Deputy Director, The Preston Robert Tisch Brain Tumor CenterDepartments / Divisions
Durham, NC 27710
919-684-5301 (New patients), 919-668-6688 (Return patients)
Adults and children with primary and secondary brain and spinal-cord tumors; laboratory and clinical design of new therapeutic strategies utilizing alkylating agents, monoclonal antibodies, small-molecule inhibitors, gene therapy
Overview: Our laboratory is pursuing a comprehensive analysis of the biology and therapy of adult and childhood central nervous system malignancies, particularly high-grade medulloblastoma, glioma, and ependymoma.
Laboratory Studies: Active programs, using human adult and pediatric CNS tumor continuous cell lines, transplantable xenografts growing subcutaneously and intracranially in athymic nude mice and rats, and as well as in the subarachnoid space of the athymic nude rats, and patients tumor specimens, are defining:
1) the chemotherapeutic profile of medulloblastoma, adult and childhood glioma and ependymoma
2) mechanisms of resistance to classical bifunctional alkylators, nitrosoureas and methylators operational in malignant glioma and medulloblastoma, particularly DNA adduct and crosslink repair, O6-alkylguanine-DNA alkyltransferase elevation and DNA mismatch repair deficiency.
3) modulations designed to over come or circumvent specific mechanisms of resistance
4) the activity of signal pathway inhibitors of EGFR, m-tor and other targets
5) the therapeutic advantages of intrathecal and intratumoral drug delivery in the treatment of neoplastic meningitis and intracranial malignancies, respectively.
The results of the therapeutic studies to date have demonstrated the marked activity of alkylating agents, particularly melphalan and cyclophosphamide and the role of glutathione, AGT glutathione-S-transferase, abnormal drug transport and alterations in formation and repair of DNA-DNA crosslinks in modulating cytotoxicity of these agents. Modulations shown to be effective in enhancing alkylator activity/reversing alkylator resistance include BSO-mediated glutathione depletion, inhibition of DNA-DNA crosslink repair and inhibition of 06-alkylguanine-DNA alkyltransferase by 06-benzylguanine. Recent studies have demonstrated profound activity of temozolomide, CPT-11 topotecan, irofulven, and karenitecin as well as the combination of CPT-11 or topotecan plus BCNU or temozolomide. Successful treatment of neoplastic meningitis in nude rats with intrathecal 4-hydroperoxycyclophosphamide, melphalan, temozolomide and busulfan, and intracranial glioma in nude rats with intratumoral temozolomide has also been demonstrated. More recent studies have revealed cyclophosphamide resistance secondary to DNA interstrand crosslink repair. Additional studies have shown that cyclophosphamide crosslinks are formed at the 1,3 N7 position, serving as the basis for construction of a defined crosslink in a plasmid vector to assay for crosslink repair and allowing demonstration of the lack of a role of nucleotide excision repair. Mismatch repair deficiency has been shown as a mechanism mediating acquired methylator (procarbazine and temozolomide) resistance in an adult glioblastoma xenograft.
Clinical Studies: Clinical investigations are designed to translate laboratory programs into successful treatment for adults and children with malignant brain tumors, particularly medulloblastoma. Clinical trials for adults include phase II trials of temozolomide, ZD1839 (Iressa), karenitecin, and temozolomide plus O6-BG as well as phase I trials of topotecan plus BCNU, CPT-11 plus temozolomide, and PTK787 ± temozolomide or CCNU. Studies are in progress in children evaluating the activity CPT-11 plus temozolomide, intrathecal busulfan and cyclophosphamide/melphalan or cyclophosphamide/busulfan plus autologous bone marrow support . Extension of these studies to a larger cohort of patients is being performed nationally under the auspices of the Pediatric Brain Tumor Consortium (Henry S. Friedman -- Head of New Agents Committee).
Future studies will address the role of agents designed to decrease repair of interstrand crosslinks when given in combination with alkylating agents, as well as newer signal pathway inhibitors such as RAD001, PKI166, and DB-6
This faculty member (or a member of their immediate family) has a working relationship (i.e. consulting, research, and/or educational services) with the companies listed below. These relations have been reported to the health system leadership and, when appropriate, management plans are in place to address potential conflicts.
