Henry Seth Friedman, MD

Professor of Neurosurgery
James B. Powell, Jr. Professor of Pediatric Oncology, in the School of Medicine
Assistant Professor of Pathology
Associate Professor of Medicine
Professor of Pediatrics
Member of the Duke Cancer Institute
Campus mail 047 Baker House, Durham, NC 27710
Phone (919) 684-5301
Email address henry.friedman@duke.edu

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.

Education and Training

  • M.D., SUNY Upstate Medical University, 1977

Publications

Affronti, ML, Jackman, JG, McSherry, F, Herndon, JE, Massey, EC, Lipp, E, Desjardins, A, Friedman, HS, Vlahovic, G, Vredenburgh, J, and Peters, KB. "Phase II Study to Evaluate the Efficacy and Safety of Rilotumumab and Bevacizumab in Subjects with Recurrent Malignant Glioma." The oncologist (April 17, 2018).

PMID
29666296
Full Text

Peters, KB, Lipp, ES, Miller, E, Herndon, JE, McSherry, F, Desjardins, A, Reardon, DA, and Friedman, HS. "Phase I/II trial of vorinostat, bevacizumab, and daily temozolomide for recurrent malignant gliomas." Journal of neuro-oncology 137, no. 2 (April 2018): 349-356.

PMID
29264836
Full Text

Keir, ST, Chandramohan, V, Hemphill, CD, Grandal, MM, Melander, MC, Pedersen, MW, Horak, ID, Kragh, M, Desjardins, A, Friedman, HS, and Bigner, DD. "Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models." Journal of neuro-oncology (March 21, 2018).

PMID
29564747
Full Text

Ghiaseddin, A, Reardon, D, Massey, W, Mannerino, A, Lipp, ES, Herndon, JE, McSherry, F, Desjardins, A, Randazzo, D, Friedman, HS, and Peters, KB. "Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma." The oncologist 23, no. 2 (February 2018): 157-e21.

PMID
29133513
Full Text

Waitkus, MS, Pirozzi, CJ, Moure, CJ, Diplas, BH, Hansen, LJ, Carpenter, AB, Yang, R, Wang, Z, Ingram, BO, Karoly, ED, Mohney, RP, Spasojevic, I, McLendon, RE, Friedman, HS, He, Y, Bigner, DD, and Yan, H. "Adaptive Evolution of the GDH2 Allosteric Domain Promotes Gliomagenesis by Resolving IDH1R132H-Induced Metabolic Liabilities." Cancer research 78, no. 1 (January 2018): 36-50.

PMID
29097607
Full Text

Reap, EA, Suryadevara, CM, Batich, KA, Sanchez-Perez, L, Archer, GE, Schmittling, RJ, Norberg, PK, Herndon, JE, Healy, P, Congdon, KL, Gedeon, PC, Campbell, OC, Swartz, AM, Riccione, KA, Yi, JS, Hossain-Ibrahim, MK, Saraswathula, A, Nair, SK, Dunn-Pirio, AM, Broome, TM, Weinhold, KJ, Desjardins, A, Vlahovic, G, McLendon, RE, Friedman, AH, Friedman, HS, Bigner, DD, Fecci, PE, Mitchell, DA, and Sampson, JH. "Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma." Cancer research 78, no. 1 (January 2018): 256-264.

PMID
29093005
Full Text

Randazzo, D, McSherry, F, II, HJE, Affronti, ML, Healy, P, Lipp, ES, Desjardins, A, Friedman, HS, and Peters, KB. "A SINGLE INSTITUTION'S EXPERIENCE EXPLORING THE ASSOCIATION OF INTEGRATIVE MEDICINE AND SURVIVORSHIP IN GLIOBLASTOMA." November 2017.

Scholars@Duke

Peters, KB, Affronti, ML, Threatt, S, Healy, P, II, HJE, Lipp, ES, Panta, S, Randazzo, D, Friedman, HS, and Desjardins, A. "INCREASED FATIGUE ASSOCIATED WITH TUMOR PROGRESSION IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PATIENTS." November 2017.

Scholars@Duke

Affronti, ML, Randazzo, D, Peters, KB, Herndon, SC, Healy, P, II, HJE, Woodring, S, Hawkins, K, Lipp, ES, Kohrman, O, Desjardins, A, Vlahovic, G, Friedman, HS, Kim, J-Y, Miller, ES, and Schneider, S. "PILOT STUDY TO DESCRIBE THE TRAJECTORY OF SYMPTOMS AND ADAPTIVE STRATEGIES OF ADULTS LIVING WITH LOW GRADE GLIOMAS (LGG)." November 2017.

Scholars@Duke

Peters, KB, Affronti, ML, Threatt, S, Healy, P, II, HJE, Lipp, ES, Panta, S, Randazzo, D, Friedman, HS, and Desjardins, A. "MAINTENANCE OF HEALTH RELATED QUALITY OF LIFE (QOL) BEYOND PROGRESSION IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS TREATED WITH BEVACIZUMAB." November 2017.

Scholars@Duke

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