Publications by authors named "Mikael L Rinne"

25 Publications

  • Page 1 of 1

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.18.00071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448806PMC
March 2019

Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial.

J Clin Oncol 2019 03 4;37(9):741-750. Epub 2019 Feb 4.

1 Dana-Farber Cancer Institute, Boston, MA.

Purpose: Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.

Methods: This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.

Results: Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKT immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]).

Conclusion: Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.01207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553812PMC
March 2019

Genotype-targeted local therapy of glioma.

Proc Natl Acad Sci U S A 2018 09 6;115(36):E8388-E8394. Epub 2018 Aug 6.

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;

Aggressive neurosurgical resection to achieve sustained local control is essential for prolonging survival in patients with lower-grade glioma. However, progression in many of these patients is characterized by local regrowth. Most lower-grade gliomas harbor isocitrate dehydrogenase 1 () or mutations, which sensitize to metabolism-altering agents. To improve local control of mutant gliomas while avoiding systemic toxicity associated with metabolic therapies, we developed a precision intraoperative treatment that couples a rapid multiplexed genotyping tool with a sustained release microparticle (MP) drug delivery system containing an -directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX-1778). We validated our genetic diagnostic tool on clinically annotated tumor specimens. GMX-1778 MPs showed mutant genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic mutant glioma murine models. Our strategy enables immediate intraoperative genotyping and local application of a genotype-specific treatment in surgical scenarios where local tumor control is paramount and systemic toxicity is therapeutically limiting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1805751115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130372PMC
September 2018

Synergistic interactions with PI3K inhibition that induce apoptosis.

Elife 2017 05 31;6. Epub 2017 May 31.

Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States.

Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a mutant human breast cancer cell. We identified 5 genes () whose suppression induced cell death upon PI3K inhibition. We showed that small molecule inhibitors of the PIM2 and ZAK kinases synergize with PI3K inhibition. In addition, using a microscale implementable device to deliver either siRNAs or small molecule inhibitors in vivo, we showed that suppressing these 5 genes with PI3K inhibition induced tumor regression. These observations identify targets whose inhibition synergizes with PI3K inhibitors and nominate potential combination therapies involving PI3K inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.24523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479695PMC
May 2017

A randomized, placebo-controlled pilot trial of armodafinil for fatigue in patients with gliomas undergoing radiotherapy.

Neuro Oncol 2016 06 21;18(6):849-54. Epub 2016 Feb 21.

Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., M.L.R., B.M.A., N.D.A., L.D., J.S., D.L., S.F.R., J.P., K.H.S., S.C.G., S.H., P.Y.W.); Harvard Medical School, Boston, Massachusetts (E.Q.L., E.T.W., D.A.R., A.D.N., L.N., M.L.R., B.M.A., N.D.A., P.Y.W.); Massachusetts General Hospital, Boston, Massachusetts (A.M.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); University of California San Diego, La Jolla, California (S.K.); Beth Israel Deaconess Medical Center, Boston, Massachusetts (E.T.W.); Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire (C.E.F.); Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (C.E.F.).

Background: Fatigue is common among glioma patients undergoing radiotherapy (RT) and impacts quality of life (QOL). We evaluated whether armodafinil, a wakefulness-promoting medication, improves fatigue in glioma patients undergoing RT.

Methods: Eligibility criteria included age ≥18 years, Karnofsky performance status ≥60, and grade 2-4 glioma undergoing RT to a total dose of 50-60 Gy. Patients were randomized 1:1 to armodafinil or placebo for 8 weeks beginning within 10 days of starting RT. Fatigue and QOL were assessed at baseline, day 22, day 43, and day 56 with the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F), the Functional Assessment of Cancer Therapy - General (FACT-G), the Brief Fatigue Inventory (BFI), and the Cancer Fatigue Scale (CFS). The primary aim was to detect a difference in the 42-day change in FACIT-F fatigue subscale between the 2 groups using a 2-sample Wilcoxon statistic.

Results: We enrolled 81 patients total (42 armodafinil and 39 placebo). Armodafinil did not significantly improve fatigue or QOL based on the 42-day change in FACIT-F fatigue subscale, FACT-G, CFS, or BFI. Further analysis suggests no difference between the arms even after accounting for the potential bias of missing data. Treatment was well tolerated with few grade 3 or 4 toxicities.

