Publications by authors named "Louis Burt Nabors"

15 Publications

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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

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 11 2;18(11):1537-1570. Epub 2020 Nov 2.

5The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.
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http://dx.doi.org/10.6004/jnccn.2020.0052DOI Listing
November 2020

Handedness and the risk of glioma.

J Neurooncol 2018 May 13;137(3):639-644. Epub 2018 Jan 13.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612-9416, USA.

Gliomas are the most common type of malignant primary brain tumor and few risk factors have been linked to their development. Handedness has been associated with several pathologic neurological conditions such as schizophrenia, autism, and epilepsy, but few studies have evaluated a connection between handedness and risk of glioma. In this study, we examined the relationship between handedness and glioma risk in a large case-control study (1849 glioma cases and 1354 healthy controls) and a prospective cohort study (326,475 subjects with 375 incident gliomas). In the case-control study, we found a significant inverse association between left handedness and glioma risk, with left-handed persons exhibiting a 35% reduction in the risk of developing glioma [odds ratio (OR) = 0.65, 95% confidence interval (CI) 0.51-0.83] after adjustment for age, gender, race, education, and state of residence; similar inverse associations were observed for GBM (OR = 0.69, 95% CI 0.52-0.91), and non-GBM (OR = 0.59, 95% CI 0.42-0.82) subgroups. The association was consistent in both males and females, and across age strata, and was observed in both glioblastoma and in lower grade tumors. In the prospective cohort study, we found no association between handedness and glioma risk (hazards ratio = 0.92, 95% CI 0.67-1.28) adjusting for age, gender, and race. Further studies on this association may help to elucidate mechanisms of pathogenesis in glioma.
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http://dx.doi.org/10.1007/s11060-018-2759-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924459PMC
May 2018

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017.

J Natl Compr Canc Netw 2017 11;15(11):1331-1345

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.
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http://dx.doi.org/10.6004/jnccn.2017.0166DOI Listing
November 2017

Central Nervous System: Notable Developments in the Management of Primary and Recurrent Gliomas.

J Natl Compr Canc Netw 2016 05;14(5 Suppl):681-4

Presented by Louis Burt Nabors, MD, Department of Neurology, Division of Neuro-Oncology, University of Alabama at Birmingham, Birmingham, Alabama.

Over the past 30 years, the incidence of primary brain tumors has been increasing. Primary brain tumors are a heterogeneous group of central nervous system cancers with a wide range of outcomes and therapeutic strategies. As a result, prognostic features and molecular markers play a critical role in selecting treatment options for patients with brain tumors. At the NCCN 21st Annual Conference, Louis Burt Nabors, MD, reviewed the most appropriate adjuvant therapy for 3 types of brain tumors-primary low-grade gliomas, anaplastic oligodendrogliomas, and malignant gliomas-and shared supportive clinical trial data and NCCN recommendations.
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http://dx.doi.org/10.6004/jnccn.2016.0192DOI Listing
May 2016

Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome.

Oncotarget 2016 Mar;7(12):15018-32

Department of Oncology, University Hospital Zurich, Zurich, Switzerland.

Integrins αvβ3 and αvβ5 regulate angiogenesis and invasiveness in cancer, potentially by modulating activation of the transforming growth factor (TGF)-β pathway. The randomized phase III CENTRIC and phase II CORE trials explored the integrin inhibitor cilengitide in patients with newly diagnosed glioblastoma with versus without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. These trials failed to meet their primary endpoints.Immunohistochemistry was used to assess the levels of the target integrins of cilengitide, αvβ3 and αvβ5 integrins, of αvβ8 and of their putative target, phosphorylation of SMAD2, in tumor tissues from CENTRIC (n=274) and CORE (n=224).αvβ3 and αvβ5 expression correlated well in tumor and endothelial cells, but showed little association with αvβ8 or pSMAD2 levels. In CENTRIC, there was no interaction between the biomarkers and treatment for prediction of outcome. In CORE, higher αvβ3 levels in tumor cells were associated with improved progression-free survival by central review and with improved overall survival in patients treated with cilengitide.Integrins αvβ3, αvβ5 and αvβ8 are differentially expressed in glioblastoma. Integrin levels do not correlate with the activation level of the canonical TGF-β pathway. αvβ3 integrin expression may predict benefit from integrin inhibition in patients with glioblastoma lacking MGMT promoter methylation.
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http://dx.doi.org/10.18632/oncotarget.7588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924768PMC
March 2016

Central Nervous System Cancers, Version 1.2015.

J Natl Compr Canc Netw 2015 Oct;13(10):1191-202

From University of Alabama at Birmingham Comprehensive Cancer Center; City of Hope Comprehensive Cancer Center; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; Yale Cancer Center/Smilow Cancer Hospital; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; The University of Texas MD Anderson Cancer Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of Washington/Seattle Cancer Care Alliance; Roswell Park Cancer Institute; Duke Cancer Institute; UC San Diego Moores Cancer Center; University of Michigan Comprehensive Cancer Center; Memorial Sloan Kettering Cancer Center; St. Jude Children's Research Hospital/University of Tennessee Health Science Center; Massachusetts General Hospital Cancer Center; American Brain Tumor Association; Vanderbilt-Ingram Cancer Center; Mayo Clinic Cancer Center; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Stanford Cancer Institute; Fred & Pamela Buffet Cancer Center; Huntsman Cancer Institute at the University of Utah; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; Moffitt Cancer Center; Fox Chase Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; National Comprehensive Cancer Network.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas.
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http://dx.doi.org/10.6004/jnccn.2015.0148DOI Listing
October 2015

Growth factor dependent regulation of centrosome function and genomic instability by HuR.

