Papers by Tobey Macdonald
Neuro-oncology, Nov 1, 2016
Frontiers in Oncology
Medulloblastoma (MB) is the most common malignant brain tumor in children with standard of care c... more Medulloblastoma (MB) is the most common malignant brain tumor in children with standard of care consisting of surgery, radiation, and chemotherapy. Recent molecular profiling led to the identification of four molecularly distinct MB subgroups – Wingless (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4. Despite genomic MB characterization and subsequent tumor stratification, clinical treatment paradigms are still largely driven by histology, degree of surgical resection, and presence or absence of metastasis rather than molecular profile. Patients usually undergo resection of their tumor followed by craniospinal radiation (CSI) and a 6 month to one-year multi-agent chemotherapeutic regimen. While there is clearly a need for development of targeted agents specific to the molecular alterations of each patient, targeting proteins responsible for DNA damage repair could have a broader impact regardless of molecular subgrouping. DNA damage response (DDR) protein inhibitors have recently ...
Neuro-Oncology Advances
Background ONC201, a dopamine receptor D2 (DRD2) antagonist and caseinolytic protease P (ClpP) ag... more Background ONC201, a dopamine receptor D2 (DRD2) antagonist and caseinolytic protease P (ClpP) agonist, has induced durable tumor regressions in adults with recurrent H3 K27M-mutant glioma. We report results from the first phase I pediatric clinical trial of ONC201. Methods This open-label, multi-center clinical trial (NCT03416530) of ONC201 for pediatric H3 K27M-mutant diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) employed a dose-escalation and dose-expansion design. The primary endpoint was the recommended phase II dose (RP2D). A standard 3 + 3 dose escalation design was implemented. The target dose was the previously established adult RP2D (625 mg), scaled by body weight. Twenty-two pediatric patients with DMG/DIPG were treated following radiation; prior lines of systemic therapy in addition to radiation were permitted providing sufficient time had elapsed prior to study treatment. Results The RP2D of orally administered ONC201 in this pediatric populati...
Scientific Reports
Y-box binding protein 1 (YBX1 or YB1) is a therapeutically relevant oncoprotein capable of RNA an... more Y-box binding protein 1 (YBX1 or YB1) is a therapeutically relevant oncoprotein capable of RNA and DNA binding and mediating protein–protein interactions that drive proliferation, stemness, and resistance to platinum-based therapies. Given our previously published findings, the potential for YB1-driven cisplatin resistance in medulloblastoma (MB), and the limited studies exploring YB1-DNA repair protein interactions, we chose to investigate the role of YB1 in mediating radiation resistance in MB. MB, the most common pediatric malignant brain tumor, is treated with surgical resection, cranio-spinal radiation, and platinum-based chemotherapy, and could potentially benefit from YB1 inhibition. The role of YB1 in the response of MB to ionizing radiation (IR) has not yet been studied but remains relevant for determining potential anti-tumor synergy of YB1 inhibition with standard radiation therapy. We have previously shown that YB1 drives proliferation of cerebellar granular neural precu...
Acta Neuropathologica Communications
Medulloblastoma (MB) is the most common pediatric brain malignancy and is divided into four molec... more Medulloblastoma (MB) is the most common pediatric brain malignancy and is divided into four molecularly distinct subgroups: WNT, Sonic Hedgehog (SHHp53mut and SHHp53wt), Group 3, and Group 4. Previous reports suggest that SHH MB features a unique tumor microenvironment compared with other MB groups. To better understand how SHH MB tumor cells interact with and potentially modify their microenvironment, we performed cytokine array analysis of culture media from freshly isolated MB patient tumor cells, spontaneous SHH MB mouse tumor cells and mouse and human MB cell lines. We found that the SHH MB cells produced elevated levels of IGFBP2 compared to non-SHH MBs. We confirmed these results using ELISA, western blotting, and immunofluorescence staining. IGFBP2 is a pleiotropic member of the IGFBP super-family with secreted and intracellular functions that can modulate tumor cell proliferation, metastasis, and drug resistance, but has been understudied in medulloblastoma. We found that I...