Conclusions: While treatment was well-tolerated, an 8-week course of armodafinil did not improve fatigue or QOL in glioma patients undergoing RT in this pilot study. Further studies are needed to determine whether pharmacologic treatment improves fatigue in glioma patients undergoing RT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/now007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864265PMC
June 2016

Central nervous system involvement by Waldenström macroglobulinaemia (Bing-Neel syndrome): a multi-institutional retrospective study.

Br J Haematol 2016 Mar 21;172(5):709-15. Epub 2015 Dec 21.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Bing-Neel syndrome (BNS) is a rare complication seen in patients with Waldenström macroglobulinaemia (WM), in which lymphoplasmacytic lymphoma cells colonize the central nervous system. In this retrospective multi-centre study, we present the clinicopathological features, imaging findings, therapy, response and outcomes of 34 patients with BNS. The median time from WM diagnosis to BNS diagnosis was 3 years, 15% of patients were diagnosed with BNS at the time of WM diagnosis, and 22% of patients developed BNS when responding to active treatment for WM. Patients with BNS presented with variable clinical features including limb motor deficits, change in mental status and cranial nerve palsies. The diagnosis was made using a combination of cerebrospinal fluid cytology, flow cytometry and detection of the MYD88 L265 mutation, and magnetic resonance imaging. The estimated 3-year overall survival rate was 59%. Of the survivors, 40% have evidence of pathological and/or radiological persistence of disease. Age older than 65 years, platelet count lower than 100 × 10(9) /l, and treatment for WM prior to BNS diagnosis were associated with worse outcome. Exposure to rituximab for treatment of BNS was associated with a better outcome. Multi-institutional collaboration is warranted to improve treatment and outcomes in patients with BNS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.13883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480405PMC
March 2016

A prognostic cytogenetic scoring system to guide the adjuvant management of patients with atypical meningioma.

Neuro Oncol 2016 Feb 30;18(2):269-74. Epub 2015 Aug 30.

Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (A.A.A., M.C.H., N.D.A., B.M.A.); Department of Pathology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (M.A., K.L.L., A.H.L., S.S.); Department of Neurosurgery, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (W.L.B., O.A-M., I.F.D.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (E.Q.L., L.N., M.L.R., A.D.N., D.A.R., P.Y.W., R.B.).

Background: The appropriate use of adjuvant therapy in patients with gross totally resected atypical meningioma requires an accurate assessment of recurrence risk. We sought to determine whether cytogenetic/genetic characterization may facilitate better estimation of the probability of recurrence.

Methods: We first analyzed our clinical database, including high-resolution DNA copy number data, to identify 11 common copy number aberrations in a pilot cohort of meningiomas of all grades. We summed these aberrations to devise a cytogenetic abnormality score (CAS) and determined the CAS from archived tissue of a separate cohort of 32 patients with gross totally resected atypical meningioma managed with surgery alone. Propensity score adjusted Cox regression was used to determine whether the CAS was predictive of recurrence.

Results: An association between higher CAS and higher grade was noted in our pilot cohort with heterogeneity among atypical tumors. Among the 32 patients who underwent gross total resection of an atypical meningioma, the CAS was not significantly associated with age, gender, performance status, or tumor size/location but was associated with the risk of recurrence on univariable analysis (hazard ratio per aberration = 1.52; 95% CI = 1.08-2.14; P = .02). After adjustment, the impact of the dichotomized number of copy aberrations remained significantly associated with recurrence risk (hazard ratio = 4.47; 95% CI = 1.01-19.87; P = .05).

Conclusions: The number of copy number aberrations is strongly associated with recurrence risk in patients with atypical meningioma following gross total resection and may inform the appropriate use of adjuvant radiation therapy in these patients or be useful for stratification in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/nov177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724184PMC
February 2016

Extent of resection and overall survival for patients with atypical and malignant meningioma.

Cancer 2015 Dec 26;121(24):4376-81. Epub 2015 Aug 26.

Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts.

Background: The prognosis for patients with atypical and malignant meningioma is guarded; whether the extent of resection is associated with survival-based outcomes in this population remains poorly defined. This study investigated the association between gross total resection (GTR) and all-cause mortality in patients with atypical and malignant meningioma.

