A5053226567- Neuroblastoma Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Cancer therapeutics and mechanisms
- Lung Cancer Research Studies
- Neuroendocrine Tumor Research Advances
- CAR-T cell therapy research
- Asthma and respiratory diseases
- Protein Degradation and Inhibitors
- Cancer Treatment and Pharmacology
- Neonatal Respiratory Health Research
- Virus-based gene therapy research
- Ubiquitin and proteasome pathways
- PARP inhibition in cancer therapy
- Cancer Genomics and Diagnostics
- Immune Response and Inflammation
- Pediatric health and respiratory diseases
- Nanoparticle-Based Drug Delivery
- Air Quality and Health Impacts
- Cancer Immunotherapy and Biomarkers
- Medical Imaging Techniques and Applications
- Peptidase Inhibition and Analysis
- Radiopharmaceutical Chemistry and Applications
- Pancreatic and Hepatic Oncology Research
- Receptor Mechanisms and Signaling
- Pharmacological Effects and Assays
Children's Hospital of Philadelphia
2014-2025
Virginia Commonwealth University
2023
University of Pennsylvania
2007-2021
Thomas Jefferson University
2012
Uzhhorod National University
2007-2008
Philadelphia University
2007
Abstract Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically the third-generation inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children adults relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, we report here on three cohorts that have met pre-specified primary endpoints: as single agent (12 months <18 years); (≥18 combination topotecan/cyclophosphamide...
Neuroblastomas harboring activating point mutations in anaplastic lymphoma kinase (ALK) are differentially sensitive to the ALK inhibitor crizotinib, with certain conferring intrinsic crizotinib resistance. To overcome this clinical obstacle, our goal was identify inhibitors improved potency that can target intractable variants such as F1174L. We find PF-06463922 has high across and inhibits more effectively than vitro. Most importantly, induces complete tumor regression both...
Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving diagnosis relapsed disease, limited therapeutic options. To systematically prioritize rationally test novel agents in preclinical murine models, researchers the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)—many which refractory to current...
Fewer than half of children with high-risk neuroblastoma survive. Many these tumors harbor high-level amplification MYCN, which correlates poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA paradoxical, MYCN-driven upregulation NOXA. Screening for enhancers...
The presence of an ALK aberration correlates with inferior survival for patients high-risk neuroblastoma. emergence inhibitors such as crizotinib has provided novel treatment opportunities. However, certain mutations result in de novo resistance, and a phase I trial showed lack response harboring those mutations. Thus, understanding mechanisms resistance defining circumvention strategies the clinic is critical.The sensitivity human neuroblastoma-derived cell lines, line-derived,...
Purpose: Anaplastic lymphoma kinase (ALK) is the most frequently mutated oncogene in pediatric cancer neuroblastoma. We performed an vitro screen for synergistic drug combinations that target neuroblastomas with mutations ALK to determine whether could enhance antitumor efficacy.Experimental Design: screened of eight molecularly targeted agents against 17 comprehensively characterized human neuroblastoma-derived cell lines. investigated combination ceritinib and ribociclib on proliferation,...
Abstract Purpose: Patients with relapsed pediatric solid malignancies have few therapeutic options, and many of these patients die their disease. B7-H3 is an immune checkpoint protein encoded by the CD276 gene that overexpressed in cancers. Here, we investigate activity B7-H3–targeting antibody–drug conjugate (ADC) m276-SL-PBD malignancy patient-derived (PDX) cell line–derived xenograft (CDX) models. Experimental Design: expression was quantified RNA sequencing IHC on PDX microarrays. We...
Abstract Activating point mutations in Anaplastic Lymphoma Kinase (ALK ) have positioned ALK as the only mutated oncogene tractable for targeted therapy neuroblastoma. Cells with these respond to lorlatinib pre-clinical studies, providing rationale a first-in-child Phase 1 trial (NCT03107988) patients ALK-driven To track evolutionary dynamics and heterogeneity of tumors, detect early emergence resistance, we collected serial circulating tumor DNA samples from enrolled on this trial. Here...
Checkpoint kinase 1 (CHK1) inhibitors potentiate the DNA-damaging effects of cytotoxic therapies and/or promote elevated levels replication stress, leading to tumor cell death. Prexasertib (LY2606368) is a CHK1 small-molecule inhibitor under clinical evaluation in multiple adult and pediatric cancers. In this study, prexasertib was tested large panel preclinical models solid malignancies alone or combination with chemotherapy.DNA damage changes signaling following vitro treatment sarcoma...
ALK is a tractable antibody-drug conjugate target in neuroblastoma.
