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

Detecting somatic mutations in genomic sequences by means of Kolmogorov-Arnold analysis.

The Kolmogorov-Arnold stochasticity parameter technique is applied for the first time to the study of cancer genome sequencing, to reveal mutations. Using data generated by next-generation sequencing technologies, we have analysed the exome sequences of brain tumour patients with matched tumour and normal blood. We show that mutations contained in sequencing data can be revealed using this technique, thus providing a new methodology for determining subsequences of given length containing mutations, i.e. its value differs from those of subsequences without mutations. A potential application for this technique involves simplifying the procedure of finding segments with mutations, speeding up genomic research and accelerating its implementation in clinical diagnostics. Moreover, the prediction of a mutation associated with a family of frequent mutations in numerous types of cancers based purely on the value of the Kolmogorov function indicates that this applied marker may recognize genomic sequences that are in extremely low abundance and can be used in revealing new types of mutations.
Authors
Gurzadyan, VG; Yan, H; Vlahovic, G; Kashin, A; Killela, P; Reitman, Z; Sargsyan, S; Yegorian, G; Milledge, G; Vlahovic, B
MLA Citation
Gurzadyan, V. G., et al. “Detecting somatic mutations in genomic sequences by means of Kolmogorov-Arnold analysis.R Soc Open Sci, vol. 2, no. 8, Aug. 2015, p. 150143. Pubmed, doi:10.1098/rsos.150143.
URI
https://scholars.duke.edu/individual/pub1096923
PMID
26361546
Source
pubmed
Published In
Royal Society Open Science
Volume
2
Published Date
Start Page
150143
DOI
10.1098/rsos.150143

2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations.

BACKGROUND: Gliomas frequently contain mutations in the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase (IDH1) or the mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2). Several different amino acid substitutions recur at either IDH1 R132 or IDH2 R172 in glioma patients. Genetic evidence indicates that these mutations share a common gain of function, but it is unclear whether the shared function is dominant negative activity, neomorphic production of (R)-2-hydroxyglutarate (2HG), or both. METHODOLOGY/PRINCIPAL FINDINGS: We show by coprecipitation that five cancer-derived IDH1 R132 mutants bind IDH1-WT but that three cancer-derived IDH2 R172 mutants exert minimal binding to IDH2-WT. None of the mutants dominant-negatively lower isocitrate dehydrogenase activity at physiological (40 µM) isocitrate concentrations in mammalian cell lysates. In contrast to this, all of these mutants confer 10- to 100-fold higher 2HG production to cells, and glioma tissues containing IDH1 R132 or IDH2 R172 mutations contain high levels of 2HG compared to glioma tissues without IDH mutations (54.4 vs. 0.1 mg 2HG/g protein). CONCLUSIONS: Binding to, or dominant inhibition of, WT IDH1 or IDH2 is not a shared feature of the IDH1 and IDH2 mutations, and thus is not likely to be important in cancer. The fact that the gain of the enzymatic activity to produce 2HG is a shared feature of the IDH1 and IDH2 mutations suggests that this is an important function for these mutants in driving cancer pathogenesis.
Authors
Jin, G; Reitman, ZJ; Spasojevic, I; Batinic-Haberle, I; Yang, J; Schmidt-Kittler, O; Bigner, DD; Yan, H
MLA Citation
Jin, Genglin, et al. “2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations.Plos One, vol. 6, no. 2, Feb. 2011, p. e16812. Pubmed, doi:10.1371/journal.pone.0016812.
URI
https://scholars.duke.edu/individual/pub748455
PMID
21326614
Source
pubmed
Published In
Plos One
Volume
6
Published Date
Start Page
e16812
DOI
10.1371/journal.pone.0016812

Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila.

Gain-of-function mutations in nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase (IDH)1 and IDH2 frequently arise in human leukemias and other cancers and produce high levels of D-2-hydroxyglutarate (D-2HG). We expressed the R195H mutant of Drosophila Idh (CG7176), which is equivalent to the human cancer-associated IDH1-R132H mutant, in fly tissues using the UAS-Gal4 binary expression system. Idh-R195H caused a >25-fold elevation of D-2HG when expressed ubiquitously in flies. Expression of mutant Idh in larval blood cells (hemocytes) resulted in higher numbers of circulating blood cells. Mutant Idh expression in fly neurons resulted in neurologic and wing-expansion defects, and these phenotypes were rescued by genetic modulation of superoxide dismutase 2, p53, and apoptotic caspase cascade mediators. Idh-R163Q, which is homologous to the common leukemia-associated IDH2-R140Q mutant, resulted in moderately elevated D-2HG and milder phenotypes. We identified the fly homolog of D-2-hydroxyglutaric acid dehydrogenase (CG3835), which metabolizes D-2HG, and showed that coexpression of this enzyme with mutant Idh abolishes mutant Idh-associated phenotypes. These results provide a flexible model system to interrogate a cancer-related genetic and metabolic pathway and offer insights into the impact of IDH mutation and D-2HG on metazoan tissues.
Authors
Reitman, ZJ; Sinenko, SA; Spana, EP; Yan, H
MLA Citation
Reitman, Zachary J., et al. “Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila.Blood, vol. 125, no. 2, Jan. 2015, pp. 336–45. Pubmed, doi:10.1182/blood-2014-05-577940.
URI
https://scholars.duke.edu/individual/pub1050554
PMID
25398939
Source
pubmed
Published In
Blood
Volume
125
Published Date
Start Page
336
End Page
345
DOI
10.1182/blood-2014-05-577940

IDH1(R132) mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain.

Isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are enzymes which convert isocitrate to alpha-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+to NADPH). IDH1/2 were recently identified as mutated in a large percentage of progressive gliomas. These mutations occur at IDH1(R132) or the homologous IDH2(R172). Melanomas share some genetic features with IDH1/2-mutated gliomas, such as frequent TP53 mutation. We sought to test whether melanoma is associated with IDH1/2 mutations. Seventy-eight human melanoma samples were analyzed for IDH1(R132) and IDH2(R172) mutation status. A somatic, heterozygous IDH1 c.C394T (p.R132C) mutation was identified in one human melanoma metastasis to the lung. Having identified this mutation in one metastasis, we sought to test the hypothesis that certain selective pressures in the brain environment may specifically favor the cell growth or survival of tumor cells with mutations in IDH1/2, regardless of primary tumor site. To address this, we analyzed IDH1(R132) and IDH2(R172) mutation status 53 metastatic brain tumors, including nine melanoma metastases. Results revealed no mutations in any samples. This lack of mutations would suggest that mutations in IDH1(R132) or IDH2(R172) may be necessary for the formation of tumors in a cell-lineage dependent manner, with a particularly strong selective pressure for mutations in progressive gliomas; this also suggests the lack of a particular selective pressure for growth in brain tissue in general. Studies on the cell-lineages of tumors with IDH1/2 mutations may help clarify the role of these mutations in the development of brain tumors.
Authors
Lopez, GY; Reitman, ZJ; Solomon, D; Waldman, T; Bigner, DD; McLendon, RE; Rosenberg, SA; Samuels, Y; Yan, H
MLA Citation
Lopez, Giselle Y., et al. “IDH1(R132) mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain.Biochem Biophys Res Commun, vol. 398, no. 3, July 2010, pp. 585–87. Pubmed, doi:10.1016/j.bbrc.2010.06.125.
URI
https://scholars.duke.edu/individual/pub724131
PMID
20603105
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
398
Published Date
Start Page
585
End Page
587
DOI
10.1016/j.bbrc.2010.06.125

Research Areas:

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