Publications by authors named "Evanthia Galanis"

159 Publications

Aurora-A kinase oncogenic signaling mediates TGF-β-induced triple-negative breast cancer plasticity and chemoresistance.

Oncogene 2021 Mar 5. Epub 2021 Mar 5.

Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.

Triple-negative breast cancer (TNBCs) account for 15-20% of all breast cancers and represent the most aggressive subtype of this malignancy. Early tumor relapse and progression are linked to the enrichment of a sub-fraction of cancer cells, termed breast tumor-initiating cells (BTICs), that undergo epithelial to mesenchymal transition (EMT) and typically exhibit a basal-like CD44/CD24 and/or ALDH1 phenotype with critical cancer stem-like features such as high self-renewal capacity and intrinsic (de novo) resistance to standard of care chemotherapy. One of the major mechanisms responsible for the intrinsic drug resistance of BTICs is their high ALDH1 activity leading to inhibition of chemotherapy-induced apoptosis. In this study, we demonstrated that aurora-A kinase (AURKA) is required to mediate TGF-β-induced expression of the SNAI1 gene, enrichment of ALDH1 BTICs, self-renewal capacity, and chemoresistance in TNBC experimental models. Significantly, the combination of docetaxel (DTX) with dual TGF-β and AURKA pharmacologic targeting impaired tumor relapse and the emergence of distant metastasis. We also showed in unique chemoresistant TNBC cells isolated from patient-derived TNBC brain metastasis that dual TGF-β and AURKA pharmacologic targeting reversed cancer plasticity and enhanced the sensitivity of TNBC cells to DTX-based-chemotherapy. Taken together, these findings reveal for the first time the critical role of AURKA oncogenic signaling in mediating TGF-β-induced TNBC plasticity, chemoresistance, and tumor progression.
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http://dx.doi.org/10.1038/s41388-021-01711-xDOI Listing
March 2021

Parameters of immunoglobulin extraction from dried blood spot cards and immunoassays for detection of antibody response to pathogens including the novel SARS-CoV-2.

J Immunol Methods 2021 Feb 11;492:112996. Epub 2021 Feb 11.

Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

Dried blood spots (DBS) are routinely used in screening newborns for treatable disorders. Immunoglobulin extraction from DBS, serum or other biological fluids loaded on filter paper cards could represent a valuable method of specimen preservation in monitoring immune response against pathogens as well as vaccination efficiency. In this study using different sources including serum, and monoclonal antibodies we established parameters for antibody extraction from the filter cards to assess antibody reactivity against Helicobacter pylori, measles virus (MV) and the novel coronavirus SARS-CoV-2 antigens. We demonstrated that DBS and dried undiluted serum result in completely preserved antibody activity for immunoassays, including in virus neutralization assays against MV. Extraction efficiency was determined by IgG concentration measurements. The plaque-reduction neutralization titer 50% of dried human serum spots remained stable after more than 10-day storage - 1:359 vs. 1:345 for the corresponding frozen sample. DBSs could be used to monitor immune response to bacterial and viral antigens following natural exposure or immunization. Mice immunized with recombinant spike protein receptor-binding domain of SARS-CoV-2 developed a strong antibody response by day 14 and reached titers above 1:64,000 on day 21 following the secondary boost immunization as measured on DBS samples in antigen-mediated ELISA. Variability in IgG concentration of eluted DBS could be influenced by factors involved in sample application, extraction process and sample characteristics. Adjustment of antibody specific activity to the eluted IgG concentration can increase accuracy of the result interpretation, including in SARS-CoV-2 serological diagnostics.
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http://dx.doi.org/10.1016/j.jim.2021.112996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877893PMC
February 2021

Live Attenuated Measles Virus Vaccine Expressing Heat Shock Protein A.

Mol Ther Oncolytics 2020 Dec 23;19:136-148. Epub 2020 Sep 23.

Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

Measles virus (MV) Edmonston derivative strains are attractive vector platforms in vaccine development and oncolytic virotherapy. heat shock protein A (HspA) is a bacterial heat shock chaperone with essential function as a Ni-ion scavenging protein. We generated and characterized the immunogenicity of an attenuated MV strain encoding the HspA transgene (MV-HspA). MV-HspA showed faster replication within 48 h of infection with >10-fold higher titers and faster accumulation of the MV proteins. It also demonstrated a superior tumor-killing effect against a variety of human solid tumor cell lines, including sarcoma, ovarian and breast cancer. Two intraperitoneal (i.p.) doses of 10 50% tissue culture infectious dose (TCID) MV-HspA significantly improved survival in an ovarian cancer xenograft model: 63.5 days versus 27 days for the control group. The HspA transgene induced a humoral immune response in measles-permissive Ifnarko-CD46Ge transgenic mice. Eight of nine animals developed a long-term anti-HspA antibody response with titers of 1:400 to 1:12,800 without any negative impact on development of protective anti-MV immune memory. MV-HspA triggered an immunogenic cytopathic effect as measured by an HMGB1 assay. The absence of significant elevation of PD-L1 expression indicated that vector-encoded HspA could act as an immunomodulator on the immune check point axis. These data demonstrate that MV-HspA is a potent oncolytic agent and vaccine candidate for clinical translation in cancer treatment and immunoprophylaxis against .
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http://dx.doi.org/10.1016/j.omto.2020.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585873PMC
December 2020

Response to Letter to Editor.

Neuro Oncol 2020 11;22(11):1706-1707

UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

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http://dx.doi.org/10.1093/neuonc/noaa202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690353PMC
November 2020

CODEL: Phase III study of RT, RT + Temozolomide (TMZ), or TMZ for newly-diagnosed 1p/19q Codeleted Oligodendroglioma. Analysis from the initial study design.

Neuro Oncol 2020 Jul 17. Epub 2020 Jul 17.

Dept. of Neurosurgery, Cleveland Clinic, Cleveland OH.

Background: We report the analysis involving patients treated on the initial CODEL design.

Methods: Adults (>18) with newly-diagnosed 1p/19q WHO grade III oligodendroglioma were randomized to RT (5940 cGy) alone (Arm A); RT with concomitant and adjuvant temozolomide (TMZ) (Arm B); or TMZ alone (Arm C). Primary endpoint was overall survival (OS), Arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm.

Results: Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared to RT-treated patients (HR=3.12; 95% CI: 1.26, 7.69; p=0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT Arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for IDH status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as co-variables (Arm C vs pooled Arms A+B), PFS remained shorter for patients not receiving RT, (HR= 3.33; 95% CI: 1.31, 8.45; p=0.011), but not OS ((HR = 2.78; 95% CI 0.58, 13.22, p=0.20). Grade 3+ adverse events occurred in 25%, 42% and 33% of patients (Arms A, B, and C). There were no differences between Arms in neurocognitive decline comparing baseline to 3 months.

Conclusions: TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT Arms. The ongoing CODEL trial has been redesigned to compare RT+PCV versus RT+TMZ.
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http://dx.doi.org/10.1093/neuonc/noaa168DOI Listing
July 2020

Phase 0 and window of opportunity clinical trial design in neuro-oncology: a RANO review.

Neuro Oncol 2020 11;22(11):1568-1579

Department of Neurosurgery, University of California San Francisco, San Francisco, California, USA.

Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been expended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients who receive subtherapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements and determining intratumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood-brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this paper, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0-like ("window of opportunity") studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include (i) only patients in whom a resection of the tumor is planned, (ii) use of clinical doses of an investigational agent, (iii) tissue sampling from enhancing and non-enhancing portions of the tumor, and (iv) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma.
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http://dx.doi.org/10.1093/neuonc/noaa149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690357PMC
November 2020

Consensus recommendations for a dynamic susceptibility contrast MRI protocol for use in high-grade gliomas.

Neuro Oncol 2020 09;22(9):1262-1275

Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Despite the widespread clinical use of dynamic susceptibility contrast (DSC) MRI, DSC-MRI methodology has not been standardized, hindering its utilization for response assessment in multicenter trials. Recently, the DSC-MRI Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition issued an updated consensus DSC-MRI protocol compatible with the standardized brain tumor imaging protocol (BTIP) for high-grade gliomas that is increasingly used in the clinical setting and is the default MRI protocol for the National Clinical Trials Network. After reviewing the basis for controversy over DSC-MRI protocols, this paper provides evidence-based best practices for clinical DSC-MRI as determined by the Committee, including pulse sequence (gradient echo vs spin echo), BTIP-compliant contrast agent dosing (preload and bolus), flip angle (FA), echo time (TE), and post-processing leakage correction. In summary, full-dose preload, full-dose bolus dosing using intermediate (60°) FA and field strength-dependent TE (40-50 ms at 1.5 T, 20-35 ms at 3 T) provides overall best accuracy and precision for cerebral blood volume estimates. When single-dose contrast agent usage is desired, no-preload, full-dose bolus dosing using low FA (30°) and field strength-dependent TE provides excellent performance, with reduced contrast agent usage and elimination of potential systematic errors introduced by variations in preload dose and incubation time.
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http://dx.doi.org/10.1093/neuonc/noaa141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523451PMC
September 2020

Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions.

