Publications by authors named "Erik P Sulman"

136 Publications

Glioblastoma Clinical Trials: Current Landscape and Opportunities for Improvement.

Clin Cancer Res 2021 Sep 24. Epub 2021 Sep 24.

Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on ClinicalTrials.gov as "recruiting" or "not yet recruiting" as of February 2021.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2750DOI Listing
September 2021

Inhibition of nonsense-mediated decay rescues p53β/γ isoform expression and activates the p53 pathway in MDM2-overexpressing and select p53-mutant cancers.

J Biol Chem 2021 Sep 2:101163. Epub 2021 Sep 2.

Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Inactivation of p53 is present in almost every tumor and hence, p53-reactivation strategies are an important aspect of cancer therapy. Common mechanisms for p53 loss in cancer include expression of p53 negative regulators such as MDM2, which mediate the degradation of wild-type (WT) p53 (p53α), and inactivating mutations in the TP53 gene. Currently, approaches to overcome p53 deficiency in these cancers are limited. Here, using non-small cell lung cancer (NSCLC) and glioblastoma multiforme (GBM) cell line models, we show that two alternatively-spliced, functional truncated isoforms of p53 (p53β and p53γ, comprising exons 1 to 9β or 9γ, respectively) and which lack the C-terminal MDM2 binding domain have markedly reduced susceptibility to MDM2-mediated degradation but are highly susceptible to nonsense mediated decay (NMD), a regulator of aberrant mRNA stability. In cancer cells harboring MDM2 overexpression or TP53 mutations downstream of exon 9, NMD inhibition markedly upregulates p53β and p53γ, and restores activation of the p53 pathway. Consistent with p53 pathway activation, NMD inhibition induces tumor suppressive activities such as apoptosis, reduced cell viability and enhanced tumor radiosensitivity, in a relatively p53-dependent manner. In addition, NMD inhibition also inhibits tumor growth in a MDM2 overexpressing xenograft tumor model. These results identify NMD inhibition as a novel therapeutic strategy for restoration of p53 function in p53-deficient tumors bearing MDM2 overexpression or p53 mutations downstream of exon 9, subgroups which comprise approximately 6% of all cancers.
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http://dx.doi.org/10.1016/j.jbc.2021.101163DOI Listing
September 2021

Phase II trial of proton therapy versus photon IMRT for GBM: secondary analysis comparison of progression-free survival between RANO versus clinical assessment.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab073. Epub 2021 Jun 1.

Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas, USA.

Background: This secondary image analysis of a randomized trial of proton radiotherapy (PT) versus photon intensity-modulated radiotherapy (IMRT) compares tumor progression based on clinical radiological assessment versus Response Assessment in Neuro-Oncology (RANO).

Methods: Eligible patients were enrolled in the randomized trial and had MR imaging at baseline and follow-up beyond 12 weeks from completion of radiotherapy. "Clinical progression" was based on a clinical radiology report of progression and/or change in treatment for progression.

Results: Of 90 enrolled patients, 66 were evaluable. Median clinical progression-free survival (PFS) was 10.8 (range: 9.4-14.7) months; 10.8 months IMRT versus 11.2 months PT ( = .14). Median RANO-PFS was 8.2 (range: 6.9, 12): 8.9 months IMRT versus 6.6 months PT ( = .24). RANO-PFS was significantly shorter than clinical PFS overall ( = .001) and for both the IMRT ( = .01) and PT ( = .04) groups. There were 31 (46.3%) discrepant cases of which 17 had RANO progression more than a month prior to clinical progression, and 14 had progression by RANO but not clinical criteria.

Conclusions: Based on this secondary analysis of a trial of PT versus IMRT for glioblastoma, while no difference in PFS was noted relative to treatment technique, RANO criteria identified progression more often and earlier than clinical assessment. This highlights the disconnect between measures of tumor response in clinical trials versus clinical practice. With growing efforts to utilize real-world data and personalized treatment with timely adaptation, there is a growing need to improve the consistency of determining tumor progression within clinical trials and clinical practice.
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http://dx.doi.org/10.1093/noajnl/vdab073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320688PMC
June 2021

Insight into the public's interest in tumour treating fields.

Br J Cancer 2021 Sep 27;125(6):901-903. Epub 2021 Jul 27.

Department of Radiation Oncology, NYU Grossman School of Medicine, New York, NY, USA.

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http://dx.doi.org/10.1038/s41416-021-01504-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437973PMC
September 2021

Hippocampal sparing in patients receiving radiosurgery for ≥25 brain metastases.