Methods: The Surveillance, Epidemiology, and End Results program was used to identify 575 and 64 patients betweens the ages of 18 and 70 years who were diagnosed with atypical and malignant meningioma, respectively, between 2004 and 2009. Multivariate Cox proportional hazards regression was used to assess the adjusted impact of GTR versus subtotal resection on all-cause mortality.

Results: Baseline patient characteristics were similar for patients who did undergo GTR and patients who did not undergo GTR. The 5-year overall survival rates were 91.3% (95% confidence interval [CI], 86.2%-94.5%) and 78.2% (95% CI, 70.0%-84.3%) for patients with atypical meningioma who did and did not undergo GTR, respectively, and 64.5% (95% CI, 45.9%-78.1%) and 41.1% (95% CI, 17.9%-63.1%) for patients with malignant meningioma who did and did not undergo GTR, respectively. After adjustments for available, pertinent confounding variables, GTR was associated with lower all-cause mortality in patients with atypical (hazard ratio, 0.39; 95% CI, 0.23-0.67; P < .001) and malignant meningioma (hazard ratio, 0.35; 95% CI, 0.15-0.81; P = .01).

Conclusions: The extent of resection is a powerful predictor of outcome for patients with atypical and malignant meningioma. These data highlight the hazard associated with the presence of gross tumor bulk after surgery and suggest a value for more extensive resections that should be balanced against the additional potential morbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.29639DOI Listing
December 2015

Rapid Intraoperative Molecular Characterization of Glioma.

JAMA Oncol 2015 Aug;1(5):662-7

Cancer Program, Broad Institute, Cambridge, Massachusetts3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts7Department of Pathology, Harvard Medical School, Boston, Massachusetts.

Importance: Conclusive intraoperative pathologic confirmation of diffuse infiltrative glioma guides the decision to pursue definitive neurosurgical resection. Establishing the intraoperative diagnosis by histologic analysis can be difficult in low-cellularity infiltrative gliomas. Therefore, we developed a rapid and sensitive genotyping assay to detect somatic single-nucleotide variants in the telomerase reverse transcriptase (TERT) promoter and isocitrate dehydrogenase 1 (IDH1).

Observations: This assay was applied to tissue samples from 190 patients with diffuse gliomas, including archived fixed and frozen specimens and tissue obtained intraoperatively. Results demonstrated 96% sensitivity (95% CI, 90%-99%) and 100% specificity (95% CI, 95%-100%) for World Health Organization grades II and III gliomas. In a series of live cases, glioma-defining mutations could be identified within 60 minutes, which could facilitate the diagnosis in an intraoperative timeframe.

Conclusions And Relevance: The genotyping method described herein can establish the diagnosis of low-cellularity tumors like glioma and could be adapted to the point-of-care diagnosis of other lesions that are similarly defined by highly recurrent somatic mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2015.0917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872045PMC
August 2015

Clinical implementation of integrated whole-genome copy number and mutation profiling for glioblastoma.

Neuro Oncol 2015 Oct 9;17(10):1344-55. Epub 2015 Mar 9.

Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.H.R., L.A.R., S.H., D.K., Y.J.K., K.L.L.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (S.E.S., L.B., M.B., D.A.R., E.Q.L., M.L.R., A.D.N., L.N., S.R., L.M.D., D.C.L., P.K., B.J.R., P.Y.W., R.B., K.L.L.); Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts (W.L.B., E.B.C, O.A.-M., M.D.J., A.J.G., I.F.D., E.A.C.); Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (L.T.); Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts (M.H., A.A.A., N.D.A., B.M.A.); Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (M.H., A.A.A., N.D.A., B.M.A.); Harvard Radiation Oncology Program, Boston, Massachusetts (A.R.); Kravis Center for Molecular Oncology & Department of Epidemiology and Biostatistics, Memorial Sloan- Kettering Cancer Center, New York, New York (N.S.); Broad Institute, Cambridge, Massachusetts (R.B.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., A.D., J.B.C., M.A., S.S., R.D.F., N.I.L., A.H.L., K.L.L.).

