Ivan Spasojevic

Positions:

Associate Professor in Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1999

Duke University

Grants:

The Role of IDH1 Mutations in Gliomagenesis and Metabolism

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

Biomarker Studies for Novel Anti-Cancer Agents

Administered By
Medicine, Medical Oncology
Awarded By
National Institutes of Health
Role
Research Associate
Start Date
End Date

Development of CaMKK2 inhibitor drug for acute radiation syndrome

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
Columbia University
Role
Investigator
Start Date
End Date

Human EGFRvIII-specific BiTE for the treatment of Glioblastoma

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

New therapeutic strategy in reversing radiation-induced erectile dysfunction with prostate cancer pa-tients

Administered By
Radiation Oncology
Role
Co Investigator
Start Date
End Date

Publications:

Mn Porphyrin-Based Redox-Active Drugs: Differential Effects as Cancer Therapeutics and Protectors of Normal Tissue Against Oxidative Injury.

SIGNIFICANCE: After approximatelty three decades of research, two Mn(III) porphyrins (MnPs), MnTE-2-PyP5+ (BMX-010, AEOL10113) and MnTnBuOE-2-PyP5+ (BMX-001), have progressed to five clinical trials. In parallel, another similarly potent metal-based superoxide dismutase (SOD) mimic-Mn(II)pentaaza macrocycle, GC4419-has been tested in clinical trial on application, identical to that of MnTnBuOE-2-PyP5+-radioprotection of normal tissue in head and neck cancer patients. This clearly indicates that Mn complexes that target cellular redox environment have reached sufficient maturity for clinical applications. Recent Advances: While originally developed as SOD mimics, MnPs undergo intricate interactions with numerous redox-sensitive pathways, such as those involving nuclear factor κB (NF-κB) and nuclear factor E2-related factor 2 (Nrf2), thereby impacting cellular transcriptional activity. An increasing amount of data support the notion that MnP/H2O2/glutathione (GSH)-driven catalysis of S-glutathionylation of protein cysteine, associated with modification of protein function, is a major action of MnPs on molecular level. CRITICAL ISSUES: Differential effects of MnPs on normal versus tumor cells/tissues, which support their translation into clinic, arise from differences in their accumulation and redox environment of such tissues. This in turn results in different yields of MnP-driven modifications of proteins. Thus far, direct evidence for such modification of NF-κB, mitogen-activated protein kinases (MAPK), phosphatases, Nrf2, and endogenous antioxidative defenses was provided in tumor, while indirect evidence shows the modification of NF-κB and Nrf2 translational activities by MnPs in normal tissue. FUTURE DIRECTIONS: Studies that simultaneously explore differential effects in same animal are lacking, while they are essential for understanding of extremely intricate interactions of metal-based drugs with complex cellular networks of normal and cancer cells/tissues.
Authors
Batinic-Haberle, I; Tovmasyan, A; Spasojevic, I
MLA Citation
Batinic-Haberle, Ines, et al. “Mn Porphyrin-Based Redox-Active Drugs: Differential Effects as Cancer Therapeutics and Protectors of Normal Tissue Against Oxidative Injury..” Antioxid Redox Signal, vol. 29, no. 16, Dec. 2018, pp. 1691–724. Pubmed, doi:10.1089/ars.2017.7453.
URI
https://scholars.duke.edu/individual/pub1324934
PMID
29926755
Source
pubmed
Published In
Antioxid Redox Signal
Volume
29
Published Date
Start Page
1691
End Page
1724
DOI
10.1089/ars.2017.7453

Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression.

IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutant IDH1 (IDH1-R132H) on both the neural stem cell (NSC) population and brain tumorigenesis, genetically faithful cell lines and mouse model systems were generated. Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell-cycle arrest as well as a decreased ability to undergo neuronal differentiation. In vivo, Idh1-R132H expression reduced proliferation of cells within the germinal zone of the subventricular zone (SVZ). The NSCs within this area were dispersed and disorganized in mutant animals, suggesting that Idh1-R132H perturbed the NSCs and the microenvironment from which gliomas arise. In addition, tumor-bearing animals expressing mutant Idh1 displayed a prolonged survival and also overexpressed Olig2, features consistent with IDH1-mutated human gliomas. These data indicate that mutant Idh1 disrupts the NSC microenvironment and the candidate cell-of-origin for glioma; thus, altering the progression of tumorigenesis. In addition, this study provides a mutant Idh1 brain tumor model that genetically recapitulates human disease, laying the foundation for future investigations on mutant IDH1-mediated brain tumorigenesis and targeted therapy.Implications: Through the use of a conditional mutant mouse model that confers a less aggressive tumor phenotype, this study reveals that mutant Idh1 impacts the candidate cell-of-origin for gliomas. Mol Cancer Res; 15(5); 507-20. ©2017 AACR.
Authors
Pirozzi, CJ; Carpenter, AB; Waitkus, MS; Wang, CY; Zhu, H; Hansen, LJ; Chen, LH; Greer, PK; Feng, J; Wang, Y; Bock, CB; Fan, P; Spasojevic, I; McLendon, RE; Bigner, DD; He, Y; Yan, H
MLA Citation
Pirozzi, Christopher J., et al. “Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression..” Mol Cancer Res, vol. 15, no. 5, May 2017, pp. 507–20. Pubmed, doi:10.1158/1541-7786.MCR-16-0485.
URI
https://scholars.duke.edu/individual/pub1175644
PMID
28148827
Source
pubmed
Published In
Mol Cancer Res
Volume
15
Published Date
Start Page
507
End Page
520
DOI
10.1158/1541-7786.MCR-16-0485

A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models.

Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumour-specific uptake and therapeutic potential. To this end, here we conjugated paclitaxel (PTX) to recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into ∼60 nm near-monodisperse nanoparticles that increased the systemic exposure of PTX by sevenfold compared with free drug and twofold compared with the Food and Drug Administration-approved taxane nanoformulation (Abraxane). The tumour uptake of the CP-PTX nanoparticle was fivefold greater than free drug and twofold greater than Abraxane. In a murine cancer model of human triple-negative breast cancer and prostate cancer, CP-PTX induced near-complete tumour regression after a single dose in both tumour models, whereas at the same dose, no mice treated with Abraxane survived for >80 days (breast) and 60 days (prostate), respectively. These results show that a molecularly engineered nanoparticle with precisely engineered design features outperforms Abraxane, the current gold standard for PTX delivery.
Authors
Bhattacharyya, J; Bellucci, JJ; Weitzhandler, I; McDaniel, JR; Spasojevic, I; Li, X; Lin, C-C; Chi, J-TA; Chilkoti, A
MLA Citation
Bhattacharyya, Jayanta, et al. “A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models..” Nat Commun, vol. 6, Aug. 2015. Pubmed, doi:10.1038/ncomms8939.
URI
https://scholars.duke.edu/individual/pub1080989
PMID
26239362
Source
pubmed
Published In
Nature Communications
Volume
6
Published Date
Start Page
7939
DOI
10.1038/ncomms8939

The complex mechanistic aspects of redox-active compounds, commonly regarded as SOD mimics

© 2013 Walter de Gruyter GmbH. All rights reserved. This review aims to clarify (1) what is a true mimic of superoxide dismutase family of enzymes, SOD; and (2) whether such compound could act as SOD mimic in a complex biological milieu. Several groups of compounds (metalloporphyrins, metallocorroles, Mn biliverdins, Mn cyclic polyamines, Mn salens, and metal oxides and salts) have been described. Their ability to catalyze the dismutation of O2·-, [kcat(O2·-)], thermodynamic property that supports high catalytic ability (E1/2), kinetic factors that facilitate the catalysis, and the stability of compounds, which assures the integrity of metal coordination sphere where reactions of interest occur have been discussed. The other possible in vivo actions of those compounds, such as peroxynitrite and hypochlorite reduction, peroxidase-like activity, thiol oxidase activity etc., have been described as well. Based on in vivo studies it appears that kcat(O2·-) for Mn(III) N-substituted pyridylporphyrins parallels their therapeutic ability. The reason for that lies in their electrophilic nature which favors reactions with nucleophilic (anionic) reactive species (O2·-, ONOO-, ClO-, HO2-, CO3·-) and simple or protein thiolates. Their in vivo multiple rather than single modes of actions, would be determined by: (a) their redox properties; (b) localization at targeted cellular site; and (c) redox environment of diseased or mutated/cancer cell. Quality of any drug preparation and the knowledge of researchers on its properties are essential when its mechanistic aspects are explored.
Authors
Batinic-Haberle, I; Tovmasyan, A; Spasojevic, I
MLA Citation
Batinic-Haberle, I., et al. “The complex mechanistic aspects of redox-active compounds, commonly regarded as SOD mimics.” Bioinorganic Reaction Mechanisms, vol. 9, no. 1–4, Dec. 2013, pp. 35–58. Scopus, doi:10.1515/irm-2013-0004.
URI
https://scholars.duke.edu/individual/pub1339066
Source
scopus
Published In
Bioinorganic Reaction Mechanisms
Volume
9
Published Date
Start Page
35
End Page
58
DOI
10.1515/irm-2013-0004

Sampling and mass spectrometric analytical methods for five antineoplastic drugs in the healthcare environment.

CONTEXT: Healthcare worker exposure to antineoplastic drugs continues to be reported despite safe handling guidelines published by several groups. Sensitive sampling and analytical methods are needed so that occupational safety and health professionals may accurately assess environmental and biological exposure to these drugs in the workplace. OBJECTIVE: To develop liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) analytical methods for measuring five antineoplastic drugs in samples from the work environment, and to apply these methods in validating sampling methodology. A single method for quantifying several widely used agents would decrease the number of samples required for method development, lower cost, and time of analysis. METHODS: for measuring these drugs in workers' urine would also be useful in monitoring personal exposure levels. RESULTS: LC-MS/MS methods were developed for individual analysis of five antineoplastic drugs in wipe and air sample media projected for use in field sampling: cyclophosphamide, ifosfamide, paclitaxel, doxorubicin, and 5-fluorouracil. Cyclophosphamide, ifosfamide, and paclitaxel were also measured simultaneously in some stages of the work. Extraction methods for air and wipe samples were developed and tested using the aforementioned analytical methods. Good recoveries from the candidate air and wipe sample media for most of the compounds, and variable recoveries for test wipe samples depending on the surface under study, were observed. Alternate LC-MS/MS methods were also developed to detect cyclophosphamide and paclitaxel in urine samples. CONCLUSIONS: The sampling and analytical methods were suitable for determining worker exposure to antineoplastics via surface and breathing zone contamination in projected surveys of healthcare settings.
Authors
Pretty, JR; Connor, TH; Spasojevic, I; Kurtz, KS; McLaurin, JL; B'Hymer, C; Debord, DG
MLA Citation
Pretty, Jack R., et al. “Sampling and mass spectrometric analytical methods for five antineoplastic drugs in the healthcare environment..” J Oncol Pharm Pract, vol. 18, no. 1, Mar. 2012, pp. 23–36. Pubmed, doi:10.1177/1078155210389215.
URI
https://scholars.duke.edu/individual/pub808360
PMID
21183556
Source
pubmed
Published In
J Oncol Pharm Pract
Volume
18
Published Date
Start Page
23
End Page
36
DOI
10.1177/1078155210389215