Radiother Oncol 2021 08 27;161:65-71. Epub 2021 May 27.

Department of Neurosurgery, NYU Grossman School of Medicine, New York, USA; Brain and Spine Tumor Center, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, USA; Department of Radiation Oncology, NYU Grossman School of Medicine, New York, USA.

Purpose/objectives: To report our dosimetric analysis of the hippocampi (HC) and the incidence of perihippocampal tumor location in patients with ≥25 brain metastases who received stereotactic radiosurgery (SRS) in single or multiple sessions.

Materials/methods: Analysis of our prospective registry identified 89 patients treated with SRS for ≥25 brain metastases. HC avoidance regions (HA-region) were created on treatment planning MRIs by 5 mm expansion of HC. Doses from each session were summed to calculate HC dose. The distribution of metastases relative to the HA-region and the HC was analyzed.

Results: Median number of tumors irradiated per patient was 33 (range 25-116) in a median of 3 (range1-12) sessions. Median bilateral HC D (D), D, D, D, and D (Gy) was 1.88, 3.94, 3.62, 16.6, and 3.97 for all patients, and 1.43, 2.99, 2.88, 5.64, and 3.07 for patients with tumors outside the HA-region. Multivariate linear regression showed that the median HC D, D, and D were significantly correlated with the tumor number and tumor volume (p < 0.001). Of the total 3059 treated tumors, 83 (2.7%) were located in the HA-region in 57% evaluable patients; 38 tumors (1.2%) abutted or involved the HC itself.

Conclusions: Hippocampal dose is higher in patients with tumors in the HA-region; however, even for patients with a high burden of intracranial disease and tumors located in the HA-regions, SRS affords hippocampal sparing. This is particularly relevant in light of our finding of eventual perihippocampal metastases in more than half of our patients.
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http://dx.doi.org/10.1016/j.radonc.2021.05.019DOI Listing
August 2021

Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer.

Nat Genet 2021 07 27;53(7):1088-1096. Epub 2021 May 27.

The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.

Ionizing radiation causes DNA damage and is a mainstay for cancer treatment, but understanding of its genomic impact is limited. We analyzed mutational spectra following radiotherapy in 190 paired primary and recurrent gliomas from the Glioma Longitudinal Analysis Consortium and 3,693 post-treatment metastatic tumors from the Hartwig Medical Foundation. We identified radiotherapy-associated significant increases in the burden of small deletions (5-15 bp) and large deletions (20+ bp to chromosome-arm length). Small deletions were characterized by a larger span size, lacking breakpoint microhomology and were genomically more dispersed when compared to pre-existing deletions and deletions in non-irradiated tumors. Mutational signature analysis implicated classical non-homologous end-joining-mediated DNA damage repair and APOBEC mutagenesis following radiotherapy. A high radiation-associated deletion burden was associated with worse clinical outcomes, suggesting that effective repair of radiation-induced DNA damage is detrimental to patient survival. These results may be leveraged to predict sensitivity to radiation therapy in recurrent cancer.
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http://dx.doi.org/10.1038/s41588-021-00874-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483261PMC
July 2021

World Cancer Day 2021 - Perspectives in Pediatric and Adult Neuro-Oncology.

Front Oncol 2021 10;11:659800. Epub 2021 May 10.

Section of Neuro-oncology & Neurosurgical Oncology, Frontiers in Oncology and Frontiers in Neurology, Lausanne, Switzerland.

Significant advances in our understanding of the molecular genetics of pediatric and adult brain tumors and the resulting rapid expansion of clinical molecular neuropathology have led to improvements in diagnostic accuracy and identified new targets for therapy. Moreover, there have been major improvements in all facets of clinical care, including imaging, surgery, radiation and supportive care. In selected cohorts of patients, targeted and immunotherapies have resulted in improved patient outcomes. Furthermore, adaptations to clinical trial design have facilitated our study of new agents and other therapeutic innovations. However, considerable work remains to be done towards extending survival for all patients with primary brain tumors, especially children and adults with diffuse midline gliomas harboring Histone H3 K27 mutations and adults with isocitrate dehydrogenase (IDH) wild-type, O guanine DNA-methyltransferase gene () promoter unmethylated high grade gliomas. In addition to improvements in therapy and care, access to the advances in technology, such as particle radiation or biologic therapy, neuroimaging and molecular diagnostics in both developing and developed countries is needed to improve the outcome of patients with brain tumors.
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http://dx.doi.org/10.3389/fonc.2021.659800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142853PMC
May 2021

Medium-Chain Acyl-CoA Dehydrogenase Protects Mitochondria from Lipid Peroxidation in Glioblastoma.

