Zachary Reitman

Overview:

Dr. Reitman’s clinical interests include radiotherapy for primary and metastatic tumors of the brain and spine.  He is also interested in basic and translational research studies to develop new treatment approaches for pediatric and adult brain tumors.  He uses genomic analysis, radiation biology studies, and genetically engineered animal models of cancer to carry out this research

Positions:

Assistant Professor of Radiation Oncology

Radiation Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2012

Duke University School of Medicine

M.D. 2014

Duke University School of Medicine

Internship, Internal Medicine

Union Memorial Hospital

Resident, Radiation Oncology

Massachusetts General Hospital

Grants:

Prioritizing PPM1D mutations as a target for new DIPG therapies

Administered By
Radiation Oncology
Awarded By
Michael Mosier Defeat DIPG Foundation
Role
Principal Investigator
Start Date
End Date

Generation of a genetically-modified microorganism for adipic acid production

Administered By
Pathology
Awarded By
North Carolina Biotechnology Center
Role
Principal Investigator
Start Date
End Date

Identifying brainstem glioma subtypes that can be radiosensitized by ATM inhibition

Administered By
Radiation Oncology
Awarded By
Pediatric Brain Tumor Foundation
Role
Principal Investigator
Start Date
End Date

Enhancing the efficacy of radiation therapy for DIPG

Administered By
Radiation Oncology
Awarded By
Michael Mosier Defeat DIPG Foundation
Role
Principal Investigator
Start Date
End Date

Enhancing the efficacy of radiation therapy for brainstem gliomas

Administered By
Radiation Oncology
Awarded By
St. Baldrick's Foundation
Role
PI-Fellow
Start Date
End Date

Publications:

Picornavirus genome replication. Identification of the surface of the poliovirus (PV) 3C dimer that interacts with PV 3Dpol during VPg uridylylation and construction of a structural model for the PV 3C2-3Dpol complex.

Picornaviruses have a peptide termed VPg covalently linked to the 5'-end of the genome. Attachment of VPg to the genome occurs in at least two steps. First, Tyr-3 of VPg, or some precursor thereof, is used as a primer by the viral RNA-dependent RNA polymerase, 3Dpol, to produce VPg-pUpU. Second, VPg-pUpU is used as a primer to produce full-length genomic RNA. Production of VPg-pUpU is templated by a single adenylate residue located in the loop of an RNA stem-loop structure termed oriI by using a slide-back mechanism. Recruitment of 3Dpol to and its stability on oriI have been suggested to require an interaction between the back of the thumb subdomain of 3Dpol and an undefined region of the 3C domain of viral protein 3CD. We have performed surface acidic-to-alanine-scanning mutagenesis of 3C to identify the surface of 3C with which 3Dpol interacts. This analysis identified numerous viable poliovirus mutants with reduced growth kinetics that correlated to reduced kinetics of RNA synthesis that was attributable to a change in VPg-pUpU production. Importantly, these 3C derivatives were all capable of binding to oriI as well as wild-type 3C. Synthetic lethality was observed for these mutants when placed in the context of a poliovirus mutant containing 3Dpol-R455A, a residue on the back of the thumb required for VPg uridylylation. These data were used to guide molecular docking of the structures for a poliovirus 3C dimer and 3Dpol, leading to a structural model for the 3C(2)-3Dpol complex that extrapolates well to all picornaviruses.
Authors
Shen, M; Reitman, ZJ; Zhao, Y; Moustafa, I; Wang, Q; Arnold, JJ; Pathak, HB; Cameron, CE
URI
https://scholars.duke.edu/individual/pub998134
PMID
17993457
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
283
Published Date
Start Page
875
End Page
888
DOI
10.1074/jbc.M707907200

The genome-wide mutational landscape of pituitary adenomas.

Authors
Song, Z-J; Reitman, ZJ; Ma, Z-Y; Chen, J-H; Zhang, Q-L; Shou, X-F; Huang, C-X; Wang, Y-F; Li, S-Q; Mao, Y; Zhou, L-F; Lian, B-F; Yan, H; Shi, Y-Y; Zhao, Y
MLA Citation
Song, Zhi-Jian, et al. “The genome-wide mutational landscape of pituitary adenomas.Cell Res, vol. 26, no. 11, Nov. 2016, pp. 1255–59. Pubmed, doi:10.1038/cr.2016.114.
URI
https://scholars.duke.edu/individual/pub1160317
PMID
27670697
Source
pubmed
Published In
Cell Res
Volume
26
Published Date
Start Page
1255
End Page
1259
DOI
10.1038/cr.2016.114

Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.

Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.
Authors
Jiao, Y; Killela, PJ; Reitman, ZJ; Rasheed, AB; Heaphy, CM; de Wilde, RF; Rodriguez, FJ; Rosemberg, S; Oba-Shinjo, SM; Nagahashi Marie, SK; Bettegowda, C; Agrawal, N; Lipp, E; Pirozzi, C; Lopez, G; He, Y; Friedman, H; Friedman, AH; Riggins, GJ; Holdhoff, M; Burger, P; McLendon, R; Bigner, DD; Vogelstein, B; Meeker, AK; Kinzler, KW; Papadopoulos, N; Diaz, LA; Yan, H
MLA Citation
Jiao, Yuchen, et al. “Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.Oncotarget, vol. 3, no. 7, July 2012, pp. 709–22. Pubmed, doi:10.18632/oncotarget.588.
URI
https://scholars.duke.edu/individual/pub747985
PMID
22869205
Source
pubmed
Published In
Oncotarget
Volume
3
Published Date
Start Page
709
End Page
722
DOI
10.18632/oncotarget.588

Radiolabeled inhibitors as probes for imaging mutant IDH1 expression in gliomas: Synthesis and preliminary evaluation of labeled butyl-phenyl sulfonamide analogs.

