Deputy Director, The Preston Robert Tisch Brain Tumor Center

• Surgery / Neurosurgery
• Pediatrics / Neurosurgery
• Medicine / Neurology
• Pediatrics / Neuro-Oncology

Address:
DUMC 3624
Durham, NC 27710

Appointment Telephone:
919-684-3621 (New patient) or 919-668-7600 (Return patient)

Office Telephone:
919-684-5301

Fax Telephone:
919-684-6674

• MD, SUNY Upstate Medical University College of Medicine, 1977

• Pediatrics, State University of New York at Syracuse, 1977-1979
• Pediatric Hematology-Oncology, Upstate Medical Center (New York), 1979-1981

• Pediatric Hematology-Oncology, Duke University Medical Center, 1981-1983

Clinical Interests:
Adults and children with primary and secondary brain and spinal cord tumors, focusing on the laboratory and clinical design of new therapeutic strategies utilizing alkylating agents, monoclonal antibodies, small molecule inhibitors, and gene therapy

Research Interests:
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-67.

Representative Publications:
Quinn JA, Reardon DA, Friedman AH, Rich JN, Sampson JH, Provenzale JM, McLendon RE, Gururangan S, Bigner DD, Herndon JE 2nd, 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. J Clin Oncol. 2003 Feb 15;21(4):646-51. (2003) Abstract

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. J Neurosurg. 2003 Jan;98(1):14-20. (2003) 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-oncol. 2002 Apr;4(2):102-8. (2002) Abstract

Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, Herndon JE 2nd, 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. J Clin Oncol. 2002 Mar 1;20(5):1389-97. (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 May 15;94(10):2688-97. (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 2nd, Bigner DD, Friedman HS. Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma. J Clin Oncol. 2002 May 1;20(9):2277-83. (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. J Neurosurg. 2002 May;96(5):941-5. (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. Clin Cancer Res. 2002 Sep;8(9):3000-7. (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 Res. 2002 Jun 15;62(12):3335-9. (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). Clin Cancer Res. 2002 Nov;8(11):3496-502. (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 Jan;50(1):158-64; discussion 164-6. (2002) Abstract

Gururangan S, Cavazos CM, Ashley D, Herndon JE 2nd, 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. J Clin Oncol. 2002 Jul 1;20(13):2951-8. (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-oncol. 2002 Oct;4(4):261-7. (2002) Abstract

Friedman HS, Keir S, Pegg AE, Houghton PJ, Colvin OM, Moschel RC, Bigner DD, Dolan ME. O6-benzylguanine-mediated enhancement of chemotherapy. Mol Cancer Ther. 2002 Sep;1(11):943-8. (2002) Abstract

Friedman HS, Johnson SP, Colvin OM. Cellular mechanisms of cyclophosphamide resistance: model studies in human medulloblastoma cell lines. Cancer Treat Res. 2002;112:199-209. (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 Jan 15;94(2):552-60. (2002) Abstract

Cokgor I, Friedman AH, Friedman HS. Current options for the treatment of neoplastic meningitis. J Neurooncol. 2002 Oct;60(1):79-88. (2002) Abstract

Cloughesy,R.F., Filka,E.,Nelson,G., Kabbinavar,F., Friedman,H., Miller,L.L. Elgring,G.L.:  Irinotecan treatment for recurrent malignant glioma using an every 3-week regimen.  Am J.Clin.Oncol. 25:204-208,2002. (2002)

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. Mol Cancer Ther. 2002 Jul;1(9):727-36. (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-oncol. 2002 Apr;4(2):75-85. (2002) 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. Arch Pathol Lab Med. 2002 May;126(5):540-4. (2002) Abstract

Keir, S.T., Hausheer, F., Lawless, A.A., Bigner, D.D., and Friedman, H.S.: Therapeutic activity of karenitecin (7-[(2-trimethylsllyl)ethyl)]-20(S)-camptothecin against central nervous system tumor-derived xenografts in athymic mice. Cancer Chemother. Pharmacol. 48:83-87, 2001. (2001)

Friedman, H.S., Keir, S.T., Houghton, P.J., Lawless, A.A., Bigner, D.D., and Waters, S.: Activity of Irofulven (6-hydroxymethylacylfulvene) in the treatment of glioblastoma multiforme-derived xenografts in athymic mice. Cancer Chemother. Pharmacol., in press, 2001. (2001)

Cavazos, C.M., Keir, S.T., Yoshinari, T., Bigner, D.D, and Friedman, H.S.: Therapeutic activity of the topoisomerase I inhibitor J-107088 [6-N-(1-hydroxymethyla-2-hydroxy)ethylamino-12,13-dihydro-13-(b-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 Chemother. Pharmacol., in press, 2001. (2001)

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 Chemother Pharmacol. 2001 Sep;48(3):250-4. (2001) Abstract

Keir, S.T., Dolan, M.E., Pegg, A.E., Lawless, A., Moschel, R.C., Bigner, D.D., and Friedman, H.S.: O6-benzylguanine-mediated enhancement of nitrosourea activity in mer-central nervous system tumor xenografts - implications for clinical trials. Cancer Chemother. Pharmacol. 45:437-440, 2000. (2000)

Friedman, H.S., Pluda, J., Quinn, J.A., Ewesuedo, R.B., Long, L., Friedman, A.H., Cokgor, I., Colvin, O.M., Haglund, M.M., Ashley, D.M., Rich, J.R., Sampson, J., Pegg, A.E., Moschel, R.C., McLendon, R.E., Provenzale, J.M., Stewart, E.S., Tourt-Uhlig, S., Garcia-Turner, A.M., Herndon, J.E., II, Bigner, D.D., and Dolan, M.E.: Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. J. Clin. Oncol. 18:3522-3528, 2000. (2000)