Background: Multidimensional genotyping of formalin-fixed paraffin-embedded (FFPE) samples has the potential to improve diagnostics and clinical trials for brain tumors, but prospective use in the clinical setting is not yet routine. We report our experience with implementing a multiplexed copy number and mutation-testing program in a diagnostic laboratory certified by the Clinical Laboratory Improvement Amendments.

Methods: We collected and analyzed clinical testing results from whole-genome array comparative genomic hybridization (OncoCopy) of 420 brain tumors, including 148 glioblastomas. Mass spectrometry-based mutation genotyping (OncoMap, 471 mutations) was performed on 86 glioblastomas.

Results: OncoCopy was successful in 99% of samples for which sufficient DNA was obtained (n = 415). All clinically relevant loci for glioblastomas were detected, including amplifications (EGFR, PDGFRA, MET) and deletions (EGFRvIII, PTEN, 1p/19q). Glioblastoma patients ≤40 years old had distinct profiles compared with patients >40 years. OncoMap testing reliably identified mutations in IDH1, TP53, and PTEN. Seventy-seven glioblastoma patients enrolled on trials, of whom 51% participated in targeted therapeutic trials where multiplex data informed eligibility or outcomes. Data integration identified patients with complete tumor suppressor inactivation, albeit rarely (5% of patients) due to lack of whole-gene coverage in OncoMap.

Conclusions: Combined use of multiplexed copy number and mutation detection from FFPE samples in the clinical setting can efficiently replace singleton tests for clinical diagnosis and prognosis in most settings. Our results support incorporation of these assays into clinical trials as integral biomarkers and their potential to impact interpretation of results. Limited tumor suppressor variant capture by targeted genotyping highlights the need for whole-gene sequencing in glioblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/nov015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578577PMC
October 2015

Phase II study of panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma.

Neuro Oncol 2015 Jun 7;17(6):862-7. Epub 2015 Jan 7.

Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts (E.Q.L., D.A.R., A.D.N., L.N., R.B., M.L.R., K.H., C.M., K.H.S., S.C.G., B.W., K.L.L., P.Y.W.); University of Virginia, Charlottesville, Virginia (D.S.); University of Pittsburgh, Pittsburgh, Pennsylvania (J.D.); Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (A.S.C., T,T.B., A.M.); Central DuPage Hospital, Warrenville, Illinois (S.A.G.); Northwestern University, Chicago, Illinois (J.J.R.).

Background: Panobinostat is a histone deacetylase inhibitor with antineoplastic and antiangiogenic effects in glioma that may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat combined with bevacizumab in patients with recurrent high-grade glioma (HGG).

Methods: Patients with recurrent HGG were treated with oral panobinostat 30 mg 3 times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was a 6-month progression-fee survival (PFS6) rate for participants with recurrent glioblastoma (GBM). Patients with recurrent anaplastic glioma (AG) were evaluated as an exploratory arm of the study.

Results: At interim analysis, the GBM arm did not meet criteria for continued accrual, and the GBM arm was closed. A total of 24 patients with GBM were accrued prior to closure. The PFS6 rate was 30.4% (95%, CI 12.4%-50.7%), median PFS was 5 months (range, 3-9 months), and median overall survival (OS) was 9 months (range, 6-19 months). Accrual in the AG arm continued to completion, and a total of 15 patients were enrolled. The PFS6 rate was 46.7% (range, 21%-73%), median PFS was 7 months (range, 2-10 months), and median OS was 17 months (range, 5 months-27 months).

Conclusions: This phase II study of panobinostat and bevacizumab in participants with recurrent GBM did not meet criteria for continued accrual, and the GBM cohort of the study was closed. Although it was reasonably well tolerated, the addition of panobinostat to bevacizumab did not significantly improve PFS6 compared with historical controls of bevacizumab monotherapy in either cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/nou350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483124PMC
June 2015

Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma.

J Neurooncol 2015 Feb 20;121(3):557-63. Epub 2014 Nov 20.