Biomolecules 2015 Mar 20;5(1):263-81. Epub 2015 Mar 20.

Department of Neurology, University of Alabama at Birmingham, 510 20th Street South, FOT 1020, Birmingham, AL 35209, USA.

The mRNA binding protein HuR is over expressed in cancer cells and contributes to disease progression through post-transcriptional regulation of mRNA. The regulation of HuR and how this relates to glioma is the focus of this report. SRC and c-Abl kinases regulate HuR sub-cellular trafficking and influence accumulation in the pericentriolar matrix (PCM) via a growth factor dependent signaling mechanism. Growth factor stimulation of glioma cell lines results in the associate of HuR with the PCM and amplification of centrosome number. This process is regulated by tyrosine phosphorylation of HuR and is abolished by mutating tyrosine residues. HuR is overexpressed in tumor samples from patients with glioblastoma and associated with a reduced survival. These findings suggest HuR plays a significant role in centrosome amplification and genomic instability, which contributes to a worse disease outcome.
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http://dx.doi.org/10.3390/biom5010263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384122PMC
March 2015

Central nervous system cancers, version 2.2014. Featured updates to the NCCN Guidelines.

J Natl Compr Canc Netw 2014 Nov;12(11):1517-23

From University of Alabama at Birmingham Comprehensive Cancer Center; City of Hope Comprehensive Cancer Center; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; The University of Texas MD Anderson Cancer Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of Washington/Seattle Cancer Care Alliance; Memorial Sloan Kettering Cancer Center; Roswell Park Cancer Institute; Duke Cancer Institute; UC San Diego Moores Cancer Center; American Brain Tumor Association; University of Michigan Comprehensive Cancer Center; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; Massachusetts General Hospital Cancer Center; Vanderbilt-Ingram Cancer Center; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Stanford Comprehensive Cancer Center; Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center; Huntsman Cancer Institute at the University of Utah; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; Moffitt Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; and National Comprehensive Cancer Network.

The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.
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http://dx.doi.org/10.6004/jnccn.2014.0151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337873PMC
November 2014

Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

Lancet Oncol 2014 Sep 19;15(10):1100-8. Epub 2014 Aug 19.

Seoul National University Bundang Hospital, SNU College of Medicine, Seoul, South Korea.

Background: Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter.

Methods: In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221.

Findings: Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8-28·8) in the cilengitide group and 26·3 months (23·9-34·7) in the control group (hazard ratio 1·02, 95% CI 0·81-1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]).

Interpretation: The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma.

Funding: Merck KGaA, Darmstadt, Germany.
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http://dx.doi.org/10.1016/S1470-2045(14)70379-1DOI Listing
September 2014

Central nervous system cancers.

J Natl Compr Canc Netw 2013 Sep;11(9):1114-51

Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.
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http://dx.doi.org/10.6004/jnccn.2013.0132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124889PMC
September 2013

SSBP2 variants are associated with survival in glioblastoma patients.

Clin Cancer Res 2012 Jun 3;18(11):3154-62. Epub 2012 Apr 3.

Department of Epidemiology and Biostatistics, University of California, San Francisco 185 Berry St, Suite 5700, San Francisco, CA 94107, USA.

Purpose: Glioblastoma is a devastating, incurable disease with few known prognostic factors. Here, we present the first genome-wide survival and validation study for glioblastoma.

Experimental Design: Cox regressions for survival with 314,635 inherited autosomal single-nucleotide polymorphisms (SNP) among 315 San Francisco Adult Glioma Study patients for discovery and three independent validation data sets [87 Mayo Clinic, 232 glioma patients recruited from several medical centers in Southeastern United States (GliomaSE), and 115 The Cancer Genome Atlas patients] were used to identify SNPs associated with overall survival for Caucasian glioblastoma patients treated with the current standard of care, resection, radiation, and temozolomide (total n = 749). Tumor expression of the gene that contained the identified prognostic SNP was examined in three separate data sets (total n = 619). Genotype imputation was used to estimate hazard ratios (HR) for SNPs that had not been directly genotyped.

Results: From the discovery and validation analyses, we identified a variant in single-stranded DNA-binding protein 2 (SSBP2) on 5q14.1 associated with overall survival in combined analyses (HR, 1.64; P = 1.3 × 10(-6)). Expression of SSBP2 in tumors from three independent data sets also was significantly related to patient survival (P = 5.3 × 10(-4)). Using genotype imputation, the SSBP2 SNP rs17296479 had the strongest statistically significant genome-wide association with poorer overall patient survival (HR, 1.79; 95% CI, 1.45-2.22; P = 1.0 × 10(-7)).

Conclusion: The minor allele of SSBP2 SNP rs17296479 and the increased tumor expression of SSBP2 were statistically significantly associated with poorer overall survival among glioblastoma patients. With further confirmation, previously unrecognized inherited variations influencing survival may warrant inclusion in clinical trials to improve randomization. Unaccounted for genetic influence on survival could produce unwanted bias in such studies.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-2778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607457PMC
June 2012

Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies.

Future Oncol 2011 Mar;7(3):339-54

Department of Surgery, Division of Neurosurgery, 047 Baker House, Duke University Medical Center, Box 3624, Durham, NC 27710, USA.

Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.
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http://dx.doi.org/10.2217/fon.11.8DOI Listing
March 2011
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