Neuro Oncol 2020 08;22(8):1073-1113

Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.
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http://dx.doi.org/10.1093/neuonc/noaa106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594557PMC
August 2020

Consensus recommendations for a standardized brain tumor imaging protocol for clinical trials in brain metastases.

Neuro Oncol 2020 06;22(6):757-772

UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The "minimum standard" recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)-prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An "ideal" protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.
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http://dx.doi.org/10.1093/neuonc/noaa030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283031PMC
June 2020

Final report from Intergroup NCCTG 86-72-51 (Alliance): a phase III randomized clinical trial of high-dose versus low-dose radiation for adult low-grade glioma.

Neuro Oncol 2020 06;22(6):830-837

Wake Forest Baptist Health, Winston-Salem, North Carolina.

Background: The optimal radiation dose for adult supratentorial low-grade glioma is unknown. The aim of this study was to provide a final update on oncologic and cognitive outcomes of high-dose versus low-dose radiation for low-grade glioma.

Methods: Between 1986 and 1994, 203 patients with supratentorial low-grade glioma were randomized (1:1) to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection.

Results: For all patients, median overall survival (OS) was 8.4 years (95% CI: 7.2-10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3-6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve 15-year OS (22.4%) versus low-dose radiation (24.9%, log-rank P = 0.978) or 15-year PFS (high dose, 15.2% vs low dose, 9.5%; P = 0.7142). OS was significantly better for patients with preoperative tumor diameter <5 cm and baseline Mini-Mental State Examination (MMSE) >27 and who underwent gross total resection. PFS was improved for patients with oligodendroglioma versus astrocytoma, preoperative tumor diameter <5 cm, patients who had gross total resection, and patients with baseline MMSE >27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years.

Conclusions: Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Cognitive function appeared to be stable after radiation as measured by MMSE.
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http://dx.doi.org/10.1093/neuonc/noaa021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283016PMC
June 2020

Optimizing eligibility criteria and clinical trial conduct to enhance clinical trial participation for primary brain tumor patients.

Neuro Oncol 2020 05;22(5):601-612

Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Building on an initiative to enhance clinical trial participation involving the Society for Neuro-Oncology, the Response Assessment in Neuro-Oncology Working Group, patient advocacy groups, clinical trial cooperative groups, and other partners, we evaluate the impact of eligibility criteria and trial conduct on neuro-oncology clinical trial participation. Clinical trials often carry forward eligibility criteria from prior studies that may be overly restrictive and unnecessary and needlessly limit patient accrual. Inclusion and exclusion criteria should be evaluated based on the goals and design of the study and whether they impact patient safety and/or treatment efficacy. In addition, we evaluate clinical trial conduct as a barrier to accrual and discuss strategies to minimize such barriers for neuro-oncology trials.
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http://dx.doi.org/10.1093/neuonc/noaa015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229255PMC
May 2020

Optimizing Whole Brain Radiation Therapy Dose and Fractionation: Results From a Prospective Phase 3 Trial (NCCTG N107C [Alliance]/CEC.3).

Int J Radiat Oncol Biol Phys 2020 02 22;106(2):255-260. Epub 2019 Oct 22.

CHUM, Montreal, QC, Canada.

Purpose: Whole brain radiation therapy (WBRT) remains a commonly used cancer treatment, although controversy exists regarding the optimal dose/fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits.

Methods And Materials: NCCTG N107C [Alliance]/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the dose/fractionation that would be used for all patients treated at that site (either 30 Gy in 10 fractions or 37.5 Gy in 15 fractions). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher's exact tests.