Neuro-Oncology
BACKGROUND Recurrent brain tumors are the leading cause of cancer death in children. We conducted... more BACKGROUND Recurrent brain tumors are the leading cause of cancer death in children. We conducted a first-in-children, two-institution, Phase 1 open-label dose-confirmation study using a 3 + 3 design, with expansion cohorts, to determine the recommended pediatric dose of the IDO pathway-inhibitor indoximod (NCT02502708). DESIGN/ METHODS Eligible patients were 3-22 years old with either recurrent malignant brain tumor or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Palliative radiation, surgery or dexamethasone were allowed as needed for patient management. Separate dose-finding arms were performed for indoximod plus temozolomide (200 mg/m2/day orally for 5 days of each 28-day cycle) and for indoximod plus conformal radiation (in patients for whom re-irradiation was planned as standard-of-care). At progression, patients who were otherwise clinically stable were offered crossover to indoximod plus a second-line chemotherapy regimen (cyclophosphamide 2.5 mg/kg/day orally an...
Neuro-Oncology
Children with Group 3 medulloblastoma (MB) have a very poor long-term outcome and many do not sur... more Children with Group 3 medulloblastoma (MB) have a very poor long-term outcome and many do not survive beyond 5 years. Several drivers for Group 3 MB have been identified but none have resulted in targeted therapy to date. LIN28B is a stem cell factor upregulated in Group 3 MB and is associated with worse survival. Here we investigate the role of the LIN28B pathway in Group 3 MB development. Pharmacologic inhibition of the LIN28B pathway is feasible and may provide a unique opportunity to target this tumor. Using LIN28B knockdown and overexpression in Group 3 MB cells we test LIN28B’s effect on proliferation, self-renewal and metastasis. We investigate the effect of LIN28B knockdown on survival as well as proliferation and apoptosis markers using orthotopic xenografts in vivo. We also investigate the role of let-7 and its downstream target PBK on Group 3 MB proliferation. Finally, we use a LIN28 inhibitor 1632 and a PBK inhibitor HITOPK032 to treat Group 3 MB cell lines and then asse...
Neuro-Oncology
Background Diffuse intrinsic pontine glioma (DIPG) is a uniformly fatal brain tumor with no avail... more Background Diffuse intrinsic pontine glioma (DIPG) is a uniformly fatal brain tumor with no available cure. Indoximod blocks the IDO (indoleamine 2,3-dioxygenase) pathway, thereby reversing IDO-mediated immune suppression in the tumor microenvironment. Methods Patients aged 3 to 21 years with treatment-naive DIPG were eligible for this phase 1b dose-confirmation study of indoximod. The treatment regimen comprised continuous oral indoximod (38.4 mg/kg/day divided twice daily) with conformal photon radiation (54 Gy in 30 fractions), followed by cycles of indoximod with temozolomide (200 mg/m2/day, days 1–5 in 28-day cycles). Results Thirteen patients (median age 9 years, range 5 to 20 years) with DIPG were treated. Median OS was 14.5 months (follow-up ranged 4.8 to 29.3 months), 12-month OS was 61.5% (8/13), and 18-month OS was 30.8% (4/13), with 1 patient remaining in follow-up at the data cutoff. This compared favorably to expected median OS of approximately 10.8 months, 12-month OS...
Neuro-Oncology
BACKGROUND: Children with Group 3 medulloblastoma (MB) have a very poor long-term outcome and man... more BACKGROUND: Children with Group 3 medulloblastoma (MB) have a very poor long-term outcome and many do not survive beyond 5 years. Several drivers for Group 3 MB have been identified but none have resulted in targeted therapy to date. LIN28B is a stem cell factor that is upregulated in Group 3 medulloblastoma and is associated with worse survival. Here we investigate the role of the LIN28B pathway in Group 3 MB development. Pharmacologic inhibition of the LIN28B pathway is feasible and may provide a unique opportunity to target this tumor. METHODS: Using LIN28B knockdown and overexpression in G3 MB cells we test LIN28B’s effect on proliferation, self-renewal and metastasis. Similarly, we used shRNAs targeting PBK and demonstrate a similar effect on G3 MB growth. We also investigate the role of let-7 as a target of LIN28B by introducing let-7 mimetics and overexpression vectors into MB cells. Finally, we use a LIN28 inhibitor 1632 and a PBK inhibitor HITOPK032 to treat G3 MB cell line...
