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:

Potential for a novel manganese porphyrin compound as adjuvant canine lymphoma therapy.

PURPOSE: Manganese porphyrins are redox-active drugs and superoxide dismutase mimics, which have been shown to chemosensitize lymphoma, a cancer which frequently occurs in dogs. This study aimed to identify critical information regarding the pharmacokinetics and toxicity of Mn(III) meso-tetrakis (N-n-butoxyetylpyridium-2-yl) porphyrin, (MnTnBuOE-2-PyP5+, MnBuOE) in dogs as a prelude to a clinical trial in canine lymphoma patients. METHODS: A single-dose pharmacokinetic (PK) study in normal dogs was performed to determine the plasma half-life (t 1/2) of MnBuOE. A dose reduction study was performed to establish the maximum tolerated dose (MTD) of MnBuOE. The safety and PK of a multi-dosing protocol was assessed. RESULTS: Peak plasma drug concentration occurred 30 min post-injection. The t 1/2 was defined as 7 h. MnBuOE induced an anaphylactic reaction and prolonged tachycardia. The MTD was defined as 0.25 mg/kg. The dogs were given MTD 3×/week for 2-3 weeks. The highest recorded tissue drug levels were in the lymph nodes (4-6 μM), followed by kidney and liver (2.5, 2.0 uM, respectively). CONCLUSIONS: We obtained critical information regarding the PK and toxicity of MnBuOE in dogs. The acute drug reaction and tachycardia post-injection have not been described in other species and may be specific to canines. The high tissue drug levels in lymph nodes have not been previously reported. MnBuOE accumulation in lymph nodes has important implications for the utility of adjuvant MnBuOE to treat lymphoma. With MnBuOE lymph node accumulation, reduction in the dose and/or administration frequency could be possible, leading to reduced toxicity.
Authors
Boss, MK; Dewhirst, MW; Sampaio, RS; Bennett, A; Tovmasyan, A; Berman, KG; Beaven, AW; Rizzieri, DA; Batinic-Haberle, I; Hauck, ML; Spasojevic, I
MLA Citation
Boss, M. K., et al. “Potential for a novel manganese porphyrin compound as adjuvant canine lymphoma therapy..” Cancer Chemother Pharmacol, vol. 80, no. 2, Aug. 2017, pp. 421–31. Pubmed, doi:10.1007/s00280-017-3372-z.
URI
https://scholars.duke.edu/individual/pub1264676
PMID
28685347
Source
pubmed
Published In
Cancer Chemother Pharmacol
Volume
80
Published Date
Start Page
421
End Page
431
DOI
10.1007/s00280-017-3372-z

A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer.

Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.
Authors
Whitley, MJ; Cardona, DM; Lazarides, AL; Spasojevic, I; Ferrer, JM; Cahill, J; Lee, C-L; Snuderl, M; Blazer, DG; Hwang, ES; Greenup, RA; Mosca, PJ; Mito, JK; Cuneo, KC; Larrier, NA; O'Reilly, EK; Riedel, RF; Eward, WC; Strasfeld, DB; Fukumura, D; Jain, RK; Lee, WD; Griffith, LG; Bawendi, MG; Kirsch, DG; Brigman, BE
MLA Citation
Whitley, Melodi Javid, et al. “A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer..” Sci Transl Med, vol. 8, no. 320, Jan. 2016. Pubmed, doi:10.1126/scitranslmed.aad0293.
URI
https://scholars.duke.edu/individual/pub1112634
PMID
26738797
Source
pubmed
Published In
Sci Transl Med
Volume
8
Published Date
Start Page
320ra4
DOI
10.1126/scitranslmed.aad0293

A joint analysis of metabolomics and genetics of breast cancer.