Stephen E. and Catherine Pappas Center for Neuro-Oncology, Division of Hematology/Oncology, Department of Neurology, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Yawkey 9E, Boston, MA, 02114, USA,

Tumor cell infiltration is a major mechanism of treatment escape in glioblastoma. Src is an intracellular tyrosine kinase that mediates tumor cell motility and invasiveness. We evaluated the efficacy and safety of bosutinib, a tyrosine kinase inhibitor that potently inhibits Src and Abl, in patients with recurrent glioblastoma. In this two-arm study, patients with histologically confirmed recurrent glioblastoma and ≤2 relapses, not previously treated with anti-vascular endothelial growth factor (VEGF) therapy, were administered oral bosutinib 400 mg daily. Arm A planned for 6 patients who were candidates for surgical resection to be given bosutinib for 7-9 days prior to resection. Arm B was a two-stage design phase 2 trial targeting 30 patients. The primary endpoint was progression-free survival at 6 months (PFS6) in Arm B. After 9 patients enrolled onto stage 1 of Arm B, 9 (100 %) patients progressed within 6 months. Therefore, the study met the pre-specified criteria for early closure and both Arms were closed. In Arm B, Median PFS was 7.71 weeks and median OS was 50 weeks. Best objective response was stable disease in one patient (11.1 %). Seven patients (77.8 %) had treatment-related AEs of any grade and 2 (22.2 %) were grade ≥3. Arm A was closed after 2 patients enrolled. Src activation was evident in all archival tumor samples. Bosutinib monotherapy does not appear to be effective in recurrent glioblastoma. However, Src remains a potential target based on its upregulation in tumor samples and role in glioma invasion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-014-1667-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323868PMC
February 2015

Phase II trial of triple tyrosine kinase receptor inhibitor nintedanib in recurrent high-grade gliomas.

J Neurooncol 2015 Jan 22;121(2):297-302. Epub 2014 Oct 22.

Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, 75 Francis St., Boston, MA, 02115, USA,

Bevacizumab is FDA-approved for patients with recurrent GBM. However, the median duration of response is only 4 months. Potential mechanisms of resistance include upregulated FGF signaling and increased PDGF-mediated pericyte coverage. Nintedanib is an oral, small-molecule tyrosine kinase inhibitor of PDGFR α/β, FGFR 1-3, and VEGFR 1-3 that may overcome resistance to anti-VEGF therapy. This was a two-stage phase II trial in adults with first or second recurrence of GBM, stratified by prior bevacizumab therapy (ClinicalTrials.gov number NCT01380782; 1199.94). The primary endpoint was PFS6 in the bevacizumab-naive arm (Arm A) and PFS3 in the post-bevacizumab arm (Arm B). Up to 10 anaplastic glioma (AG) patients were accrued to each arm in exploratory cohorts. Twenty-two patients enrolled in Arm A and 14 in Arm B. Arm A included 12 GBMs (55 %), 13 patients with one prior regimen (59 %), and median age 54 years (range 28-75). Arm B included 10 GBMs (71 %), one patient with one prior regimen (7 %), and median age 52 years (range 32-70). Median KPS overall was 90 (range 60-100). There were no responses. In Arm A (GBM only), PFS6 was 0 %, median PFS 28 days (95 % CI 27-83), and median OS 6.9 months (3.7-8.1). In Arm B (GBM only), PFS3 was 0 %, median PFS 28 days (22-28), and median OS 2.6 months (1.0-6.9). Among AG patients in each arm, PFS6 was 0 %. Treatment was well tolerated. In conclusion, nintedanib is not active against recurrent high-grade glioma, regardless of prior bevacizumab therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-014-1631-yDOI Listing
January 2015

Retrospective study of carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab.

Neuro Oncol 2014 Nov 23;16(11):1523-9. Epub 2014 Jun 23.

Harvard Medical School, Boston, Massachusetts (R.R., A.D.N., D.A.R., L.N., M.L.R., R.B., B.M.A., R.Y.H., P.Y.W., E.Q.L.); Center of Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (K.H., A.D.N., D.A.R., L.N., M.L.R., R.B., L.D., S.R., J.R., D.L., P.Y.W., E.Q.L.); Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts (A.D.N., D.A.R., L.N., M.L.R., R.B., P.Y.W., E.Q.L.); Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts (B.M.A.); Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts (R.Y.H.); Boston University School of Medicine, Boston, Massachusetts (A.R.).