Neuro-Oncology, 2017
BACKGROUND: Vemurafenib is an orally available, selective ATPcompetitive inhibitor of BRAF-V600E ... more BACKGROUND: Vemurafenib is an orally available, selective ATPcompetitive inhibitor of BRAF-V600E kinase, approved in adult metastatic melanoma patients with the V600E mutation. This study was designed to determine the recommended phase 2 dose (RP2D) in patients < 18yrs with BRAF-V600E mutant brain tumors. METHODS: Vemurafenib was given orally, beginning at the adult dose equivalent of 550 mg/m2, twice daily. Toxicity, pharmacokinetics, and response were assessed. Doses of 420 mg/ m2 and 550 mg/m2 were assessed by a 3 + 3 design in a dose de-escalation study. RESULTS: Enrollment for phase 1 completed at 19 patients, 9 male, median age 9 years (range 4-17), with pilocytic astrocytoma (n=10), and ganglioglioma (n=5) the most common histologies. Grade 3/4 adverse events judged related to vemurafenib included secondary keratoacanthoma (n=1); rash (n=16); hyponatremia (n=1), hepatic enzyme elevations (n=4) and fever (n=5). We initially found dose limiting toxicities (DLT's) of rash (2 of 3 patients at 550 mg/m2; and 2 of 3 patients at 420 mg/m2). As these rashes resolved shortly after holding drug with appropriate supportive care, we subsequently amended the study to exclude resolving rash as a DLT. Under the new DLT definitions, no further DLT's were found. Duration on treatment ranged from 2 to 31 months (ongoing); 12 patients remain on treatment. The RP2D for patients < 18 yrs is 550 mg/m2 twice daily. Investigator-assessed best radiographic responses included 1 complete response, 2 partial responses, and 15 stable disease (source data verification ongoing). CONCLUSIONS: The RP2D of vemurafenib for children < 18 yrs was determined to be 550 mg/m2 twice daily. The drug was well tolerated with manageable toxicity. The proportion of patients with responses and stable disease warrant continued evaluation of vemurafenib in patients with BRAF V600 mutated gliomas. The phase 2 component of the study is underway (NCT01748149).
Science Advances, 2021
Focused ultrasound–mediated delivery of RNA-loaded nanoparticles increases brain tumor cell apopt... more Focused ultrasound–mediated delivery of RNA-loaded nanoparticles increases brain tumor cell apoptosis through oncogene targeting.
Neuro-Oncology, 2017
NEURO-ONCOLOGY • NOVEMBER 2017 5-year EFS/OS rates of 62.8 ± 9.9% and 78.5 ± 8.3%, respectively, ... more NEURO-ONCOLOGY • NOVEMBER 2017 5-year EFS/OS rates of 62.8 ± 9.9% and 78.5 ± 8.3%, respectively, while patients with molecularly-classified HGG had an EFS/OS of 5.6 ± 3.8% and 12.0 ± 6.5%, respectively. Although the study was likely underpowered due to the early closure of CNS-PNET/PBL enrollment, there was no evidence that carboplatin or isotretinoin significantly altered outcomes for these patients. Survival for patients with HGG were similar to studies that do not use craniospinal irradiation or intensive chemotherapy. CONCLUSIONS: This trial highlights the challenges of histology-based pathology for brain tumors in children and indicates that molecular profiling should become a standard component of initial diagnosis. For patients with CNS-PNETs/PBLs, prognosis is considerably better than previously assumed when molecularly-confirmed HGG were removed from the cohort. Identification of molecular HGG will spare affected children from unhelpful intensive treatment.
Journal for ImmunoTherapy of Cancer, 2020
Brain tumors are the leading cause of cancer-related mortality in children and have distinct geno... more Brain tumors are the leading cause of cancer-related mortality in children and have distinct genomic and molecular features compared with adult glioma. However, the properties of immune cells in these tumors has been vastly understudied compared with their adult counterparts. We combined multiplex immunofluorescence immunohistochemistry coupled with machine learning and single-cell mass cytometry to evaluate T-cells infiltrating pediatric glial tumors. We show that low-grade tumors are characterized by greater T-cell density compared with high-grade glioma (HGG). However, even among low-grade tumors, T-cell infiltration can be highly variable and subtype-dependent, with greater T-cell density in pleomorphic xanthoastrocytoma and ganglioglioma. CD3+ T-cell infiltration correlates inversely with the expression of SOX2, an embryonal stem cell marker commonly expressed by glial tumors. T-cells within both HGG and low-grade glioma (LGG) exhibit phenotypic heterogeneity and tissue-residen...
