Henry Seth Friedman, MD

Professor of Neurosurgery
James B. Powell, Jr. Distinguished Professor of Pediatric Oncology, in the School of Medicine
Professor of Pediatrics
Professor of Medicine
Professor of Pathology
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., State University of New York Upstate Medical University, 1977

Publications

Peters, Katherine B., Mary L. Affronti, Sarah Woodring, Eric Lipp, Patrick Healy, James E. Herndon, Elizabeth S. Miller, et al. “Effects of low-dose naltrexone on quality of life in high-grade glioma patients: a placebo-controlled, double-blind randomized trial.” Support Care Cancer 30, no. 4 (April 2022): 3463–71. https://doi.org/10.1007/s00520-021-06738-0.

PMID
35001215
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Johnson, Margaret, Mustafa Khasraw, Jung-Young Kim, Nicole Cort, James Herndon, Luis Ramirez, Eric Lipp, et al. “QOLP-28. COMPARING KNOWLEDGE OF AND BELIEFS ABOUT PALLIATIVE CARE AMONG NEURO-ONCOLOGY PATIENTS, CAREGIVERS, PROVIDERS AND A NATIONALLY-REPRESENTATIVE U.S. SAMPLE.” In Neuro Oncology, 23:vi189–vi189. Oxford University Press (OUP), 2021. https://doi.org/10.1093/neuonc/noab196.748.

Full Text

Peters, Katherine, Mallika Patel, Candice Alford, Gerardo Chavez, Jung-Young Kim, Jennifer Durling, Tracy Novack, et al. “INNV-20. RADIOGRAPHIC RESPONSE AND SEIZURE CONTROL IN IDH1 MUTANT GLIOMA PATIENTS USING IVOSIDENIB.” In Neuro Oncology, 23:vi109–vi109. Oxford University Press (OUP), 2021. https://doi.org/10.1093/neuonc/noab196.431.

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Batich, Kristen, Duane Mitchell, Patrick Healy, James Herndon, Gloria Broadwater, Gunn Michael, Min-Nung Huang, et al. “CTIM-10. REPRODUCIBILITY OF CLINICAL TRIALS USING CMV-TARGETED DENDRITIC CELL VACCINES IN PATIENTS WITH GLIOBLASTOMA.” In Neuro Oncology, 23:vi51–vi51. Oxford University Press (OUP), 2021. https://doi.org/10.1093/neuonc/noab196.202.

Full Text

Kang, Jennifer H., Christa B. Swisher, Evan D. Buckley, James E. Herndon, Eric S. Lipp, John P. Kirkpatrick, Annick Desjardins, et al. “Primary brain tumor patients admitted to a US intensive care unit: a descriptive analysis.” Cns Oncol 10, no. 3 (September 1, 2021): CNS77. https://doi.org/10.2217/cns-2021-0009.

PMID
34545753
Full Text

Sloan, Andrew E., Robin Arthur Buerki, Christopher Murphy, Andrea True Kelly, Prakash Ambady, Michael Brown, Nicholas A. Butowski, et al. “LUMINOS-101: Phase 2 study of PVSRIPO with pembrolizumab in recurrent glioblastoma.” In Journal of Clinical Oncology, 39:TPS2065–TPS2065. American Society of Clinical Oncology (ASCO), 2021. https://doi.org/10.1200/jco.2021.39.15_suppl.tps2065.

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Gromeier, Matthias, Michael C. Brown, Gao Zhang, Xiang Lin, Yeqing Chen, Zhi Wei, Nike Beaubier, et al. “Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.” Nat Commun 12, no. 1 (January 13, 2021): 352. https://doi.org/10.1038/s41467-020-20469-6.

PMID
33441554
Full Text

Lee, Jessica W., John P. Kirkpatrick, Frances McSherry, James E. Herndon, Eric S. Lipp, Annick Desjardins, Dina M. Randazzo, et al. “Adjuvant Radiation in Older Patients With Glioblastoma: A Retrospective Single Institution Analysis.” Front Oncol 11 (2021): 631618. https://doi.org/10.3389/fonc.2021.631618.

PMID
33732649
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Lee, J. W. C., M. O. Johnson, J. P. Kirkpatrick, F. McSherry, J. Herndon, E. S. Lipp, A. Desjardins, et al. “Outcomes Following Adjuvant Radiation Therapy in Elderly Patients with Glioblastoma: A Retrospective Single Institution Analysis.” In International Journal of Radiation Oncology*Biology*Physics, 105:E102–E102. Elsevier BV, 2020. https://doi.org/10.1016/j.ijrobp.2019.06.2296.

Full Text

Tan, Aaron C., David M. Ashley, Giselle Y. López, Michael Malinzak, Henry S. Friedman, and Mustafa Khasraw. “Management of glioblastoma: State of the art and future directions.” Ca Cancer J Clin 70, no. 4 (July 2020): 299–312. https://doi.org/10.3322/caac.21613.

PMID
32478924
Full Text

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