INTRODUCTION: Malignant gliomas frequently harbor mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Studies suggest that IDH mutation contributes to tumor pathogenesis through mechanisms that are mediated by the neomorphic metabolite of the mutant IDH1 enzyme, 2-hydroxyglutarate (2-HG). The aim of this work was to synthesize and evaluate radiolabeled compounds that bind to the mutant IDH1 enzyme with the goal of enabling noninvasive imaging of mutant IDH1 expression in gliomas by positron emission tomography (PET). METHODS: A small library of nonradioactive analogs were designed and synthesized based on the chemical structure of reported butyl-phenyl sulfonamide inhibitors of mutant IDH1. Enzyme inhibition assays were conducted using purified mutant IDH1 enzyme, IDH1-R132H, to determine the IC50 and the maximal inhibitory efficiency of the synthesized compounds. Selected compounds, 1 and 4, were labeled with radioiodine ((125)I) and/or (18)F using bromo- and phenol precursors, respectively. In vivo behavior of the labeled inhibitors was studied by conducting tissue distribution studies with [(125)I]1 in normal mice. Cell uptake studies were conducted using an isogenic astrocytoma cell line that carried a native IDH1-R132H mutation to evaluate the potential uptake of the labeled inhibitors in IDH1-mutated tumor cells. RESULTS: Enzyme inhibition assays showed good inhibitory potency for compounds that have iodine or a fluoroethoxy substituent at the ortho position of the phenyl ring in compounds 1 and 4 with IC50 values of 1.7 μM and 2.3 μM, respectively. Compounds 1 and 4 inhibited mutant IDH1 activity and decreased the production of 2-HG in an IDH1-mutated astrocytoma cell line. Radiolabeling of 1 and 4 was achieved with an average radiochemical yield of 56.6 ± 20.1% for [(125)I]1 (n = 4) and 67.5 ± 6.6% for [(18)F]4 (n = 3). [(125)I]1 exhibited favorable biodistribution characteristics in normal mice, with rapid clearance from the blood and elimination via the hepatobiliary system by 4 h after injection. The uptake of [(125)I]1 in tumor cells positive for IDH1-R132H was significantly higher compared to isogenic WT-IDH1 controls, with a maximal uptake ratio of 1.67 at 3 h post injection. Co-incubation of the labeled inhibitors with the corresponding nonradioactive analogs, and decreasing the normal concentrations of FBS (10%) in the incubation media substantially increased the uptake of the labeled inhibitors in both the IDH1-mutant and WT-IDH1 tumor cell lines, suggesting significant non-specific binding of the synthesized labeled butyl-phenyl sulfonamide inhibitors. CONCLUSIONS: These data demonstrate the feasibility of developing radiolabeled probes for the mutant IDH1 enzyme based on enzyme inhibitors. Further optimization of the labeled inhibitors by modifying the chemical structure to decrease the lipophilicity and to increase potency may yield compounds with improved characteristics as probes for imaging mutant IDH1 expression in tumors.
Authors
MLA Citation
Chitneni, Satish K., et al. “Radiolabeled inhibitors as probes for imaging mutant IDH1 expression in gliomas: Synthesis and preliminary evaluation of labeled butyl-phenyl sulfonamide analogs.Eur J Med Chem, vol. 119, Aug. 2016, pp. 218–30. Pubmed, doi:10.1016/j.ejmech.2016.04.066.
URI
https://scholars.duke.edu/individual/pub1131441
PMID
27163884
Source
pubmed
Published In
Eur J Med Chem
Volume
119
Published Date
Start Page
218
End Page
230
DOI
10.1016/j.ejmech.2016.04.066

Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.

Point mutations of the NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite (R)-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. We profiled >200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1- and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG also was significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations. These metabolic changes provide clues to the pathogenesis of tumors associated with IDH gene mutations.
Authors
Reitman, ZJ; Jin, G; Karoly, ED; Spasojevic, I; Yang, J; Kinzler, KW; He, Y; Bigner, DD; Vogelstein, B; Yan, H
MLA Citation
Reitman, Zachary J., et al. “Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.Proc Natl Acad Sci U S A, vol. 108, no. 8, Feb. 2011, pp. 3270–75. Pubmed, doi:10.1073/pnas.1019393108.
URI
https://scholars.duke.edu/individual/pub748456
PMID
21289278
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
108
Published Date
Start Page
3270
End Page
3275
DOI
10.1073/pnas.1019393108

Research Areas:

Cancer
Ganglioglioma
Genomics
Glioma
Molecular Biology
Molecular radiobiology
Radiotherapy
Single Cell Biology