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

SUNY Upstate Medical University

Grants:

Therapy of Temodar plus O6-BG in Malignant Glioma

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

Temozolomide Resistance in CNS Tumors

Administered By
Pediatrics
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

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

Publications:

Second primary cancers in long-term survivors of glioblastoma.

Background: Overall survival (OS) in glioblastoma (GBM) is poor at an average of 14 to 18 months, and long-term survivors (LTS) of GBM are rare. LTS of GBM, defined as surviving >5 years postdiagnosis, represent only 2% to 10% of all GBM patients. LTS of cancer are at high risk of developing second primary neoplasms. This study looks at occurrences of second primary neoplasms in LTS of GBM. Methods: Records from adult patients newly diagnosed with GBM between January 1, 1998 and February 8, 2010, were retrospectively reviewed to identify LTS, defined as patients who survived ≥5 years. We focused on the identification of a new diagnosis of cancer occurring at least 2 years after the initial GBM diagnosis. Results: We identified 155 LTS of GBM, with a median OS of 11.0 years (95% CI: 9.0 to 13.1 years) and a median follow-up of 9.6 years (95% CI: 8.7 to 10.7 years). In this cohort of patients, 13 (8.4%) LTS of GBM developed 17 secondary cancers. Eight could potentially be attributed to previous radiation and chemotherapy (skin cancer in radiation field [n = 4], leukemia [n = 2], low-grade glioma [n = 1], and sarcoma of the scalp [n = 1]). The other 9 cases included melanoma (n = 2), prostate cancer (n = 2), bladder cancer (n = 1), endometrioid adenocarcinoma (n = 1), basal cell carcinoma (n = 1), and renal cell carcinoma (n = 1). Conclusions: Although second primary cancers are rare in GBM LTS, providers should continue close monitoring with appropriate oncologic care. Moreover, this highlights the need for survivorship care of patients with GBM.
Authors
Kim, J-Y; Jackman, JG; Woodring, S; McSherry, F; Herndon, JE; Desjardins, A; Friedman, HS; Peters, KB
MLA Citation
Kim, Jung-Young, et al. “Second primary cancers in long-term survivors of glioblastoma..” Neurooncol Pract, vol. 6, no. 5, Sept. 2019, pp. 386–91. Pubmed, doi:10.1093/nop/npz001.
URI
https://scholars.duke.edu/individual/pub1411790
PMID
31555453
Source
pubmed
Published In
Neuro Oncology Practice
Volume
6
Published Date
Start Page
386
End Page
391
DOI
10.1093/nop/npz001

Outcomes Following Adjuvant Radiation Therapy in Elderly Patients with Glioblastoma: A Retrospective Single Institution Analysis

Authors
Lee, JWC; Johnson, MO; Kirkpatrick, JP; McSherry, F; Herndon, J; Lipp, ES; Desjardins, A; Randazzo, D; Friedman, HS; Ashley, DM; Peters, KB
MLA Citation
Lee, J. W. C., et al. “Outcomes Following Adjuvant Radiation Therapy in Elderly Patients with Glioblastoma: A Retrospective Single Institution Analysis.” International Journal of Radiation Oncology*Biology*Physics, vol. 105, no. 1, Elsevier BV, 2019, pp. E102–E102. Crossref, doi:10.1016/j.ijrobp.2019.06.2296.
URI
https://scholars.duke.edu/individual/pub1414293
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
105
Published Date
Start Page
E102
End Page
E102
DOI
10.1016/j.ijrobp.2019.06.2296

First in Human Clinical Trial of a Metalloporphyrin Dual Radioprotectant and Radiosensitizer, BMX-001, in Newly Diagnosed High-Grade Glioma Undergoing Concurrent Chemoradiation

Authors
Peters, KB; Kirkpatrick, JP; Batinic-Haberle, I; Affronti, ML; Woodring, S; Iden, D; Lipp, ES; Boyd, K; Healy, P; Herndon, J; Spasojevic, I; Penchev, S; Gad, S; Silberstein, D; Johnson, MO; Randazzo, D; Desjardins, A; Friedman, HS; Ashley, DM; Crapo, J
MLA Citation
Peters, K. B., et al. “First in Human Clinical Trial of a Metalloporphyrin Dual Radioprotectant and Radiosensitizer, BMX-001, in Newly Diagnosed High-Grade Glioma Undergoing Concurrent Chemoradiation.” International Journal of Radiation Oncology*Biology*Physics, vol. 105, no. 1, Elsevier BV, 2019, pp. E106–E106. Crossref, doi:10.1016/j.ijrobp.2019.06.2305.
URI
https://scholars.duke.edu/individual/pub1415097
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
105
Published Date
Start Page
E106
End Page
E106
DOI
10.1016/j.ijrobp.2019.06.2305

Safety of nivolumab in combination with dendritic cell vaccines in recurrent high-grade glioma.

Authors
Peters, KB; Archer, GE; Norberg, P; Xie, W; Threatt, S; Lipp, ES; Herndon, JE; Healy, P; Congdon, K; Sanchez-Perez, L; Friedman, HS; Desjardins, A; Vlahovic, G; Sampson, JH
MLA Citation
Peters, Katherine B., et al. “Safety of nivolumab in combination with dendritic cell vaccines in recurrent high-grade glioma..” Journal of Clinical Oncology, vol. 37, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2019, pp. e13526–e13526. Crossref, doi:10.1200/jco.2019.37.15_suppl.e13526.
URI
https://scholars.duke.edu/individual/pub1415015
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
37
Published Date
Start Page
e13526
End Page
e13526
DOI
10.1200/jco.2019.37.15_suppl.e13526

Oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG): Experience with retreatment of survivors from the phase I trial.

Authors
Desjardins, A; Gromeier, M; Herndon, JE; Randazzo, D; Threatt, S; Lipp, ES; Miller, ES; Jackman, J; Bolognesi, DP; Friedman, AH; Friedman, HS; McSherry, F; Peters, KB; Johnson, MO; Sampson, JH; Ashley, DM; Bigner, DD
MLA Citation
Desjardins, Annick, et al. “Oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG): Experience with retreatment of survivors from the phase I trial..” Journal of Clinical Oncology, vol. 37, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2019, pp. 2060–2060. Crossref, doi:10.1200/jco.2019.37.15_suppl.2060.
URI
https://scholars.duke.edu/individual/pub1415615
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
37
Published Date
Start Page
2060
End Page
2060
DOI
10.1200/jco.2019.37.15_suppl.2060