Henry Friedman

Overview:

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.

Positions:

James B. Powell, Jr. Distinguished Professor of Pediatric Oncology, in the School of Medicine

Neurosurgery, Neuro-Oncology
School of Medicine

Professor of Neurosurgery

Neurosurgery, Neuro-Oncology
School of Medicine

Professor of Pediatrics

Pediatrics
School of Medicine

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1977

State University of New York Upstate Medical University

Grants:

Targeting Brain Tumor Stem Cells

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

AGT Depletion for therapy of CNS tumors

Administered By
Neurology, General & Community Neurology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

A Molecular Classification of Brain Tumors

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Intrathecal Busulfan Therapy of Neoplastic Meningitis

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
Food and Drug Administration
Role
Principal Investigator
Start Date
End Date

GRT-Photo-Documentary/Patients/Brain Tumors

Administered By
Pediatrics
Awarded By
The Mary Duke Biddle Foundation
Role
Principal Investigator
Start Date
End Date

Publications:

Primary brain tumor patients admitted to a US intensive care unit: a descriptive analysis.

Purpose: To describe our population of primary brain tumor (PBT) patients, a subgroup of cancer patients whose intensive care unit (ICU) outcomes are understudied. Methods: Retrospective analysis of PBT patients admitted to an ICU between 2013 to 2018 for an unplanned need. Using descriptive analyses, we characterized our population and their outcomes. Results: Fifty-nine PBT patients were analyzed. ICU mortality was 19% (11/59). The most common indication for admission was seizures (n = 16, 27%). Conclusion: Our ICU mortality of PBT patients was comparable to other solid tumor patients and the general ICU population and better than patients with hematological malignancies. Further study of a larger population would inform guidelines for triaging PBT patients who would most benefit from ICU-level care.
Authors
Kang, JH; Swisher, CB; Buckley, ED; Herndon, JE; Lipp, ES; Kirkpatrick, JP; Desjardins, A; Friedman, HS; Johnson, MO; Randazzo, DM; Ashley, DM; Peters, KB
MLA Citation
Kang, Jennifer H., et al. “Primary brain tumor patients admitted to a US intensive care unit: a descriptive analysis.Cns Oncol, vol. 10, no. 3, Sept. 2021, p. CNS77. Pubmed, doi:10.2217/cns-2021-0009.
URI
https://scholars.duke.edu/individual/pub1497219
PMID
34545753
Source
pubmed
Published In
Cns Oncology
Volume
10
Published Date
Start Page
CNS77
DOI
10.2217/cns-2021-0009

Cognitive Outcomes of Phase I Trial of Novel Metalloporphyrin Radioprotectant and Radiosensitizer in Newly Diagnosed High Grade Glioma Patients.

MASCC20-ABS-1534
Authors
Peters, KB; Kirkpatrick, J; Batinic-Haberle, I; Affronti, ML; Woodring, S; Iden, D; Lipp, ES; Healy, P; Herndon, JE; Boyd, K; Hahn, K; Spasojevic, I; Gad, S; Silberstein, D; Johnson, MO; Randazzo, D; Desjardins, A; Friedman, HS; Ashley, D; Crapo, J
MLA Citation
Peters, Katherine B., et al. “Cognitive Outcomes of Phase I Trial of Novel Metalloporphyrin Radioprotectant and Radiosensitizer in Newly Diagnosed High Grade Glioma Patients.Supportive Care in Cancer, Springer (part of Springer Nature), 2020.
URI
https://scholars.duke.edu/individual/pub1458678
Source
manual
Published In
Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer
Published Date

PATTERNS OF RELAPSE AFTER SUCCESSFUL COMPLETION OF INITIAL THERAPY IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

RATE-36 INTRODUCTION Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin’s lymphoma that involves the brain, spinal cord or leptomeninges, without evidence of systemic disease. This rare disease accounts for ~3% of all primary central nervous system (CNS) tumors. Methotrexate-based regimens are the standard of care for this disease with overall survival rates ranging from 14 to 55 months. Relapse after apparent complete remission can occur. We sought to understand the outcomes of patients who relapsed. METHODS This is an IRB-approved investigation of patients treated at our institution between 12/31/2004 and 10/12/2016. All cases of PCNSL were retrospectively identified as part of a database registry and data were evaluated for demographic information, absence or presence of relapse, location of relapse, treatment regimens, and median time to relapse. RESULTS Forty-four patients were identified with a diagnosis of PCNSL. Mean age at diagnosis was 63.1 yrs (range 20-86, SD=13.2 yrs). Of the 44 patients, 28 patients successfully completed an initial treatment regimen without recurrence or toxicity requiring a change in therapy. Relapse occurred in 11 patients with the location of relapse being in the CNS only (n=5), eye only (n=1), outside CNS only (n=3), or a combination of CNS and outside CNS (n=2). Sites of relapse outside of the CNS included testes (n=1), lung (n=1), adrenal gland (n=1), kidney/adrenal gland (n=1), and retroperitoneum (n=1). Median time to relapse from successful completion of therapy (95% CI) was 12.9 months (95% CI: 4.8-48.6 months). CONCLUSION After successful initial treatment, PCNSL can relapse and this relapse can occur in the CNS and outside the CNS. Vigilant monitoring of off-treatment patients with a history of PCNSL is necessary to guide early diagnosis of relapse and to initiate aggressive treatment.
Authors
Weant, MP; Kirkpatrick, J; Johnson, MO; Dunn-Pirio, A; Healy, P; Herndon, JE; Lipp, E; Fountain, E; Desjardins, A; Randazzo, D; Friedman, H; Peters, K
MLA Citation
Weant, Mallika P., et al. “PATTERNS OF RELAPSE AFTER SUCCESSFUL COMPLETION OF INITIAL THERAPY IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA.” Neuro Oncology, vol. 19, no. suppl. 6; abstr RARE-36, Oxford University Press (OUP), 2017, pp. vi217–vi217. Manual, doi:10.1093/neuonc/nox168.878.
URI
https://scholars.duke.edu/individual/pub1458265
Source
manual
Published In
Neuro Oncology
Volume
19
Published Date
Start Page
vi217
End Page
vi217
DOI
10.1093/neuonc/nox168.878

Psychosocial distress and its effects on the health-related quality of life of primary brain tumor patients.

Authors
Randazzo, DM; McSherry, F; Herndon, JE; Affronti, ML; Lipp, ES; Flahiff, C; Miller, E; Woodring, S; Freeman, M; Healy, P; Minchew, J; Boulton, S; Desjardins, A; Vlahovic, G; Friedman, HS; Keir, ST; Peters, KB
MLA Citation
Randazzo, Dina M., et al. “Psychosocial distress and its effects on the health-related quality of life of primary brain tumor patients.Journal of Clinical Oncology, vol. 33, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2015, pp. 9553–9553. Crossref, doi:10.1200/jco.2015.33.15_suppl.9553.
URI
https://scholars.duke.edu/individual/pub1460334
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Published Date
Start Page
9553
End Page
9553
DOI
10.1200/jco.2015.33.15_suppl.9553

Dose escalation study of D2C7-IT administered intratumorally via convection-enhanced delivery for recurrent malignant glioma.

Authors
Desjardins, A; Randazzo, D; Chandramohan, V; Peters, KB; Johnson, MO; Threatt, S; Herndon, JE; Boulton, S; Healy, P; Lipp, E; Fecci, P; Sampson, J; Friedman, A; Friedman, H; Ashley, D; Bigner, D
URI
https://scholars.duke.edu/individual/pub1458679
Source
manual