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
Awarded By
North Carolina Biotechnology Center
Role
Co Investigator
Start Date
End Date

Publications:

A phase i study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors

© 2017 Becher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The PI3K/Akt/mTOR signaling pathway is aberrantly activated in various pediatric tumors. We conducted a phase I study of the Akt inhibitor perifosine in patients with recurrent/refractory pediatric CNS and solid tumors. This was a standard 3+3 open-label dose-escalation study to assess pharmacokinetics, describe toxicities, and identify the MTD for single-agent perifosine. Five dose levels were investigated, ranging from 25 to 125 mg/m2/day for 28 days per cycle. Twenty-three patients (median age 10 years, range 4±18 years) with CNS tumors (DIPG [n = 3], high-grade glioma [n = 5], medulloblastoma [n = 2], ependymoma [n = 3]), neuroblastoma (n = 8), Wilms tumor (n = 1), and Ewing sarcoma (n = 1) were treated. Only one DLT occurred (grade 4 hyperuricemia at dose level 4). The most common grade 3 or 4 toxicity at least possibly related to perifosine was neutropenia (8.7%), with the remaining grade 3 or 4 toxicities (fatigue, hyperglycemia, fever, hyperuricemia, and catheter- related infection) occurring in one patient each. Pharmacokinetics was dose-saturable at doses above 50 mg/m2/day with significant inter-patient variability, consistent with findings reported in adult studies. One patient with DIPG (dose level 5) and 4 of 5 patients with highgrade glioma (dose levels 2 and 3) experienced stable disease for two months. Five subjects with neuroblastoma (dose levels 1 through 4) achieved stable disease which was prolonged (≥11 months) in three. No objective responses were noted. In conclusion, the use of perifosine was safe and feasible in patients with recurrent/refractory pediatric CNS and solid tumors. An MTD was not defined by the 5 dose levels investigated. Our RP2D is 50 mg/m2/day.
Authors
Becher, OJ; Millard, NE; Modak, S; Kushner, BH; Haque, S; Spasojevic, I; Trippett, TM; Gilheeney, SW; Khakoo, Y; Lyden, DC; De Braganca, KC; Kolesar, JM; Huse, JT; Kramer, K; Cheung, NKV; Dunkel, IJ
MLA Citation
Becher, O. J., et al. “A phase i study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors.” Plos One, vol. 12, no. 6, 2017. Scopus, doi:10.1371/journal.pone.0178593.
URI
https://scholars.duke.edu/individual/pub1150205
Source
scopus
Published In
Plos One
Volume
12
Published Date
DOI
10.1371/journal.pone.0178593

Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.

The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.
Authors
Mook, RA; Wang, J; Ren, X-R; Chen, M; Spasojevic, I; Barak, LS; Lyerly, HK; Chen, W
MLA Citation
Mook, Robert A., et al. “Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.Bioorg Med Chem, vol. 23, no. 17, Sept. 2015, pp. 5829–38. Pubmed, doi:10.1016/j.bmc.2015.07.001.
URI
https://scholars.duke.edu/individual/pub1083908
PMID
26272032
Source
pubmed
Published In
Bioorg Med Chem
Volume
23
Published Date
Start Page
5829
End Page
5838
DOI
10.1016/j.bmc.2015.07.001

Differential localization and potency of manganese porphyrin superoxide dismutase-mimicking compounds in Saccharomyces cerevisiae

Authors
Li, AM; Martins, J; Tovmasyan, A; Valentine, JS; Batinic-Haberle, I; Spasojevic, I; Gralla, EB
MLA Citation
Li, Alice Ma, et al. “Differential localization and potency of manganese porphyrin superoxide dismutase-mimicking compounds in Saccharomyces cerevisiae.” Redox Biology, vol. 3, ELSEVIER SCIENCE BV, Jan. 2014, pp. 1–6. Wos, doi:10.1016/j.redox.2014.0.003.
URI
https://scholars.duke.edu/individual/pub1063307
Source
wos
Published In
Redox Biology
Volume
3
Published Date
Start Page
1
End Page
6
DOI
10.1016/j.redox.2014.0.003

Manganese superoxide dismutase, MnSOD and its mimics.