Background: Currently, there are no known effective treatments for recurrent glioblastoma once patients have progressed on a bevacizumab-containing regimen. We examined the efficacy of adding nitrosoureas to bevacizumab in patients who progressed while on an initial bevacizumab-containing regimen.

Methods: In this retrospective study, we identified adult patients with histologically confirmed glioblastoma (WHO grade IV) who were treated with lomustine or carmustine in combination with bevacizumab as a second or third regimen after failing an alternative initial bevacizumab-containing regimen. Response rate (RR), 6-month progression free survival (PFS6), and progression-free survival (PFS) were assessed for each treatment.

Results: Forty-two patients were identified (28 males) with a median age of 49 years (range, 24-78 y). Of 42 patients, 28 received lomustine (n = 22) or carmustine (n = 6) with bevacizumab as their second bevacizumab-containing regimen, and 14 received lomustine (n = 11) or carmustine (n = 3) as their third bevacizumab-containing regimen. While the median PFS for the initial bevacizumab-containing regimen was 16.3 weeks, the median PFS for the nitrosourea-containing bevacizumab regimen was 6.3 weeks. Patients had an RR of 44% and a PFS6 rate of 26% during the initial bevacizumab regimen and an RR of 0% and a PFS6 rate of 3% during the nitrosourea-containing bevacizumab regimen. There was increased grade 3-4 toxicity (45% vs 19%, P = .010) during the nitrosourea-containing bevacizumab regimen relative to the initial bevacizumab regimen. Median overall survival was 18.7 weeks from initiation of the nitrosourea-containing bevacizumab regimen.

Conclusion: The addition of lomustine or carmustine to bevacizumab after a patient has already progressed on a bevacizumab-containing regimen does not appear to provide benefit for most patients and is associated with additional toxicity with the doses used in this cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/nou118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201074PMC
November 2014

Adjuvant radiation therapy, local recurrence, and the need for salvage therapy in atypical meningioma.

Neuro Oncol 2014 Nov 2;16(11):1547-53. Epub 2014 Jun 2.

Harvard Radiation Oncology Program, Brigham and Women's Hospital, Boston, Massachusetts (A.A.A.); Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (N.D.A., B.M.A.); Department of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts (P.C.); Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts (E.B.C., A.J.G., M.D.J., O.A-M., I.F.D.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (P.Y.W., D.A.R., E.Q.L., L.N., M.L.R., R.B.); Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (S.E.W.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., S.S., M.A.).

Background: The impact of adjuvant radiation in patients with atypical meningioma remains poorly defined. We sought to determine the impact of adjuvant radiation therapy in this population.

Methods: We identified 91 patients with World Health Organization grade II (atypical) meningioma managed at Dana-Farber/Brigham and Women's Cancer Center between 1997 and 2011. A propensity score model incorporating age at diagnosis, gender, Karnofsky performance status, tumor location, tumor size, reason for diagnosis, and era of treatment was constructed using logistic regression for the outcome of receipt versus nonreceipt of radiation therapy. Propensity scores were then used as continuous covariates in a Cox proportional hazards model to determine the adjusted impact of adjuvant radiation therapy on both local recurrence and the combined endpoint of use of salvage therapy and death due to progressive meningioma.

Results: The median follow-up in patients without recurrent disease was 4.9 years. After adjustment for pertinent confounding variables, radiation therapy was associated with decreased local recurrence in those undergoing gross total resection (hazard ratio, 0.25; 95% CI, 0.07-0.96; P = .04). No differences in overall survival were seen in patients who did and did not receive radiation therapy.

Conclusion: Patients who have had a gross total resection of an atypical meningioma should be considered for adjuvant radiation therapy given the improvement in local control. Multicenter, prospective trials are required to definitively evaluate the potential impact of radiation therapy on survival in patients with atypical meningioma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/nou098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201070PMC
November 2014

Update on bevacizumab and other angiogenesis inhibitors for brain cancer.

Expert Opin Emerg Drugs 2013 Jun 14;18(2):137-53. Epub 2013 May 14.

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

Introduction: Primary and metastatic brain tumors remain a major challenge. The most common primary adult malignant brain tumor, glioblastoma (GBM), confers a dismal prognosis as does the development of CNS metastases for most systemic malignancies. Anti-angiogenic therapy has been a major clinical research focus in neuro-oncology over the past 5 years.