Cancer Discov 2021 May 26. Epub 2021 May 26.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes medium-chain fatty acids (MCFA), due to its consistently high score and high expression among models and upregulation in GBM compared with normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism may exploit a key metabolic feature of GBM. SIGNIFICANCE: MCAD exerts a protective role to prevent accumulation of toxic metabolic by-products in glioma cells, actively catabolizing lipid species that would otherwise affect mitochondrial integrity and induce cell death. This work represents a first demonstration of a nonenergetic role for dependence on fatty acid metabolism in cancer.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1437DOI Listing
May 2021

The state of neuro-oncology during the COVID-19 pandemic: a worldwide assessment.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab035. Epub 2021 Feb 20.

Departments of Medicine and Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.

Background: It remains unknown how the COVID-19 pandemic has changed neuro-oncology clinical practice, training, and research efforts.

Methods: We performed an international survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents, April 24-May 17, 2020. We assessed clinical practice and research environments, institutional preparedness and support, and perceived impact on patients.

Results: Of 582 respondents, 258 (45%) were US-based and 314 (55%) international. Ninety-four percent of participants reported changes in their clinical practice. Ninety-five percent of respondents converted at least some practice to telemedicine. Ten percent of practitioners felt the need to see patients in person, specifically because of billing concerns and pressure from their institutions. Sixty-seven percent of practitioners suspended enrollment for at least one clinical trial, including 62% suspending phase III trial enrollments. More than 50% believed neuro-oncology patients were at increased risk for COVID-19. Seventy-one percent of clinicians feared for their own personal safety or that of their families, specifically because of their clinical duties; 20% had inadequate personal protective equipment. While 69% reported increased stress, 44% received no psychosocial support from their institutions. Thirty-seven percent had salary reductions and 63% of researchers temporarily closed their laboratories. However, the pandemic created positive changes in perceived patient satisfaction, communication quality, and technology use to deliver care and mediate interactions with other practitioners.

Conclusions: The pandemic has changed treatment schedules and limited investigational treatment options. Institutional lack of support created clinician and researcher anxiety. Communication with patients was satisfactory. We make recommendations to guide clinical and scientific infrastructure moving forward and address the personal challenges of providers and researchers.
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http://dx.doi.org/10.1093/noajnl/vdab035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928618PMC
February 2021

A randomized phase II trial of veliparib, radiotherapy, and temozolomide in patients with unmethylated MGMT glioblastoma: the VERTU study.

Neuro Oncol 2021 10;23(10):1736-1749

NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.

Background: Temozolomide offers minimal benefit in patients with glioblastoma with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence, the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly(ADP-ribose) polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide.

Methods: VERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the progression-free survival rate at six months (PFS-6m) in the experimental arm.

Results: A total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36%-57%) in the experimental arm and 31% (95% CI: 18%-46%) in the standard arm. Median overall survival was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals.

Conclusion: The veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.
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http://dx.doi.org/10.1093/neuonc/noab111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485443PMC
October 2021

A prospective phase II randomized trial of proton radiotherapy vs intensity-modulated radiotherapy for patients with newly diagnosed glioblastoma.

Neuro Oncol 2021 08;23(8):1337-1347

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM).

Methods: Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs).

Results: A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02).

Conclusions: In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.
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http://dx.doi.org/10.1093/neuonc/noab040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328012PMC
August 2021

PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells.

Mol Cell 2021 03 3;81(6):1276-1291.e9. Epub 2021 Feb 3.

The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

Aberrant cell proliferation is a hallmark of cancer, including glioblastoma (GBM). Here we report that protein arginine methyltransferase (PRMT) 6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells (GSCs), a subpopulation in GBM critical for malignancy. We identified a casein kinase 2 (CK2)-PRMT6-regulator of chromatin condensation 1 (RCC1) signaling axis whose activity is an important contributor to the stem-like properties and tumor biology of GSCs. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation, which promotes PRMT6 methylation of RCC1, which in turn is required for RCC1 association with chromatin and activation of RAN. Disruption of this pathway results in defects in mitosis. EPZ020411, a specific small-molecule inhibitor for PRMT6, suppresses RCC1 arginine methylation and improves the cytotoxic activity of radiotherapy against GSC brain tumor xenografts. This study identifies a CK2α-PRMT6-RCC1 signaling axis that can be therapeutically targeted in the treatment of GBM.
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http://dx.doi.org/10.1016/j.molcel.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979509PMC
March 2021

Breaking Tradition to Bridge Bench and Bedside: Accelerating the MD-PhD-Residency Pathway.