Results: Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fractions (53%), and 43 were treated with 37.5 Gy in 15 fractions (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology was more frequent with protracted WBRT: 72% vs 45%, P = .01), and 93% of patients completed the full course of WBRT. A more protracted WBRT dose regimen (37.5 Gy in 15 fractions) did not significantly affect time to cognitive failure (hazard ratio [HR], 0.9; 95% confidence interval [CI], 0.6-1.39; P = .66), surgical bed control (HR, 0.52 [95% CI, 0.22-1.25], P = .14), intracranial tumor control (HR, 0.56 [95% CI, 0.28-1.12], P = .09), or overall survival (HR, 0.72 [95% CI, 0.45-1.16], P = .18). Although there was no reported radionecrosis, there is a statistically significant increase in the risk of at least 1 grade ≥3 adverse event with 37.5 Gy in 15 fractions versus 30 Gy in 10 fractions (54% vs 31%, respectively, P = .03).

Conclusions: This post hoc analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with the lengthened course of WBRT. For patients with brain metastases where WBRT is recommended, shorter course hypofractionated regimens remain the current standard of care.
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http://dx.doi.org/10.1016/j.ijrobp.2019.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957747PMC
February 2020

Examiner accuracy in cognitive testing in multisite brain-tumor clinical trials: an analysis from the Alliance for Clinical Trials in Oncology.

Neurooncol Pract 2019 Jul 24;6(4):283-288. Epub 2018 Nov 24.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN.

Background: Cognitive function is an important outcome in brain-tumor clinical trials. Cognitive examiners are often needed across multiple sites, many of whom have no prior testing experience. To ensure quality, we looked at examiner errors in administering a commonly used cognitive test battery, determined whether the errors were correctable upon central review, and considered whether the same errors would be detected using onsite electronic data entry.

Methods: We looked at 500 cognitive exams administered for brain-tumor trials led by the Alliance for Clinical Trials in Oncology (Alliance). Of 2277 tests examined, 32 noncorrectable errors were detected with routine central review (1.4% of tests administered), and thus removed from the database of the respective trial. The invalidation rate for each test was 0.8% for each part of the Hopkins Verbal Learning Test-Revised, 0.8% for Controlled Oral Word Association, 1.8% for Trail Making Test-A and 2.6% for Trail Making Test-B. It was estimated that, with onsite data entry and no central review, 4.9% of the tests entered would have uncorrected errors and 1.3% of entered tests would be frankly invalid but not removed.

Conclusions: Cognitive test results are useful and robust outcome measures for brain-tumor clinical trials. Error rates are extremely low, and almost all are correctable with central review of scoring, which is easy to accomplish. We caution that many errors could be missed if onsite electronic entry is utilized instead of central review, and it would be important to mitigate the risk of invalid scores being entered.

Clinicaltrialsgov Identifiers: NCT01781468 (Alliance A221101), NCT01372774 (NCCTG N107C), NCT00731731 (NCCTG N0874), and NCT00887146 (NCCTG N0577).
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http://dx.doi.org/10.1093/nop/npy048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660817PMC
July 2019

Targeted treatment of papillary craniopharyngiomas harboring BRAF V600E mutations.

Cancer 2019 09 17;125(17):2910-2914. Epub 2019 Jul 17.

Divisions of Neuro-Oncology and Hematology/Oncology, Departments of Neurology and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1002/cncr.32197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032527PMC
September 2019

A phase 1 and randomized, placebo-controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma: Alliance/North Central Cancer Treatment Group N0872.

Cancer 2019 11 10;125(21):3790-3800. Epub 2019 Jul 10.

Department of Neurology, University of Virginia Medical Center, Charlottesville, Virginia.

Background: Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM.

Methods: After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100 mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14-day cycle combined with 10 mg/kg of intravenous bevacizumab on day 1 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS6).

Results: In the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9% [95% CI, 19.5%-40.0%] vs 18.4% [95% CI, 7.7%-34.4%]; P = .22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3 months and 7.7 months, respectively; P = .93). The objective response rate was 15.7% in arm A and 26.3% in arm B (P = .52), but with a significantly longer duration in patients treated on arm A (16.3 months vs 2 months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7% vs 7.9%) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome.

Conclusions: Despite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone.
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http://dx.doi.org/10.1002/cncr.32340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788934PMC
November 2019

The medical necessity of advanced molecular testing in the diagnosis and treatment of brain tumor patients.

Neuro Oncol 2019 12;21(12):1498-1508

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.