Areas Covered: Culmination of this work includes US FDA accelerated approval of bevacizumab for recurrent GBM and the completion of two placebo-controlled Phase III studies of bevacizumab for newly diagnosed GBM. A multitude of anti-angiogenics are in evaluation for neuro-oncology patients but none has thus far surpassed the therapeutic benefit of bevacizumab.

Expert Opinion: These agents demonstrate adequate safety and the majority of GBM patients derive benefit. Furthermore, their anti-permeability effect can substantially decrease tumor-associated edema leading to stable or improved neurologic function and quality of life. In particular, anti-angiogenics significantly prolong progression-free survival - a noteworthy achievement in the context of infiltrative and destructive brain tumors like GBM; however, in a manner analogous to other cancers, their impact on overall survival for GBM patients is modest at best. Despite substantial clinical research efforts, many fundamental questions regarding anti-angiogenic agents in brain tumor patients remain unanswered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1517/14728214.2013.794784DOI Listing
June 2013

Central nervous system complications of cancer therapy.

J Support Oncol 2012 Jul-Aug;10(4):133-41. Epub 2012 Apr 27.

Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA.

As more effective therapies prolong the survival of patients with cancer, therapy-related toxicities, particularly those affecting the central nervous system (CNS) become increasingly important. CNS complications can cause significant morbidity and can limit the dose or duration of otherwise effective treatments. Because effects on the CNS are disabling and often permanent and treatments remain limited, it is important that clinicians recognize the effects of cancer therapy on the CNS. Cytotoxic chemotherapy and radiation are well-known causes of neurotoxicity, but there is increasing recognition that novel therapies are also sources of adverse effects on the CNS. This review highlights the CNS complications that result from radiation, chemotherapy, and novel therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.suponc.2011.11.002DOI Listing
September 2012

Emerging insights into the molecular and cellular basis of glioblastoma.

Genes Dev 2012 Apr;26(8):756-84

Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Glioblastoma is both the most common and lethal primary malignant brain tumor. Extensive multiplatform genomic characterization has provided a higher-resolution picture of the molecular alterations underlying this disease. These studies provide the emerging view that "glioblastoma" represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gad.187922.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337451PMC
April 2012

Clinical problem-solving. A startling decline.

N Engl J Med 2012 Mar;366(9):836-42

Clinical Pathological Conference Series, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMcps1104209DOI Listing
March 2012

Altering DNA base excision repair: use of nuclear and mitochondrial-targeted N-methylpurine DNA glycosylase to sensitize astroglia to chemotherapeutic agents.

Glia 2007 Nov;55(14):1416-25

Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama 36688, USA.

Primary astrocyte cultures were used to investigate the modulation of DNA repair as a tool for sensitizing astrocytes to genotoxic agents. Base excision repair (BER) is the principal mechanism by which mammalian cells repair alkylation damage to DNA and involves the processing of relatively nontoxic DNA adducts through a series of cytotoxic intermediates during the course of restoring normal DNA integrity. An adenoviral expression system was employed to target high levels of the BER pathway initiator, N-methylpurine glycosylase (MPG), to either the mitochondria or nucleus of primary astrocytes to test the hypothesis that an alteration in BER results in increased alkylation sensitivity. Increasing MPG activity significantly increased BER kinetics in both the mitochondria and nuclei. Although modulating MPG activity in mitochondria appeared to have little effect on alkylation sensitivity, increased nuclear MPG activity resulted in cell death in astrocyte cultures treated with methylnitrosourea (MNU). Caspase-3 cleavage was not detected, thus indicating that these alkylation sensitive astrocytes do not undergo a typical programmed cell death in response to MNU. Astrocytes were found to express relatively high levels of antiapoptotic Bcl-2 and Bcl-XL and very low levels of proapoptotic Bad and Bid suggesting that the mitochondrial pathway of apoptosis may be blocked making astrocytes less vulnerable to proapoptotic stimuli compared with other cell types. Consequently, this unique characteristic of astrocytes may be responsible, in part, for resistance of astrocytomas to chemotherapeutic agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/glia.20556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706656PMC
November 2007

Use of biomass fuel is associated with infant mortality and child health in trend analysis.

