started 10 mg/kg intravenously biweekly, four weeks after completing therapy.From September 2009 through August 2015, 20 DIPG 18 HGG patients were...
Of the antioxidants used to scavenge oxygen in polymer gel dosimeters, tetrakis (hydroxymethyl) phosphonium chloride (THPC) has been shown hold great promise due its rapid scavenging abilities. In this study we (a) investigate use of THPC as an antioxidant for polyacrylamide (PAGAT) dosimeters conjunction with x-ray computed tomography (CT) and (b) work establish reaction mechanisms constituents. We dose response reproducibility PAGAT when imaged CT show that exhibit highly reproducible...
Background. Meningiomas constitute one-third of all primary brain tumors. Although typically benign, about 20% these tumors recur despite surgery and radiation, may ultimately prove fatal. There are currently no effective chemotherapies for meningioma. We, therefore, set out to develop patient-derived orthotopic xenograft (PDOX) mouse models human meningioma using tumor. Method. Of nine patients, four had World Health Organization (WHO) grade I tumors, five WHO II in this second group two...
10004 Background: Pediatric low-grade gliomas (LGGs) are the most common brain tumors of childhood. Genomic alterations BRAF ( KIAA1549-BRAF fusions, 50–60% and V600E mutations, 5–15%) frequent oncogenic drivers in pLGGs. Tovorafenib is an investigational, oral, selective, brain-penetrant, small molecule, type II pan-RAF inhibitor. has demonstrated clinically meaningful responses 24/35 patients (2 CR, 7 PR 15 SD) pediatric phase 1B PNOC014 (NCT03429803) trial with RAF-altered cancers...
Abstract BACKGROUND RAS/RAF/MEK/ERK pathway activation is the primary driver for most pediatric low-grade gliomas (pLGG). MEK162 (binimetinib) an orally bioavailable MEK1/2 inhibitor with superior brain penetration in a preclinical model. The objective of this multi-institutional phase II and target validation study was to assess stratum-specific efficacy binimetinib progressive pLGG. METHODS Eligible children aged 1-18 years previously treated radiographically pLGG were enrolled...
Abstract Recurrence is frequent in pediatric ependymoma (EPN). Our longitudinal integrated analysis of 30 patient-matched repeated relapses (3.67 ± 1.76 times) over 13 years (5.8 3.8) reveals stable molecular subtypes (RELA and PFA) convergent DNA methylation reprogramming during serial accompanied by increased orthotopic patient derived xenograft (PDX) (13/27) formation the late recurrences. A set differentially methylated CpGs (DMCs) regions (DMRs) are found to persist primary relapse...
Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median overall survival (OS) of 10 months and post-progression (PPS) 2–3 months. Panobinostat (LBH589) multi-histone deacetylase inhibitor activity against preclinical models DIPG. The aim this study to determine the safety, tolerability, maximum tolerated dose (MTD), toxicity profile pharmacokinetics panobinostat in children In initial cohort, was administered orally three days per week for weeks on, one off...
Abstract BACKGROUND RAF alterations are oncogenic drivers found in most pediatric low-grade gliomas (LGGs). Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. METHODS FIREFLY-1 (NCT04775485) a multicenter phase 2 study evaluating the safety and efficacy of tovorafenib monotherapy. Registrational arm 1 enrolled patients with recurrent/progressive LGG harboring activating BRAF alteration. Patients aged 6 months–25 years who progressed...
10504 Background: A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) paired with availability potent selective inhibitors has enhanced ability to target this therapeutic intent. Methods: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), MEK I/II inhibitor, children recurrent/refractory LGG assigned 6 strata and treated at 25 mg/m 2 /dose PO BID for up two years. Here we present...
The overall survival of children with acute lymphoblastic leukemia (ALL) is over 90%. Much this success comes from the daily use 6-mercaptopurine (6-MP) during maintenance therapy [1]. Mercap...
Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), which prognosis remains poor. To gain an in-depth understanding biological consequences beyond classic DNA damage, we treated 9 patient-derived orthotopic xenograft (PDOX) models, including with mismatch repair (MMR) deficiency, fractionated radiations (2 Gy/day x 5 days). Extension survival time was noted in PDOX models (P < 0.05) accompanied by γH2AX positivity >95 % tumor cells core and >85 invasive foci as...