Accurate pathologic diagnoses and molecularly informed treatment decisions for a wide variety of cancers depend on robust clinical molecular testing that uses genomic, epigenomic, and transcriptomic-based tools. Nowhere is this more essential than in the workup of brain tumors, as emphasized by the incorporation of molecular criteria into the 2016 World Health Organization classification of central nervous system tumors and the updated official guidelines of the National Comprehensive Cancer Network. Despite the medical necessity of molecular testing in brain tumors, access to and utilization of molecular diagnostics is still highly variable across institutions, and a lack of reimbursement for such testing remains a significant obstacle. The objectives of this review are (i) to identify barriers to adoption of molecular testing in brain tumors, (ii) to describe the current molecular tools recommended for the clinical evaluation of brain tumors, and (iii) to summarize how molecular data are interpreted to guide clinical care, so as to improve understanding and justification for their coverage in the routine workup of adult and pediatric brain tumor cases.
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http://dx.doi.org/10.1093/neuonc/noz119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917404PMC
December 2019

Barriers to accrual and enrollment in brain tumor trials.

Neuro Oncol 2019 09;21(9):1100-1117

Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Many factors contribute to the poor survival of malignant brain tumor patients, some of which are not easily remedied. However, one contributor to the lack of progress that may be modifiable is poor clinical trial accrual. Surveys of brain tumor patients and neuro-oncology providers suggest that clinicians do a poor job of discussing clinical trials with patients and referring patients for clinical trials. Yet, data from the Cancer Action Network of the American Cancer Society suggest that most eligible oncology patients asked to enroll on a clinical trial will agree to do so. To this end, the Society for Neuro-Oncology (SNO) in collaboration with the Response Assessment in Neuro-Oncology (RANO) Working Group, patient advocacy groups, clinical trial cooperative groups, including the Adult Brain Tumor Consortium (ABTC), and other partners are working together with the intent to double clinical trial accrual over the next 5 years. Here we describe the factors contributing to poor clinical trial accrual in neuro-oncology and offer possible solutions.
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http://dx.doi.org/10.1093/neuonc/noz104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594546PMC
September 2019

Phase I-II trial of imatinib mesylate (Gleevec; STI571) in treatment of recurrent oligodendroglioma and mixed oligoastrocytoma. North central cancer treatment group study N0272 (ALLIANCE/NCCTG).

J Neurooncol 2019 Jul 22;143(3):573-581. Epub 2019 May 22.

Mayo Clinic Rochester, Rochester, MN, USA.

Purpose: To evaluate the pharmacokinetics and efficacy of imatinib in patients with recurrent oligodendroglial tumors.

Methods: Patients with progressive WHO grade II-III recurrent tumors after prior RT and chemotherapy were eligible. A phase I dose-escalation study was conducted for patients on enzyme-inducing anticonvulsants (EIAC). A phase II study for non-EIAC patients utilized a fixed dose of 600 mg/D. Primary efficacy endpoint was 6-month progression-free survival (PFS6). A 2-stage design was utilized, with 90% power to detect PFS6 increase from 25 to 45%.

Results: In the Phase I, maximum tolerated dose was not reached at 1200 mg/D. For phase II patients, overall PFS6 was 33% and median PFS 4.0 months (95% CI 2.1, 5.7). Median overall survival (OS) was longer in imatinib-treated patients compared with controls (16.6 vs. 8.0 months; HR = 0.64, 95% CI 0.41,1.0, p = 0.049), and longer in patients with 1p/19q-codeleted tumors (19.2 vs. 6.2 months, HR = 0.43, 95% CI 0.21,0.89, p = 0.019). Confirmed response rate was 3.9% (PR = 1; REGR = 1), with stable disease observed in 52.9%. At 600 mg/D, mean steady-state imatinib plasma concentration was 2513 ng/ml (95% CI 1831,3195). Grade 3-4 adverse events (hematologic, fatigue, GI, hypophosphatemia, or hemorrhage) occurred in 61%.

Conclusions: Although adequate plasma levels were achieved, the observed PFS6 of 33% did not reach our pre-defined threshold for success. Although OS was longer in imatinib-treated patients than controls, this finding would require forward validation in a larger cohort. Imatinib might show greater activity in a population enriched for PDGF-dependent pathway activation in tumor tissue.
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http://dx.doi.org/10.1007/s11060-019-03194-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717651PMC
July 2019

Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A Bayesian Adaptive Platform Trial to Develop Precision Medicines for Patients With Glioblastoma.