Acad Med 2021 04;96(4):518-521

J. Cangiarella is associate dean, Education and Faculty, associate professor of pathology, and director, the Accelerated 3-Year MD Pathway, New York University Grossman School of Medicine, New York, New York; ORCID: https://orcid.org/0000-0002-9364-2672.

Problem: Physician-scientists are individuals trained in both clinical practice and scientific research. Often, the goal of physician-scientist training is to address pressing questions in biomedical research. The established pathways to formally train such individuals are mainly MD-PhD programs and physician-scientist track residencies. Although graduates of these pathways are well equipped to be physician-scientists, numerous factors, including funding and length of training, discourage application to such programs and impede success rates.

Approach: To address some of the pressing challenges in training and retaining burgeoning physician-scientists, New York University Grossman School of Medicine formed the Accelerated MD-PhD-Residency Pathway in 2016. This pathway builds on the previously established accelerated 3-year MD pathway to residency at the same institution. The Accelerated MD-PhD-Residency Pathway conditionally accepts MD-PhD trainees to a residency position at the same institution through the National Resident Matching Program.

Outcomes: Since its inception, 2 students have joined the Accelerated MD-PhD-Residency Pathway, which provides protected research time in their chosen residency. The pathway reduces the time to earn an MD and PhD by 1 year and reduces the MD training phase to 3 years, reducing the cost and lowering socioeconomic barriers. Remaining at the same institution for residency allows for the growth of strong research collaborations and mentoring opportunities, which foster success.

Next Steps: The authors and institutional leaders plan to increase the number of trainees who are accepted into the Accelerated MD-PhD-Residency Pathway and track the success of these students through residency and into practice to determine if the pathway is meeting its goal of increasing the number of practicing physician-scientists. The authors hope this model can serve as an example to leaders at other institutions who may wish to adopt this pathway for the training of their MD-PhD students.
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http://dx.doi.org/10.1097/ACM.0000000000003920DOI Listing
April 2021

Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity.

Genome Biol 2020 11 4;21(1):271. Epub 2020 Nov 4.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary.

Results: We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases.

Conclusions: Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.
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http://dx.doi.org/10.1186/s13059-020-02175-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640699PMC
November 2020

Full automation of spinal stereotactic radiosurgery and stereotactic body radiation therapy treatment planning using Varian Eclipse scripting.

J Appl Clin Med Phys 2020 Oct 23;21(10):122-131. Epub 2020 Sep 23.

Department of Radiation Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.

The purpose of this feasibility study is to develop a fully automated procedure capable of generating treatment plans with multiple fractionation schemes to improve speed, robustness, and standardization of plan quality. A fully automated script was implemented for spinal stereotactic radiosurgery/stereotactic body radiation therapy (SRS/SBRT) plan generation using Eclipse v15.6 API. The script interface allows multiple dose/fractionation plan requests, planning target volume (PTV) expansions, as well as information regarding distance/overlap between spinal cord and targets to drive decision-making. For each requested plan, the script creates the course, plans, field arrangements, and automatically optimizes and calculates dose. The script was retrospectively applied to ten computed tomography (CT) scans of previous cervical, thoracic, and lumbar spine SBRT patients. Three plans were generated for each patient - simultaneous integrated boost (SIB) 1800/1600 cGy to gross tumor volume (GTV)/PTV in one fraction; SIB 2700/2100 cGy to GTV/PTV in three fractions; and 3000 cGy to PTV in five fractions. Plan complexity and deliverability patient-specific quality assurance (QA) was performed using ArcCHECK with an Exradin A16 chamber inserted. Dose objectives were met for all organs at risk (OARs) for each treatment plan. Median target coverage was GTV V100% = 87.3%, clinical target volume (CTV) V100% = 95.7% and PTV V100% = 88.0% for single fraction plans; GTV V100% = 95.6, CTV V100% = 99.6% and PTV V100% = 97.2% for three fraction plans; and GTV V100% = 99.6%, CTV V100% = 99.1% and PTV V100% = 97.2% for five fraction plans. All plans (n = 30) passed patient-specific QA (>90%) at 2%/2 mm global gamma. A16 chamber dose measured at isocenter agreed with planned dose within 3% for all cases. Automatic planning for spine SRS/SBRT through scripting increases efficiency, standardizes plan quality and approach, and provides a tool for target coverage comparison of different fractionation schemes without the need for additional resources.
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http://dx.doi.org/10.1002/acm2.13017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592968PMC
October 2020

Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy.