Am J Trop Med Hyg 2007 Mar;76(3):585-91

Department of Veterinary Pathobiology, Purdue University, West Lafayette, Indiana, USA.

Biomass fuel used for cooking results in widespread exposure to indoor air pollution (IAP), affecting nearly 3 billion people throughout the world. Few studies, however, have tested for an exposure-response relationship between biomass fuel and health outcomes. The aim of this study was to explore the relationship between biomass fuel, infant mortality, and children's respiratory symptoms. Eighty households in a rural community in Ecuador were selected based on their use of biomass fuel and questioned regarding a history of infant mortality and children's respiratory symptoms. Carbon monoxide (CO) and particulate matter (PM) were measured in a subset of these homes to confirm the relationship between biomass fuel use and IAP. Results showed a significant trend for higher infant mortality among households that cooked with a greater proportion of biomass fuel (P=0.008). Similar trends were noted for history of cough (P=0.02) and earache (P<0.001) among children living in these households.
View Article and Find Full Text PDF

Download full-text PDF

Source
March 2007

Relationship of pulmonary function among women and children to indoor air pollution from biomass use in rural Ecuador.

Respir Med 2006 Jul 28;100(7):1208-15. Epub 2005 Nov 28.

Department of Veterinary Pathobiology, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.

Approximately half the world uses biomass fuel for domestic energy, resulting in widespread exposure to indoor air pollution (IAP) from biomass smoke. IAP has been associated with many respiratory diseases, though it is not clear what relationship exists between biomass use and pulmonary function. Four groups containing 20 households each were selected in Santa Ana, Ecuador based on the relative amount of liquid petroleum gas and biomass fuel that they used for cooking. Pulmonary function tests were conducted on each available member of the households 7 years of age. The pulmonary functions of both children (7-15 years) and women (16 years) were then compared between cooking fuel categories using multivariate linear regression, controlling for the effects of age, gender, height, and exposure to tobacco smoke. Among the 80 households, 77 children and 91 women performed acceptable and reproducible spirometry. In multivariate analysis, children living in homes that use biomass fuel and children exposed to environmental tobacco smoke had lower forced vital capacity and lower forced expiratory volume in 1s (P<0.05). However, no significant difference in pulmonary function was observed among women in different cooking categories. Results of this study demonstrate the harmful effects of IAP from biomass smoke on the lung function of children and emphasize the need for public health efforts to decrease exposure to biomass smoke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmed.2005.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622701PMC
July 2006

Protection of pulmonary epithelial cells from oxidative stress by hMYH adenine glycosylase.

Respir Res 2004 Sep 27;5:16. Epub 2004 Sep 27.

Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Background: Oxygen toxicity is a major cause of lung injury. The base excision repair pathway is one of the most important cellular protection mechanisms that responds to oxidative DNA damage. Lesion-specific DNA repair enzymes include hOgg1, hMYH, hNTH and hMTH.

Methods: The above lesion-specific DNA repair enzymes were expressed in human alveolar epithelial cells (A549) using the pSF91.1 retroviral vector. Cells were exposed to a 95% oxygen environment, ionizing radiation (IR), or H2O2. Cell growth analysis was performed under non-toxic conditions. Western blot analysis was performed to verify over-expression and assess endogenous expression under toxic and non-toxic conditions. Statistical analysis was performed using the paired Student's t test with significance being accepted for p < 0.05.

Results: Cell killing assays demonstrated cells over-expressing hMYH had improved survival to both increased oxygen and IR. Cell growth analysis of A549 cells under non-toxic conditions revealed cells over-expressing hMYH also grow at a slower rate. Western blot analysis demonstrated over-expression of each individual gene and did not result in altered endogenous expression of the others. However, it was observed that O2 toxicity did lead to a reduced endogenous expression of hNTH in A549 cells.

Conclusion: Increased expression of the DNA glycosylase repair enzyme hMYH in A549 cells exposed to O2 and IR leads to improvements in cell survival. DNA repair through the base excision repair pathway may provide an alternative way to offset the damaging effects of O2 and its metabolites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1465-9921-5-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC521691PMC
September 2004