McGirt, MJ; Bulsara, KR; Cummings, TJ; New, KC; Little, KM; Friedman, HS; Friedman, AH. Prognostic value of magnetic resonance imaging-guided stereotactic biopsy in the evaluation of recurrent malignant astrocytoma compared with a lesion due to radiation effect. Journal of Neurosurgery. 2003;98:14-20. (2003) Abstract
Quinn, JA; Reardon, DA; Friedman, AH; Rich, JN; Sampson, JH; Provenzale, JM; McLendon, RE; Gururangan, S; Bigner, DD; Herndon, JE; Avgeropoulos, N; Finlay, J; Tourt-Uhlig, S; Affronti, ML; Evans, B; Stafford-Fox, V; Zaknoen, S; Friedman, HS. Phase II trial of temozolomide in patients with progressive low-grade glioma. Journal of Clinical Oncology. 2003;21:646-651. (2003) Abstract
Aldosari, N; Bigner, SH; Burger, PC; Becker, L; Kepner, JL; Friedman, HS; McLendon, RE. MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group. Archives of Pathology and Laboratory Medicine. 2002;126:540-544. (2002) Abstract
Aldosari, N; Wiltshire, RN; Dutra, A; Schrock, E; McLendon, RE; Friedman, HS; Bigner, DD; Bigner, SH. Comprehensive molecular cytogenetic investigation of chromosomal abnormalities in human medulloblastoma cell lines and xenograft. Neuro-Oncology. 2002;4:75-85. (2002) Abstract
Bacolod, MD; Johnson, SP; Ali-Osman, F; Modrich, P; Bullock, NS; Colvin, OM; Bigner, DD; Friedman, HS. Mechanisms of resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea in human medulloblastoma and rhabdomyosarcoma. Molecular Cancer Therapeutics. 2002;1:727-736. (2002) Abstract
Cokgor, I; Friedman, AH; Friedman, HS. Current options for the treatment of neoplastic meningitis. Journal of Neuro-Oncology. 2002;60:79-88. (2002) Abstract
Eberhart, CG; Kepner, JL; Goldthwaite, PT; Kun, LE; Duffner, PK; Friedman, HS; Strother, DR; Burger, PC. Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer. 2002;94:552-560. (2002) Abstract
Friedman, HS; Johnson, SP; Colvin, OM. Cellular mechanisms of cyclophosphamide resistance: model studies in human medulloblastoma cell lines. Cancer Treatment and Research. 2002;112:199-209. (2002) Abstract
Friedman, HS; Keir, S; Pegg, AE; Houghton, PJ; Colvin, OM; Moschel, RC; Bigner, DD; Dolan, ME. O6-benzylguanine-mediated enhancement of chemotherapy. Molecular Cancer Therapeutics. 2002;1:943-948. (2002) Abstract
Gilbert, MR; Friedman, HS; Kuttesch, JF; Prados, MD; Olson, JJ; Reaman, GH; Zaknoen, SL. A phase II study of temozolomide in patients with newly diagnosed supratentorial malignant glioma before radiation therapy. Neuro-Oncology. 2002;4:261-267. (2002) Abstract
Gururangan, S; Cavazos, CM; Ashley, D; Herndon, JE; Bruggers, CS; Moghrabi, A; Scarcella, DL; Watral, M; Tourt-Uhlig, S; Reardon, D; Friedman, HS. Phase II study of carboplatin in children with progressive low-grade gliomas. Journal of Clinical Oncology. 2002;20:2951-2958. (2002) Abstract
Heimberger, AB; Archer, GE; Crotty, LE; McLendon, RE; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH. Dendritic cells pulsed with a tumor-specific peptide induce long-lasting immunity and are effective against murine intracerebral melanoma. Neurosurgery. 2002;50:158-164. (2002) Abstract
Heimberger, AB; Learn, CA; Archer, GE; McLendon, RE; Chewning, TA; Tuck, FL; Pracyk, JB; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH. Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (iressa). Clinical Cancer Research. 2002;8:3496-3502. (2002) Abstract
Lal, A; Glazer, CA; Martinson, HM; Friedman, HS; Archer, GE; Sampson, JH; Riggins, GJ. Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion. Cancer Research. 2002;62:3335-3339. (2002) Abstract
Leggas, M; Stewart, CF; Woo, MH; Fouladi, M; Cheshire, PJ; Peterson, JK; Friedman, HS; Billups, C; Houghton, PJ. Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts. Clinical Cancer Research. 2002;8:3000-3007. (2002) Abstract
McGirt, MJ; Villavicencio, AT; Bulsara, KR; Friedman, HS; Friedman, AH. Management of tumor bed cysts after chemotherapeutic wafer implantation. Report of four cases. Journal of Neurosurgery. 2002;96:941-945. (2002) Abstract
Quinn, JA; Pluda, J; Dolan, ME; Delaney, S; Kaplan, R; Rich, JN; Friedman, AH; Reardon, DA; Sampson, JH; Colvin, OM; Haglund, MM; Pegg, AE; Moschel, RC; McLendon, RE; Provenzale, JM; Gururangan, S; Tourt-Uhlig, S; Herndon, JE; Bigner, DD; Friedman, HS. Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma. Journal of Clinical Oncology. 2002;20:2277-2283. (2002) Abstract
Rasheed, A; Herndon, JE; Stenzel, TT; Raetz, JG; Kendelhardt, J; Friedman, HS; Friedman, AH; Bigner, DD; Bigner, SH; McLendon, RE. Molecular markers of prognosis in astrocytic tumors. Cancer. 2002;94:2688-2697. (2002) Abstract
Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; Cokgor, I; McLendon, RE; Pegram, CN; Provenzale, JM; Quinn, JA; Rich, JN; Regalado, LV; Sampson, JH; Shafman, TD; Wikstrand, CJ; Wong, TZ; Zhao, XG; Zalutsky, MR; Bigner, DD. Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. Journal of Clinical Oncology. 2002;20:1389-1397. (2002) Abstract
Turner, CD; Gururangan, S; Eastwood, J; Bottom, K; Watral, M; Beason, R; McLendon, RE; Friedman, AH; Tourt-Uhlig, S; Miller, LL; Friedman, HS. Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: the Duke experience. Neuro-Oncology. 2002;4:102-108. (2002) Abstract
Cavazos, CM; Keir, ST; Yoshinari, T; Bigner, DD; Friedman, HS. Therapeutic activity of the topoisomerase I inhibitor J-107088 [6-N-(1-hydroxymethyla-2-hydroxyl) ethylamino-12,13-dihydro-13-(beta-D-glucopyranosyl) -5H-indolo[2,3-a]-pyrrolo[3,4-c]-carbazole-5,7(6H)-dione]] against pediatric and adult central nervous system tumor xenografts. Cancer Chemotherapy and Pharmacology. 2001;48:250-254. (2001) Abstract