Abstract Relapse rates in high-risk neuroblastoma remain exceedingly high. The malignant cells that are responsible for relapse have not been identified, and mechanisms of therapy resistance poorly understood. In this study, we used single-nucleus RNA sequencing bulk whole-genome to identify characterize the residual persister survive chemotherapy from a cohort 20 matched diagnosis definitive surgery tumor samples patients treated with induction chemotherapy. We show share common escape,...
Abstract Mutations in the tyrosine kinase domain of Anaplastic Lymphoma Kinase (ALK) oncogene neuroblastoma occur most frequently at one three hotspot amino acid residues, with F1174* and F1245* variants conferring de novo resistance to first second generation ALK inhibitors including crizotinib ceritinib. Lorlatinib, a third ALK/ROS inhibitor, overcomes induces complete sustained tumor regressions patient-derived xenograft (PDX) models unresponsive crizotinib. Lorlatinib has now completed...
Relapsed high-risk neuroblastomas (NBLs) are enriched for targetable mutations in ALK and RAS-MAPK pathways, yet the prognostic effect of these aberrations relevance subclonal at diagnosis remain undefined. We describe spectrum clinical significance clonal pathogenic alterations NBL. developed a focused NBL sequencing panel including ALK, NRAS, KRAS, HRAS, BRAF, PTPN11, TP53, ATRX genes ultra-deep applied this assay to 242 pretherapy tumors from patients enrolled on phase III trial...
Background: Ozone (O 3 ) exposure evokes asthma exacerbations by mechanisms that are poorly understood. We used a murine model to characterize the effects of O on allergic airway inflammation and hyperresponsiveness identify factors might contribute ‐induced exacerbation asthma. Methods: BALB/c mice were sensitized challenged with Aspergillus fumigatus ( Af ). A group was exposed 3.0 ppm for 2 h studied 12 later (96 after challenge). Naive alone as controls. Bronchoalveolar lavage (BAL)...
Corticosteroid insensitivity (CSI) represents a profound challenge in managing patients with asthma. We recently demonstrated that short exposure of airway smooth muscle cells (ASMCs) to proasthmatic cytokines drastically reduced their responsiveness glucocorticoids (GCs), an effect was partially mediated via interferon regulatory factor-1, suggesting the involvement additional mechanisms (Am J Respir Cell Mol Biol 2008;38:463-472). Although GC receptor (GR) can be phosphorylated at multiple...
Abstract Venetoclax is a small molecule inhibitor of the prosurvival protein BCL-2 that has gained market approval in BCL-2–dependent hematologic cancers including chronic lymphocytic leukemia and acute myeloid leukemia. Neuroblastoma heterogenous pediatric cancer with 5-year survival rate less than 50% for high-risk patients, which includes nearly all cases amplified MYCN. We previously demonstrated venetoclax active MYCN-amplified neuroblastoma but limited single-agent activity most...
Summary Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant proteins that can serve as immunotherapeutic neuroblastoma, often-fatal childhood cancer the developing nervous system. We apply this approach human-derived lines (N=9)...
Accelerating cures for children with cancer remains an immediate challenge due to extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving diagnosis relapsed disease, limited therapeutic options. To systematically prioritize rationally test novel agents in preclinical murine models, researchers the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs) from high-risk childhood cancers, many...
Neuroblastomas have neuroendocrine features and often show similar gene expression patterns to small cell lung cancer including high of delta-like ligand 3 (DLL3). Here we determine the efficacy rovalpituzumab tesirine (Rova-T), an antibody drug conjugated (ADC) with a pyrrolobenzodiazepine (PBD) dimer toxin targeting DLL3, in preclinical models human neuroblastoma. We evaluated DLL3 RNA sequencing data sets performed immunohistochemistry (IHC) on neuroblastoma patient derived xenograft...
Abstract Introduction: Rova-T (SC16LD6.5) is an ADC targeting delta-like protein 3 (DLL3), a member of the delta-notch signaling pathway, composed monoclonal antibody SC16 conjugated to DNA-damaging D6.5 pyrrolobenzodiazepine (PBD) dimer toxin. In clinical trials, demonstrated anti-tumor activity in patients with small cell lung cancer high DLL3 expression. We have identified as highly expressed NBs, especially MYCN-amplified subset. Here, we characterize expression NB patient derived...
Summary Accelerating cures for children with cancer remains an immediate challenge due to extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving diagnosis relapsed disease, limited therapeutic options. To systematically prioritize rationally test novel agents in preclinical murine models, researchers the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs) from high-risk childhood cancers,...