Elife 2020 09 10;9. Epub 2020 Sep 10.

Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, United States.

Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific 'GBM-on-a-Chip' microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-β1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.
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http://dx.doi.org/10.7554/eLife.52253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556869PMC
September 2020

Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma.

Genome Biol 2020 08 26;21(1):216. Epub 2020 Aug 26.

Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages.

Results: We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCO TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCO TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments.

Conclusions: Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.
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http://dx.doi.org/10.1186/s13059-020-02140-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448990PMC
August 2020

Proton therapy reduces the likelihood of high-grade radiation-induced lymphopenia in glioblastoma patients: phase II randomized study of protons vs photons.

Neuro Oncol 2021 02;23(2):284-294

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: We investigated differences in radiation-induced grade 3+ lymphopenia (G3+L), defined as an absolute lymphocyte count (ALC) nadir of <500 cells/µL, after proton therapy (PT) or X-ray (photon) therapy (XRT) for patients with glioblastoma (GBM).

Methods: Patients enrolled in a randomized phase II trial received PT (n = 28) or XRT (n = 56) concomitantly with temozolomide. ALC was measured before, weekly during, and within 1 month after radiotherapy. Whole-brain mean dose (WBMD) and brain dose-volume indices were extracted from planned dose distributions. Univariate and multivariate logistic regression analyses were used to identify independent predictive variables. The resulting model was evaluated using receiver operating characteristic (ROC) curve analysis.

Results: Rates of G3+L were lower in men (7/47 [15%]) versus women (19/37 [51%]) (P < 0.001), and for PT (4/28 [14%]) versus XRT (22/56 [39%]) (P = 0.024). G3+L was significantly associated with baseline ALC, WBMD, and brain volumes receiving 5‒40 Gy(relative biological effectiveness [RBE]) or higher (ie, V5 through V40). Stepwise multivariate logistic regression analysis identified being female (odds ratio [OR] 6.2, 95% confidence interval [CI]: 1.95‒22.4, P = 0.003), baseline ALC (OR 0.18, 95% CI: 0.05‒0.51, P = 0.003), and whole-brain V20 (OR 1.07, 95% CI: 1.03‒1.13, P = 0.002) as the strongest predictors. ROC analysis yielded an area under the curve of 0.86 (95% CI: 0.79-0.94) for the final G3+L prediction model.

Conclusions: Sex, baseline ALC, and whole-brain V20 were the strongest predictors of G3+L for patients with GBM treated with radiation and temozolomide. PT reduced brain volumes receiving low and intermediate doses and, consequently, reduced G3+L.
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http://dx.doi.org/10.1093/neuonc/noaa182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906048PMC
February 2021

Correlative study of epigenetic regulation of tumor microenvironment in spindle cell melanomas and cutaneous malignant peripheral nerve sheath tumors.

Sci Rep 2020 08 3;10(1):12996. Epub 2020 Aug 3.

Department of Pathology, NYU Langone Health, NYU Grossman School of Medicine, 550 First Ave, New York, NY, 10016, USA.

The tumor microenvironment (TME) plays critical roles in tumor growth and progression, however key regulators of gene expression in the TME of cutaneous malignant peripheral nerve sheath tumor (C-MPNST) and spindle cell melanoma (SCM) have not been well elucidated. Herein, we investigate the epigenetic regulation of promoters and gene bodies and their effect on the TME composition of C-MPNSTs and SCMs. A cohort of 30 patients was analyzed using differential gene expression (DGE) and gene set enrichment analysis (GSEA) using the Nanostring platform. Methylation analysis was carried out utilizing an Infinium Methylation EPIC array targeting 866,562 methylation site (CpG) islands. DGE revealed overexpression of genes related to mast cells in the TME of SCMs, and a predominance of exhausted CD8 T cells and macrophages in the TME of C-MPNSTs. Interestingly, we further observed promoter hypermethylation in key overexpressed genes and corresponding gene body hypomethylation. Analysis using ENCODE ChIP-sequencing data identified CTCF as the common transcription factor at the site of the hypomethylated probe. These findings support that the TME composition of C-MPNSTs and SCMs is at least partially independent on promoter methylation status, suggesting a possible relationship between gene body enhancers and expression of key TME genes in both entities.
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http://dx.doi.org/10.1038/s41598-020-69787-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398924PMC
August 2020

Genetic driver mutations introduced in identical cell-of-origin in murine glioblastoma reveal distinct immune landscapes but similar response to checkpoint blockade.