Abstract BACKGROUND: Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. The ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) of tovorafenib in BRAF-altered pLGG resulted antitumor activity and manageable safety. Decreased growth velocity (GV) was observed; this update on GV changes skeletally immature children receiving tovorafenib. Methods A planned safety analysis completed August 8, 2023 137 patients (Arm 1: 77 & Arm 2:...
Abstract INTRODUCTION: Panobinostat is an oral HDAC inhibitor with pre-clinical activity against DIPG. The phase I study in children progressive DIPG (stratum 1) defined the maximum-tolerated dose (MTD) as 10 mg/m2 administered 3x/week, 3 weeks on/1 week off. Herein, we report results of stratum 2, involving non-progressive DIPG/DMG using alternative schedule. Primary objectives were to describe toxicity profile and define MTD; secondary progression-free survival (PFS) overall (OS). PATIENTS...
Abstract Background Central nervous system (CNS) malignancies are the most common solid tumors among children, and novel therapies needed to help improve survival. Pomalidomide is an immunomodulatory agent that displays antiangiogenic cytotoxic activity, making it appropriate candidate explore in pediatric CNS tumors. Methods A phase 1 first trial of pomalidomide was conducted children with recurrent, progressive, refractory The primary objective determine maximum tolerated dose (MTD) and/or...
Preclinical studies have suggested that mTOR pathway signaling may be a potential therapeutic target for childhood ependymoma.A phase II clinical trial (ClinicalTrials.gov identifier: NCT02155920) of single-agent everolimus was performed to test the hypothesis inhibition would result in tumor responses children with recurrent and/or progressive ependymomas.Eleven subjects [sex: 4 females (36.4%); median age: 8 years (range: 2-15 years); race: 9 white; prior therapies: 6 3-9)] were enrolled...
10542 Background: We conducted a Phase II study of alisertib, small-molecule inhibitor Aurora A kinase, as single-agent treatment in patients < 22 y with recurrent or progressive atypical teratoid rhabdoid tumors (ATRT) (NCT02114229). Methods: Patients received alisertib once daily [80 mg/m 2 (enteric-coated tablets) 60 (liquid)] on Days 1–7 21-day cycle for until disease (PD). Therapy was considered promising if ≥10 were without PD by MR imaging at 12 wk. Molecular groups determined...
Abstract Background: The Neurologic Assessment in Neuro-Oncology (NANO) scale, a standardized metric to objectively measure neurologic function adult brain tumor patients, complements radiographic assessment evaluating outcomes of neuro-oncology patients clinical trials and practice. Currently, there is no for pediatric despite their distinct presentations locations. Therefore, we developed dedicated NANO (pNANO) scale. Methods: An international group neurologists neuro-oncologists convened...
TPS10062 Background: RAF gene fusions ( BRAF and RAF1) V600E mutations are oncogenic drivers found on a mutually exclusive basis in most pediatric low-grade gliomas (LGGs). In addition, have also been identified other solid tumors. Tovorafenib (DAY101) is an investigational, oral, highly selective, CNS-penetrant, small molecule, type II pan-RAF inhibitor. contrast to I inhibitors, tovorafenib does not induce RAS-dependent paradoxical activation of the MAPK pathway. phase 1 PNOC014 study...
Abstract BACKGROUND Treatment of pediatric CNS tumors with T-cells modified chimeric antigen receptors (CARTs) provides an innovative approach. We employ GD2-directed CART-cells (GD2.CARTs) to express a constitutively active interleukin-7 receptor (C7R) increase GD2.CART survival and function independent external cytokines, thereby augmenting activity against GD2-expressing malignancies. METHODS In Phase I study, we investigated the safety intravenous therapy for patients H3K27-altered...
Abstract Genomic alterations of BRAF are common oncogenic drivers in pediatric low-grade glioma (pLGG). Tovorafenib is an investigational, oral, selective, brain-penetrant, small molecule, type II panRAF inhibitor. FIREFLY-1 (NCT04775485) a multicenter phase 2 study evaluating the efficacy and safety tovorafenib monotherapy patients with BRAF-altered cancers. Registrational arm 1 includes 6 months-25 years age recurrent or progressive LGG previously treated ≥1 prior line systemic therapy....