Neuro-Oncology, 2020
Treatment for medulloblastoma (MB) is typically ineffective for MYC amplified or metastatic SHH, ... more Treatment for medulloblastoma (MB) is typically ineffective for MYC amplified or metastatic SHH, Group 3 and 4 subgroups. Promising preclinical and clinical results have been obtained for adult and pediatric malignant glioma treated with ONC-201, a selective antagonist of DRD2, a G-protein coupled receptor that regulates prosurvival pathways. Herein, we report the activity of ONC-201 and ONC-206, which has increased non-competitive antagonism of DRD2, against MB. We treated three different MB cell types representative of SHH- and Group 3-like cells, with varied levels of DRD2 expression, and consistently observed increased cell death in a dose-dependent manner at lower doses of ONC-206 compared to ONC-201. We also evaluated ClpP as an additional drug target in MB. ClpP is a mitochondrial protease that has been shown to directly bind and be activated by ONC 201, and is highly expressed at the protein level across pediatric MB, malignant glioma and ATRT, but not normal brain. We obser...
Neuro-Oncology, 2020
INTRODUCTION Previously thought to be rare, recent case series have shown that IDH mutations in y... more INTRODUCTION Previously thought to be rare, recent case series have shown that IDH mutations in young patients are more common than previously described. In this study, we analyzed IDH-mutant tumors to determine clinical significance of these mutations in children, adolescents and young adults. METHODS Through this multi-institution study (10 institutions), we collected 64 IDH1/2-mutant infiltrating astrocytoma specimens from 58 patients aged 4–26 (M:F, 0.4:0.6). Specimens included 46 low-grade (LGG) and 18 high-grade (HGG) astrocytomas. Tumor sequencing data (n=45), germline sequencing data (n=37) and outcome data (n=40) was analyzed. RESULTS Similar to adults, most sequenced tumors had a co-mutation in the TP53 gene, while ATRX mutations were less common and primarily seen in HGGs. Approximately 60% (n=21) of patients with germline data available had a mutation in a cancer predisposition gene. Mismatch repair (MMR) mutations were most common (n=12; MSH6 n=9), followed by TP53mutat...
Cancer Discovery, 2020
Infant high-grade gliomas appear clinically distinct from their counterparts in older children, i... more Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. Significance: Infant high-grade gliomas in the cerebral hemispher...
Neuro-Oncology, 2018
NEURO-ONCOLOGY • JUNE 2018 reactive T cells were generated ex vivo against each tumor line by emp... more NEURO-ONCOLOGY • JUNE 2018 reactive T cells were generated ex vivo against each tumor line by employing dendritic cells pulsed with tumor-RNA. Tumor-reactive T cells were adoptively transferred into tumor bearing mice with or without HSC cotransfer. RESULTS: The efficacy of adoptive cell therapy was significantly increased in cohorts that received HSC co-transfer against both brain stem glioma models. Interestingly, T-cell infiltration into BSGs was only detected in cohorts that received HSC co-transfer. In addition, our observations provide evidence that HSCs co-transferred with IFNγ-secreting anti-tumor T cells differentiate into professional antigen presenting cells as characterized by CD11c, MHC-II, and a lack of MDSC markers. These cells then mount the capacity to capture and cross-prime tumor-derived antigens to both adoptively transferred T cells and host T cells, addressing the diversity of antigens within brain tumors.
Neuro-Oncology, 2019
Medulloblastoma (MB) is the most common malignant brain tumor in children. Of the four different ... more Medulloblastoma (MB) is the most common malignant brain tumor in children. Of the four different sub-groups, the Sonic Hedgehog (SHH) subgroup accounts for about 30% of human MBs. The current standard of care (resection, cranio-spinal irradiation, and chemotherapy) for MB is typically ineffective for SHH MB in non-infants and those with metastatic disease. Survivors are frequently beset with long-term side effects including cognitive deficiencies and a severely impaired quality of life. Taken together, there is a critical need for novel targeted therapies for SHH MB. Recently, promising preclinical and clinical results have been obtained in a variety of cancers treated with a small molecule antagonist, ONC-201, which acts against DRD2, a G-protein coupled receptor that is widely expressed in MBs and regulates pro-survival pathways in tumors. In the present study we report the activity of ONC-201 and another DRD2 antagonist, ONC-206, which binds DRD2 with increased affinity. We teste...
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Papers by Tobey Macdonald