JCO Precis Oncol 2019 27;3. Epub 2019 Mar 27.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: Adequately prioritizing the numerous therapies and biomarkers available in late-stage testing for patients with glioblastoma (GBM) requires an efficient clinical testing platform. We developed and implemented INSIGhT (Individualized Screening Trial of Innovative Glioblastoma Therapy) as a novel adaptive platform trial (APT) to develop precision medicine approaches in GBM.

Methods: INSIGhT compares experimental arms with a common control of standard concurrent temozolomide and radiation therapy followed by adjuvant temozolomide. The primary end point is overall survival. Patients with newly diagnosed unmethylated GBM who are R132H mutation negative and with genomic data available for biomarker grouping are eligible. At the initiation of INSIGhT, three experimental arms (neratinib, abemaciclib, and CC-115), each with a proposed genomic biomarker, are tested simultaneously. Initial randomization is equal across arms. As the trial progresses, randomization probabilities adapt on the basis of accumulating results using Bayesian estimation of the biomarker-specific probability of treatment impact on progression-free survival. Treatment arms may drop because of low probability of treatment impact on overall survival, and new arms may be added. Detailed information on the statistical model and randomization algorithm is provided to stimulate discussion on trial design choices more generally and provide an example for other investigators developing APTs.

Conclusion: INSIGhT (NCT02977780) is an ongoing novel biomarker-based, Bayesian APT for patients with newly diagnosed unmethylated GBM. Our goal is to dramatically shorten trial execution timelines while increasing scientific power of results and biomarker discovery using adaptive randomization. We anticipate that trial execution efficiency will also be improved by using the APT format, which allows for the collaborative addition of new experimental arms while retaining the overall trial structure.
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http://dx.doi.org/10.1200/PO.18.00071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448806PMC
March 2019

Interferon signaling predicts response to oncolytic virotherapy.

Oncotarget 2019 Feb 22;10(16):1544-1545. Epub 2019 Feb 22.

Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA; Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.18632/oncotarget.26679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422185PMC
February 2019

A key anti-viral protein, RSAD2/VIPERIN, restricts the release of measles virus from infected cells.

Virus Res 2019 04 23;263:145-150. Epub 2019 Jan 23.

Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA; Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. Electronic address:

Measles virus (MV), a paramyxovirus, is one of the most contagious human pathogens and is responsible for thousands of deaths annually. Wild-type MV evolved to counter the innate immune system by avoiding both type I interferon (IFN) induction and inhibiting IFN signaling through the JAK/STAT pathway. However, virus replication is significantly inhibited in IFN-pretreated cells. Similarly, MV vaccine derived strains are inhibited by IFN pretreatment, but vaccine strains also induce IFN. Despite the significant progress in understanding the interactions between MV and the IFN pathway, the IFN stimulated genes (ISGs) that inhibit MV replication remain largely unknown. The aim of this study is to identify specific ISGs that mediate restriction of MV. In this study, we report that Radical S-adenosyl methionine domain containing 2 (RSAD2) restricts MV infection at the stage of virus release in infected 293T cells. Furthermore, attenuated MV strains are currently being developed as a novel treatment for solid and hematological malignancies. Therefore, we tested the impact of RSAD2 expression in an oncolytic virotherapy context using a MV permissive ovarian cancer line (SR-B2). As measured in 293T cells, MV release was also impaired in SR-B2 cells transduced to express RSAD2 in vitro. Additionally, oncolytic MV therapeutic efficacy was impaired in SR-B2 cells transduced to express RSAD2 in vivo. Overall, we identify RSAD2 as a novel restriction factor for MV by inhibiting the release of virus. These results provide important information regarding the interaction between MV and the innate immune system, as well as implications for the design of oncolytic MV platforms.
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http://dx.doi.org/10.1016/j.virusres.2019.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615567PMC
April 2019

Advances in multidisciplinary therapy for meningiomas.

Neuro Oncol 2019 01;21(Suppl 1):i18-i31

Department of Neurological Surgery, University of California, San Francisco, California, USA.