Glia 2020 10 8;68(10):2148-2166. Epub 2020 Jul 8.

Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Glioblastoma (GBM) is the most aggressive primary brain tumor. In addition to being genetically heterogeneous, GBMs are also immunologically heterogeneous. However, whether the differences in immune microenvironment are driven by genetic driver mutation is unexplored. By leveraging the versatile RCAS/tv-a somatic gene transfer system, we establish a mouse model for Classical GBM by introducing EGFRvIII expression in Nestin-positive neural stem/progenitor cells in adult mice. Along with our previously published Nf1-silenced and PDGFB-overexpressing models, we investigate the immune microenvironments of the three models of human GBM subtypes by unbiased multiplex profiling. We demonstrate that both the quantity and composition of the microenvironmental myeloid cells are dictated by the genetic driver mutations, closely mimicking what was observed in human GBM subtypes. These myeloid cells express high levels of the immune checkpoint protein PD-L1; however, PD-L1 targeted therapies alone or in combination with irradiation are unable to increase the survival time of tumor-bearing mice regardless of the driver mutations, reflecting the outcomes of recent human trials. Together, these results highlight the critical utility of immunocompetent mouse models for preclinical studies of GBM, making these models indispensable tools for understanding the resistance mechanisms of immune checkpoint blockade in GBM and immune cell-targeting drug discovery.
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http://dx.doi.org/10.1002/glia.23883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512141PMC
October 2020

Racial and socioeconomic disparities differentially affect overall and cause-specific survival in glioblastoma.

J Neurooncol 2020 Aug 2;149(1):55-64. Epub 2020 Jul 2.

Brain and Spine Tumor Center, Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, 240 E 38th Street, 19th Floor, New York, NY, USA.

Introduction: The prognostic role of racial and socioeconomic factors in patients with glioblastoma is controversially debated. We aimed to evaluate how these factors may affect survival outcomes in an overall and cause-specific manner using large, national cancer registry cohort data in the temozolomide chemoradiation era.

Methods: The National Cancer Institute's Surveillance, Epidemiology, and End Results database was queried for patients diagnosed with glioblastoma between 2005 and 2016. Overall survival was assessed using Cox proportional hazard models using disease intrinsic and extrinsic factors. Cause-specific mortality was assessed using cumulative incidence curves and modeled using multivariate cumulative risk regression.

Results: A total of 28,952 patients met the prespecified inclusion criteria and were included in this analysis. The following factors were associated with all-cause mortality: age, calendar year of diagnosis, sex, treatment receipt, tumor size, tumor location, extent of resection, median household income, and race. Asian/Pacific Islanders and Hispanic Whites had lower mortality compared to Non-Hispanic Whites. Cause-specific mortality was associated with both racial and socioeconomic groups. After adjusting for treatment and tumor-related factors, Asian/Pacific and black patients had lower glioblastoma-specific mortality. However, lower median household income and black race were associated with significantly higher non-glioblastoma mortality.

Conclusions: Despite the aggressive nature of glioblastoma, racial and socioeconomic factors influence glioblastoma-specific and non-glioblastoma associated mortality. Our study shows that patient race has an impact on glioblastoma-associated mortality independently of tumor and treatment related factors. Importantly, socioeconomic and racial differences largely contribute to non-glioblastoma mortality, including death from other cancers, cardio- and cerebrovascular events.
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http://dx.doi.org/10.1007/s11060-020-03572-yDOI Listing
August 2020

Radiation with STAT3 Blockade Triggers Dendritic Cell-T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy.

Clin Cancer Res 2020 09 30;26(18):4983-4994. Epub 2020 Jun 30.

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Patients with central nervous system (CNS) tumors are typically treated with radiotherapy, but this is not curative and results in the upregulation of phosphorylated STAT3 (p-STAT3), which drives invasion, angiogenesis, and immune suppression. Therefore, we investigated the combined effect of an inhibitor of STAT3 and whole-brain radiotherapy (WBRT) in a murine model of glioma.

