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Massachusetts General Hospital is a founding member of the National Cancer Institute (NCI)-sponsored New Approaches to Brain Tumor Therapy (NABTT) clinical trials consortium and has entered its eleventh consecutive year of funding as part of this cooperative group. There are currently 18 open clinical trials for patients with newly diagnosed and recurrent malignant brain tumors. With more than 4,000 outpatient visits per year, the program is one of the largest in the U.S. Faculty members in the program also collaborate closely with colleagues at multiple institutions as part of Dana-Farber/Partners CancerCare. The Stephen E. and Catherine Pappas Center is supported by cooperative group grants (NABTT, RTOG), a program project grant (gene therapy), and multiple investigator-specific NIH grants.
Most clinical trials in the program are NCI/NABTT-sponsored Phase I and II studies, with our investigators currently serving as national chairs of three such studies. In addition, institution was designated as the Pharmacology Core Laboratory for NABTT in 2004. The Neuro-Oncology Program is also an active participant in studies of agents designed to enhance the sensitivity of tumor cells to ionizing radiation as part of the Radiation Therapy Oncology Group (RTOG). In addition to these approaches, the hospital is an international leader in the development of gene therapy and oncolytic viral therapy for malignant gliomas. An NIH-funded program project on this topic has led to a Phase I trial of viral vector-based gene therapy for recurrent malignant gliomas.
Current efforts in the viral oncolytic/gene therapy program include:
In addition to NCI/NABTT, RTOG, institutional and industry clinical trials, Neuro-Oncology Program investigators have collaborated with colleagues at Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Children's Hospital Boston to conduct ongoing clinical trials of antiangiogenic therapies and a telomerase peptide vaccine trial.
The hospital investigators have established standard therapeutic approaches for primary central nervous system lymphoma (PCNSL) on the basis of national, multicenter studies. Two ongoing, national, multicenter studies of methotrexate and thio TEPA for newly diagnosed PCNSL and rituximab for recurrent PCNSL are chaired by the hospital investigators. In addition, our physicians have established useful prognostic markers in this disease. An international collaborative group to study PCNSL, chaired by a Massachusetts General Hospital investigator, has been established as part of the International Extranodal Lymphoma Study Group.
Investigators have a longstanding research interest in neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis. The Neurofibromatosis Clinic provides comprehensive care for patients and families affected by NF. The clinic director was recently awarded a four-year grant to study the role of whole body MRI scanning in these disorders. Other ongoing projects include clinical trials of antiangiogenic agents for treatment of neurofibromas and molecular characterization of SMARCB1(INI1) gene mutations in familial schwannomatosis.
Investigators at the institution have pioneered studies of the molecular classification of adult primary brain tumors. As a result of this work, chromosome 1p and chromosome 19q analysis are now routinely ordered as part of the diagnostic evaluation of patients with oligodendroglial tumors. Ongoing work utilizing gene-expression profiling has established distinct subsets of glioblastoma, and this information will be incorporated into future clinical trials. All new primary brain tumor patients are consented for entry into a clinical database and a brain tumor tissue bank at the hospital. More than 1500 primary brain tumor patients have been entered into the database since the inception of this resource in 1998. Correlative clinical-genetic studies are ongoing using these resources.
Investigators in the program have developed an active research imaging program for brain tumors utilizing spectroscopy and diffusion weighted images to predict chemosensitivity of brain tumors. This work, funded by NIH grant support, is ongoing.
1 Eichler AF, Batchelor TT Primary central nervous system lymphoma: presentation, diagnosis and staging. Neurosurg Focus. 11/30/2006; 21(5); E15.
2 Gerstner ER, Duda DG, di Tomaso E, Sorensen G, Jain RK, Batchelor TT Antiangiogenic agents for the treatment of glioblastoma. Expert Opin Investig Drugs. 11/28/2007; 16(12); 1895-908.
3 Sher DJ, Henson JW, Avutu B, Hochberg FH, Batchelor TT, Martuza RL, Barker FG, Loeffler JS, Chakravarti A The added value of concurrently administered temozolomide versus adjuvant temozolomide alone in newly diagnosed glioblastoma. J Neurooncol. 01/30/2008;
4 Reardon DA, Wen PY, Desjardins A, Batchelor TT, Vredenburgh JJ Glioblastoma multiforme: an emerging paradigm of anti-VEGF therapy. Expert Opin Biol Ther. 03/20/2008; 8(4); 541-53.
5 Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT Angiogenesis in brain tumours. Nat Rev Neurosci. 07/23/2007; 8(8); 610-22.
6 Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT Angiogenesis in brain tumours. Nat Rev Neurosci. 07/23/2007; 8(8); 610-22.
7 Shih HA, Loeffler JS Radiation therapy in acromegaly. Rev Endocr Metab Disord. 02/08/2008; 9(1); 59-65.
8 Pommier P, Liebsch NJ, Deschler DG, Lin DT, McIntyre JF, Barker FG, Adams JA, Lopes VV, Varvares M, Loeffler JS, Chan AW Proton beam radiation therapy for skull base adenoid cystic carcinoma. Arch Otolaryngol Head Neck Surg. 11/22/2006; 132(11); 1242-9.
9 Eichler AF, Loeffler JS Multidisciplinary management of brain metastases. Oncologist. 08/03/2007; 12(7); 884-98
10 Sher DJ, Henson JW, Avutu B, Hochberg FH, Batchelor TT, Martuza RL, Barker FG, Loeffler JS, Chakravarti A The added value of concurrently administered temozolomide versus adjuvant temozolomide alone in newly diagnosed glioblastoma. J Neurooncol. 01/30/2008;
11 Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 01/15/2007; 11(1); 83-95.
12 Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 01/15/2007; 11(1); 83-95.
13 Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, Batchelor TT, Futreal PA, Stratton MR, Curry WT, Iafrate AJ, Louis DN Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res. 04/03/2007; 13(7); 2038-45.
14 Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 11/02/2007; 21(21); 2683-710.
15 Louis DN Molecular pathology of malignant gliomas. Annu Rev Pathol. 11/27/2007; 1; 97-117.
16 Yip S, Iafrate AJ, Louis DN Molecular diagnostic testing in malignant gliomas: a practical update on predictive markers. J Neuropathol Exp Neurol. 01/03/2008; 67(1); 1-15.
17 Liu R, Martuza RL, Rabkin SD Intracarotid delivery of oncolytic HSV vector G47Delta to metastatic breast cancer in the brain. Gene Ther. 04/07/2005; 12(8); 647-54.
18 Aghi M, Rabkin S, Martuza RL Effect of chemotherapy-induced DNA repair on oncolytic herpes simplex viral replication. J Natl Cancer Inst. 01/04/2006; 98(1); 38-50.
19 Varghese S, Rabkin SD, Nielsen PG, Wang W, Martuza RL Systemic oncolytic herpes virus therapy of poorly immunogenic prostate cancer metastatic to lung. Clin Cancer Res. 05/05/2006; 12(9); 2919-27.
20 Fulci G, Dmitrieva N, Gianni D, Fontana EJ, Pan X, Lu Y, Kaufman CS, Kaur B, Lawler SE, Lee RJ, Marsh CB, Brat DJ, van Rooijen N, Stemmer-Rachamimov AO, Rachamimov AS, Hochberg FH, Weissleder R, Martuza RL, Chiocca EA Depletion of peripheral macrophages and brain microglia increases brain tumor titers of oncolytic viruses. Cancer Res. 10/02/2007; 67(19); 9398-406.
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