Surgery has long been established as the first-line treatment for the majority of symptomatic and enlarging meningiomas, and evidence for its success is derived from retrospective case series. Despite surgical resection, a subset of meningiomas display aggressive behavior with early recurrences that are difficult to treat. The decision to radically resect meningiomas and involved structures is balanced against the risk for neurological injury in patients. Radiation therapy has largely been used as a complementary and safe therapeutic strategy in meningiomas with evidence primarily stemming from retrospective, single-institution reports. Two of the first cooperative group studies (RTOG 0539 and EORTC 22042) evaluating the outcomes of adjuvant radiation therapy in higher-risk meningiomas have shown promising preliminary results. Historically, systemic therapy has resulted in disappointing results in meningiomas. However, several clinical trials are under way evaluating the efficacy of chemotherapies, such as trabectedin, and novel molecular agents targeting Smoothened, AKT1, and focal adhesion kinase in patients with recurrent meningiomas.
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http://dx.doi.org/10.1093/neuonc/noy136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347080PMC
January 2019

Integrating Genomics Into Neuro-Oncology Clinical Trials and Practice.

Am Soc Clin Oncol Educ Book 2018 May;38:148-157

From the Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; MacFeeters Hamilton Centre for Neuro-Oncology Research, University of Toronto, Toronto, ON, Canada; Ludwig Center at Harvard, Department of Pathology, Boston Children's Hospital, and Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Important advances in our understanding of the molecular biology of brain tumors have resulted in a rapid evolution in the taxonomy of central nervous system (CNS) tumors, which culminated in the revised 2016 World Health Organization classification of CNS tumors that incorporates an integrated molecular/histologic diagnostic approach. Our expanding understanding of brain tumor genomics and molecular evolution during the disease course has started to impact clinical management. Furthermore, incorporation of genomic information in ongoing and planned neuro-oncology clinical trials is expected to lead to improved outcomes and result in personalized treatment options for patients with CNS malignancies.
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http://dx.doi.org/10.1200/EDBK_200989DOI Listing
May 2018

NOTCH3 expression is linked to breast cancer seeding and distant metastasis.

Breast Cancer Res 2018 09 4;20(1):105. Epub 2018 Sep 4.

Department of Medical Oncology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, USA.

Background: Development of distant metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which includes dissemination of cancer cells from the primary tumor to secondary organs. NOTCH developmental signaling plays a critical role in promoting epithelial-to-mesenchymal transition, tumor stemness, and metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive.

Methods: We have established metastatic xenografts expressing high endogenous levels of NOTCH3 using estrogen receptor alpha-positive (ERα) MCF-7 breast cancer cells with constitutive active Raf-1/mitogen-associated protein kinase (MAPK) signaling (vMCF-7) and MDA-MB-231 triple-negative breast cancer (TNBC) cells. The critical role of NOTCH3 in inducing an invasive phenotype and poor outcome was corroborated in unique TNBC cells resulting from a patient-derived brain metastasis (TNBC-M25) and in publicly available claudin-low breast tumor specimens collected from participants in the Molecular Taxonomy of Breast Cancer International Consortium database.

Results: In this study, we identified an association between NOTCH3 expression and development of metastases in ERα and TNBC models. ERα breast tumor xenografts with a constitutive active Raf-1/MAPK signaling developed spontaneous lung metastases through the clonal expansion of cancer cells expressing a NOTCH3 reprogramming network. Abrogation of NOTCH3 expression significantly reduced the self-renewal and invasive capacity of ex vivo breast cancer cells, restoring a luminal CD44/CD24/ERα phenotype. Forced expression of the mitotic Aurora kinase A (AURKA), which promotes breast cancer metastases, failed to restore the invasive capacity of NOTCH3-null cells, demonstrating that NOTCH3 expression is required for an invasive phenotype. Likewise, pharmacologic inhibition of NOTCH signaling also impaired TNBC cell seeding and metastatic growth. Significantly, the role of aberrant NOTCH3 expression in promoting tumor self-renewal, invasiveness, and poor outcome was corroborated in unique TNBC cells from a patient-derived brain metastasis and in publicly available claudin-low breast tumor specimens.

Conclusions: These findings demonstrate the key role of NOTCH3 oncogenic signaling in the genesis of breast cancer metastasis and provide a compelling preclinical rationale for the design of novel therapeutic strategies that will selectively target NOTCH3 to halt metastatic seeding and to improve the clinical outcomes of patients with breast cancer.
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http://dx.doi.org/10.1186/s13058-018-1020-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123953PMC
September 2018

Proposed response assessment and endpoints for meningioma clinical trials: report from the Response Assessment in Neuro-Oncology Working Group.