Increased understanding of the role of mitochondria under physiological and pathological conditions parallels increased exploration of synthetic and natural compounds able to mimic MnSOD - endogenous mitochondrial antioxidant defense essential for the existence of virtually all aerobic organisms from bacteria to humans. This review describes most successful mitochondrially-targeted redox-active compounds, Mn porphyrins and MitoQ(10) in detail, and briefly addresses several other compounds that are either catalysts of O(2)(-) dismutation, or its non-catalytic scavengers, and that reportedly attenuate mitochondrial dysfunction. While not a true catalyst (SOD mimic) of O(2)(-) dismutation, MitoQ(10) oxidizes O(2)(-) to O(2) with a high rate constant. In vivo it is readily reduced to quinol, MitoQH(2), which in turn reduces ONOO(-) to NO(2), producing semiquinone radical that subsequently dismutes to MitoQ(10) and MitoQH(2), completing the "catalytic" cycle. In MitoQ(10), the redox-active unit was coupled via 10-carbon atom alkyl chain to monocationic triphenylphosphonium ion in order to reach the mitochondria. Mn porphyrin-based SOD mimics, however, were designed so that their multiple cationic charge and alkyl chains determine both their remarkable SOD potency and carry them into the mitochondria. Several animal efficacy studies such as skin carcinogenesis and UVB-mediated mtDNA damage, and subcellular distribution studies of Saccharomyces cerevisiae and mouse heart provided unambiguous evidence that Mn porphyrins mimic the site and action of MnSOD, which in turn contributes to their efficacy in numerous in vitro and in vivo models of oxidative stress. Within a class of Mn porphyrins, lipophilic analogs are particularly effective for treating central nervous system injuries where mitochondria play key role. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
Authors
Miriyala, S; Spasojevic, I; Tovmasyan, A; Salvemini, D; Vujaskovic, Z; St Clair, D; Batinic-Haberle, I
MLA Citation
Miriyala, Sumitra, et al. “Manganese superoxide dismutase, MnSOD and its mimics.Biochim Biophys Acta, vol. 1822, no. 5, May 2012, pp. 794–814. Pubmed, doi:10.1016/j.bbadis.2011.12.002.
URI
https://scholars.duke.edu/individual/pub759446
PMID
22198225
Source
pubmed
Published In
Biochimica Et Biophysica Acta
Volume
1822
Published Date
Start Page
794
End Page
814
DOI
10.1016/j.bbadis.2011.12.002

Effects of aerobic training on oxidative status in postsurgical non-small cell lung cancer patients: a pilot study.

BACKGROUND: Oxidative stress is postulated to contribute to the initiation, promotion, and progression of non-small cell lung cancer (NSCLC). We investigated the effects of supervised, moderate-intensity aerobic training on urinary markers of oxidative status in patients with postsurgical NSCLC. PATIENTS AND METHODS: Sixteen patients with histologically confirmed stage I-IIIB NSCLC were recruited. Exercise training consisted of aerobic cycle ergometry sessions at 60 to ≥70% of baseline peak workload 20-45 min·d(-1), 3 d·wk(-1)for 14 weeks. Oxidative status was assessed via four urinary F(2)-isoprostanes isomers: iPF (2-alpha)-III, 2,3-dinor-iPF(2 alpha)-III, iPF (2-alpha)-VI, and 8,12-iso-iPF(2 alpha)-VI using liquid chromatography with tandem mass spectrometry detection. Peak oxygen consumption (VO2peak) was assessed using a maximal, incremental, cardiopulmonary exercise test with expired gas analysis. RESULTS: A composite index of all four F2-isoprostanes isomers increased from baseline to post-intervention by 32% (p = 0.08). Concerning individual isomers, iPF (2-alpha)-III increased by 0.09 (+55%; p = .010), iPF (2-alpha)-VI by 0.81 (+29%; p = 0.04), and 8,12-iso-iPF(2 alpha)-VI by 0.59 (+28%; p = 0.07) from baseline to postintervention. There was no change in 2,3-dinor-iPF(2 alpha)-III levels. VO2peak increased 1.1 mL·kg·(-1) min(-1) (p = 0.14) and peak workload increased 10 Watts (p < .001). Change in VO2peak was not associated with change in markers of oxidative status. CONCLUSIONS: Aerobic training was associated with significant increases in urinary measures of oxidative status in postsurgical NSCLC. The clinical implications of these findings are currently unknown. Further studies are required to elucidate the complex relationship between aerobic training, oxidative stress, tumor biology, and response to cytotoxic agents in mouse and human models of cancer.
Authors
Jones, LW; Eves, ND; Spasojevic, I; Wang, F; Il'yasova, D
MLA Citation
Jones, Lee W., et al. “Effects of aerobic training on oxidative status in postsurgical non-small cell lung cancer patients: a pilot study.Lung Cancer, vol. 72, no. 1, Apr. 2011, pp. 45–51. Pubmed, doi:10.1016/j.lungcan.2010.08.002.
URI
https://scholars.duke.edu/individual/pub744046
PMID
20863590
Source
pubmed
Published In
Lung Cancer
Volume
72
Published Date
Start Page
45
End Page
51
DOI
10.1016/j.lungcan.2010.08.002