Experimental Design: C57BL/6 mice underwent intracerebral implantation of GL261 glioma cells, WBRT, and treatment with WP1066, a blood-brain barrier-penetrant inhibitor of the STAT3 pathway, or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune-incompetent backgrounds, immunofluorescence, immune phenotyping of tumor-infiltrating immune cells (via flow cytometry), and NanoString gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the tumor microenvironment.

Results: The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy in the GL261 glioma model (combination vs. control < 0.0001). Immunologic memory appeared to be induced, because mice were protected during subsequent tumor rechallenge. The therapeutic effect of the combination was completely lost in immune-incompetent animals. NanoString analysis and immunofluorescence revealed immunologic reprograming in the CNS tumor microenvironment specifically affecting dendritic cell antigen presentation and T-cell effector functions.

Conclusions: This study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against gliomas in the CNS by inducing dendritic cell and T-cell interactions in the CNS tumor.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4092DOI Listing
September 2020

Stereotactic Radiation for Treating Primary and Metastatic Neoplasms of the Spinal Cord.

Front Oncol 2020 9;10:907. Epub 2020 Jun 9.

Departments of Radiation Oncology, NYU Grossman School of Medicine, New York, NY, United States.

Stereotactic radiation treatment can be used to treat spinal cord neoplasms in patients with either unresectable lesions or residual disease after surgical resection. While treatment guidelines have been suggested for epidural lesions, the utility of stereotactic radiation for intradural and intramedullary malignancies is still debated. Prior reports have suggested that stereotactic radiation approaches can be used for effective tumor control and symptom management. Treatment-related toxicity has been documented in rare subsets of patients, though the incidences of injury are not directly correlated with higher radiation doses. Further studies are needed to assess the factors that influence the risk of radiation-induced myelopathy when treating spinal cord neoplasms with stereotactic radiation, which can include, but may not be limited to, maximum dose, dose-fractionation, irradiated volume, tumor location, histology and treatment history. This review will discuss evidence for current treatment approaches.
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http://dx.doi.org/10.3389/fonc.2020.00907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295942PMC
June 2020

Novel Therapies for Glioblastoma.

Curr Neurol Neurosci Rep 2020 05 22;20(7):19. Epub 2020 May 22.

Brain and Spine Tumor Center, Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, 240 E. 38th Street, 19th floor, New York, NY, 10019, USA.

Purpose Of Review: Glioblastoma (GBM) is the most common malignant primary brain tumor, and the available treatment options are limited. This article reviews the recent preclinical and clinical investigations that seek to expand the repertoire of effective medical and radiotherapy options for GBM.

Recent Findings: Recent phase III trials evaluating checkpoint inhibition did not result in significant survival benefit. Select vaccine strategies have yielded promising results in early phase clinical studies and warrant further validation. Various targeted therapies are being explored but have yet to see breakthrough results. In addition, novel radiotherapy approaches are in development to maximize safe dose delivery. A multitude of preclinical and clinical studies in GBM explore promising immunotherapies, targeted agents, and novel radiation modalities. Recent phase III trial failures have once more highlighted the profound tumor heterogeneity and diverse resistance mechanisms of glioblastoma. This calls for the development of biomarker-driven and personalized treatment approaches.
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http://dx.doi.org/10.1007/s11910-020-01042-6DOI Listing
May 2020

Aberrant DNA Methylation Predicts Melanoma-Specific Survival in Patients with Acral Melanoma.

Cancers (Basel) 2019 Dec 16;11(12). Epub 2019 Dec 16.

Department of Pathology, Section of Dermatopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Acral melanoma (AM) is a rare, aggressive type of cutaneous melanoma (CM) with a distinct genetic profile. We aimed to identify a methylome signature distinguishing primary acral lentiginous melanoma (PALM) from primary non-lentiginous AM (NALM), metastatic ALM (MALM), primary non-acral CM (PCM), and acral nevus (AN). A total of 22 PALM, nine NALM, 10 MALM, nine PCM, and three AN were subjected to genome-wide methylation analysis using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites. A prominent finding was that the methylation profiles of PALM and NALM were distinct. Four of the genes most differentially methylated between PALM and NALM or MALM were , , , and . However, when primary AMs (PALM + NALM) were compared with MALM, and were the most differentially methylated, highlighting their pivotal role in the metastatic potential of AMs. Patients with NALM had significantly worse disease-specific survival (DSS) than patients with PALM. Aberrant methylation was significantly associated with aggressive clinicopathologic parameters and worse DSS. Our study emphasizes the importance of distinguishing the two epigenetically distinct subtypes of AM. We also identified novel epigenetic prognostic biomarkers that may serve to risk-stratify patients with AM and may be leveraged for the development of targeted therapies.
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http://dx.doi.org/10.3390/cancers11122031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966546PMC
December 2019

Amplification Induces Increased DNA Damage Response and Renders Selective Sensitivity to Talazoparib (PARP Inhibitor) in Glioblastoma.