Neuro Oncol 2019 01;21(1):26-36

Center of Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts, USA.

No standard criteria exist for assessing response and progression in clinical trials involving patients with meningioma, and there is no consensus on the optimal endpoints for trials currently under way. As a result, there is substantial variation in the design and response criteria of meningioma trials, making comparison between trials difficult. In addition, future trials should be designed with accepted standardized endpoints. The Response Assessment in Neuro-Oncology Meningioma Working Group is an international effort to develop standardized radiologic criteria for treatment response for meningioma clinical trials. In this proposal, we present the recommendations for response criteria and endpoints for clinical trials involving patients with meningiomas.
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http://dx.doi.org/10.1093/neuonc/noy137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303427PMC
January 2019

Constitutive Interferon Pathway Activation in Tumors as an Efficacy Determinant Following Oncolytic Virotherapy.

J Natl Cancer Inst 2018 10;110(10):1123-1132

Department of Molecular Medicine, Mayo Clinic, Rochester, MN.

Background: Attenuated measles virus (MV) strains are promising agents currently being tested against solid tumors or hematologic malignancies in ongoing phase I and II clinical trials; factors determining oncolytic virotherapy success remain poorly understood, however.

Methods: We performed RNA sequencing and gene set enrichment analysis to identify pathways differentially activated in MV-resistant (n = 3) and -permissive (n = 2) tumors derived from resected human glioblastoma (GBM) specimens and propagated as xenografts (PDX). Using a unique gene signature we identified, we generated a diagonal linear discriminant analysis (DLDA) classification algorithm to predict MV responders and nonresponders, which was validated in additional randomly selected GBM and ovarian cancer PDX and 10 GBM patients treated with MV in a phase I trial. GBM PDX lines were also treated with the US Food and Drug Administration-approved JAK inhibitor, ruxolitinib, for 48 hours prior to MV infection and virus production, STAT1/3 signaling and interferon stimulated gene expression was assessed. All statistical tests were two-sided.

Results: Constitutive interferon pathway activation, as reflected in the DLDA algorithm, was identified as the key determinant for MV replication, independent of virus receptor expression, in MV-permissive and -resistant GBM PDXs. Using these lines as the training data for the DLDA algorithm, we confirmed the accuracy of our algorithm in predicting MV response in randomly selected GBM PDX ovarian cancer PDXs. Using the DLDA prediction algorithm, we demonstrate that virus replication in patient tumors is inversely correlated with expression of this resistance gene signature (ρ = -0.717, P = .03). In vitro inhibition of the interferon response pathway with the JAK inhibitor ruxolitinib was able to overcome resistance and increase virus production (1000-fold, P = .03) in GBM PDX lines.

Conclusions: These findings document a key mechanism of tumor resistance to oncolytic MV therapy and describe for the first time the development of a prediction algorithm to preselect for oncolytic treatment or combinatorial strategies.
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http://dx.doi.org/10.1093/jnci/djy033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186520PMC
October 2018

Recurrent papillary craniopharyngioma with BRAF V600E mutation treated with dabrafenib: case report.

J Neurosurg 2018 Apr 1:1-5. Epub 2018 Apr 1.

2Neurology.

The authors present the case of a man with a papillary craniopharyngioma, first diagnosed at 47 years of age, who experienced multiple recurrences. Review of the pathologic specimen from his first resection demonstrated the BRAF V600E mutation. With his most recent recurrence following previous surgery and radiotherapy, at 52 years of age, the decision was made to initiate treatment with the BRAF V600E inhibitor dabrafenib. Imaging following initiation of dabrafenib demonstrated reduction in tumor size. He remained on dabrafenib therapy for approximately 1 year and continued to demonstrate a good clinical result. At that time the decision was made to discontinue dabrafenib therapy and follow up with serial imaging. After more than 1 year of follow-up since stopping dabrafenib, the patient has continued to do well with no radiographic evidence of tumor progression and continues to be monitored with frequent interval imaging.
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http://dx.doi.org/10.3171/2017.11.JNS172373DOI Listing
April 2018

Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma.

Neuro Oncol 2018 08;20(9):1240-1250

UCLA Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

Background: In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS).

Methods: Data from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS.

Results: A log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status.

Conclusion: Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.
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http://dx.doi.org/10.1093/neuonc/noy053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071654PMC
August 2018