Clin Cancer Res 2020 03 18;26(6):1395-1407. Epub 2019 Dec 18.

Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Exploration of novel strategies to extend the benefit of PARP inhibitors beyond -mutant cancers is of great interest in personalized medicine. Here, we identified amplification as a potential biomarker to predict sensitivity to PARP inhibition, providing selection for the glioblastoma (GBM) patient population who will benefit from PARP inhibition therapy.

Experimental Design: Selective sensitivity to the PARP inhibitor talazoparib was screened and validated in two sets [test set ( = 14) and validation set ( = 13)] of well-characterized patient-derived glioma sphere-forming cells (GSC). FISH was used to detect copy number. DNA damage response following talazoparib treatment was evaluated by γH2AX and 53BP1 staining and neutral comet assay. PARP-DNA trapping was analyzed by subcellular fractionation. The selective monotherapy of talazoparib was confirmed using glioma models.

Results: -amplified GSCs showed remarkable sensitivity to talazoparib treatment. amplification was associated with increased reactive oxygen species (ROS) and subsequent increased basal expression of DNA-repair pathways to counterelevated oxidative stress, and thus rendered vulnerability to PARP inhibition. Following talazoparib treatment, -amplified GSCs showed enhanced DNA damage and increased PARP-DNA trapping, which augmented the cytotoxicity. amplification-associated selective sensitivity was further supported by the experimental results showing that talazoparib significantly suppressed tumor growth in -amplified subcutaneous models but not in nonamplified models.

Conclusions: -amplified cells are highly sensitive to talazoparib. Our data provide insight into the potential of using amplification as a selection biomarker for the development of personalized therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2549DOI Listing
March 2020

Genomic and Phenotypic Characterization of a Broad Panel of Patient-Derived Xenografts Reflects the Diversity of Glioblastoma.

Clin Cancer Res 2020 03 18;26(5):1094-1104. Epub 2019 Dec 18.

Mayo Clinic Arizona, Scottsdale, Arizona.

Purpose: Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization.

Experimental Design: PDXs were established from glioblastoma, IDH-wildtype ( = 93), glioblastoma, IDH-mutant ( = 2), diffuse midline glioma, H3 K27M-mutant ( = 1), and both primary ( = 60) and recurrent ( = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, = 83), RNA-sequencing ( = 68), and genome-wide methylation profiling ( = 76). WES data from 24 patient tumors was compared with derivative models.

Results: PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of , and , most at frequencies comparable with human glioblastoma. However, amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including amplification. However, in four patient-PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection.

Conclusions: Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056576PMC
March 2020

Functional and topographic effects on DNA methylation in IDH1/2 mutant cancers.

Sci Rep 2019 11 14;9(1):16830. Epub 2019 Nov 14.

Department of Pathology, NYU Langone Health and School of Medicine, New York, NY, USA.

IDH1/2 mutations are early drivers present in diverse human cancer types arising in various tissue sites. IDH1/2 mutation is known to induce a global hypermethylator phenotype. However, the effects on DNA methylation across IDH mutant cancers and functionally different genome regions, remain unknown. We analyzed DNA methylation data from IDH1/2 mutant acute myeloid leukemia, oligodendroglioma, astrocytoma, solid papillary breast carcinoma with reverse polarity, sinonasal undifferentiated carcinoma and cholangiocarcinoma, which clustered by their embryonal origin. Hypermethylated common probes affect predominantly gene bodies while promoters in IDH1/2 mutant cancers remain unmethylated. Enhancers showed global hypermethylation, however commonly hypomethylated enhancers were associated with tissue differentiation and cell fate determination. We demonstrate that some chromosomes, chromosomal arms and chromosomal regions are more affected by IDH1/2 mutations while others remain resistant to IDH1/2 mutation induced methylation changes. Therefore IDH1/2 mutations have different methylation effect on different parts of the genome, which may be regulated by different mechanisms.
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http://dx.doi.org/10.1038/s41598-019-53262-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856069PMC
November 2019
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