INTRODUCTION: Remodeling of cellular metabolism appears to be a consequence and possibly a cause of oncogenic transformation in human cancers. Specific aspects of altered tumor metabolism may be amenable to therapeutic intervention and could be coordinated with other targeted therapies. In breast cancer, the genetic landscape has been defined most comprehensively in efforts such as The Cancer Genome Atlas (TCGA). However, little is known about how alterations of tumor metabolism correlate with this landscape. METHODS: In total 25 cancers (23 fully analyzed by TCGA) and 5 normal breast specimens were analyzed by gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry, quantitating 399 identifiable metabolites. RESULTS: We found strong differences correlated with hormone receptor status with 18% of the metabolites elevated in estrogen receptor negative (ER-) cancers compared to estrogen receptor positive (ER+) including many glycolytic and glycogenolytic intermediates consistent with increased Warburg effects. Glutathione (GSH) pathway components were also elevated in ER- tumors consistent with an increased requirement for handling higher levels of oxidative stress. Additionally, ER- tumors had high levels of the oncometabolite 2-hydroxyglutarate (2-HG) and the immunomodulatory tryptophan metabolite kynurenine. Kynurenine levels were correlated with the expression of tryptophan-degrading enzyme (IDO1). However, high levels of 2-HG were not associated with somatic mutations or expression levels of IDH1 or IDH2. BRCA1 mRNA levels were positively associated with coenzyme A, acetyl coenzyme A, and GSH and negatively associated with multiple lipid species, supporting the regulation of ACC1 and NRF2 by BRCA1. Different driver mutations were associated with distinct patterns of specific metabolites, such as lower levels of several lipid-glycerophosphocholines in tumors with mutated TP53. A strong metabolomic signature associated with proliferation rate was also observed; the metabolites in this signature overlap broadly with metabolites that define ER status as receptor status and proliferation rate were correlated. CONCLUSIONS: The addition of metabolomic profiles to the public domain TCGA dataset provides an important new tool for discovery and hypothesis testing of the genetic regulation of tumor metabolism. Particular sets of metabolites may reveal insights into the metabolic dysregulation that underlie the heterogeneity of breast cancer.
Authors
Tang, X; Lin, C-C; Spasojevic, I; Iversen, ES; Chi, J-T; Marks, JR
MLA Citation
Tang, Xiaohu, et al. “A joint analysis of metabolomics and genetics of breast cancer..” Breast Cancer Res, vol. 16, no. 4, Aug. 2014. Pubmed, doi:10.1186/s13058-014-0415-9.
URI
https://scholars.duke.edu/individual/pub1041909
PMID
25091696
Source
pubmed
Published In
Breast Cancer Res
Volume
16
Published Date
Start Page
415
DOI
10.1186/s13058-014-0415-9

Urinary F2-isoprostanes, obesity, and weight gain in the IRAS cohort.

Obesity has been associated with increased F(2)-isoprostane (F(2)-IsoP) levels cross-sectionally. However, the prospective association may be inverse, based on our earlier finding that elevated urinary F(2)-IsoP levels predict lower risk of diabetes. This earlier finding led us to hypothesize that urinary F(2)-IsoPs reflect the intensity of oxidative metabolism and as such predict lower risk of both diabetes and weight gain. We examined cross-sectional relationships with obesity and prospective relationships with weight gain using the data from 299 participants of the Insulin Resistance Atherosclerosis Study (IRAS), all of whom were free of diabetes at baseline. Four urinary F(2)-IsoPs were assayed in stored baseline urine samples using liquid chromatography with tandem mass spectrometry: iPF(2α)-III, 2,3-dinor-iPF(2α)-III, iPF(2α)-VI, and 8,12-iso-iPF(2α)-VI (F(2)-IsoP 1-4, respectively). Baseline F(2)-IsoPs were positively associated with baseline measures of obesity; the strongest associations were found with two F(2)-IsoPs: odds ratios (95% confidence intervals) for overall and abdominal obesity were 1.74 (1.26-2.40) and 1.63 (1.18-2.24) for F(2)-IsoP2 and 1.47 (1.12-1.94) and 1.64 (1.22-2.20) for F(2)-IsoP4. F(2)-IsoP2 showed the strongest and significant inverse association with weight gain during the 5-year follow-up period: increase in F(2)-IsoP2 equal to 1 s.d. was associated with 0.90 kg lower weight gain (P = 0.02) and the odds ratios for relative (≥5%) and absolute (≥5 kg) weight gain were 0.67 (0.47-0.96) and 0.57 (0.37-0.87), respectively. The other three F(2)-IsoPs were consistently inversely associated with weight gain, although not significantly, suggesting that different F(2)-IsoPs vary in their ability to detect the association with weight gain.
Authors
Il'yasova, D; Wang, F; Spasojevic, I; Base, K; D'Agostino, RB; Wagenknecht, LE
MLA Citation
Il’yasova, Dora, et al. “Urinary F2-isoprostanes, obesity, and weight gain in the IRAS cohort..” Obesity (Silver Spring), vol. 20, no. 9, Sept. 2012, pp. 1915–21. Pubmed, doi:10.1038/oby.2011.292.
URI
https://scholars.duke.edu/individual/pub737969
PMID
21959342
Source
pubmed
Published In
Obesity (Silver Spring)
Volume
20
Published Date
Start Page
1915
End Page
1921
DOI
10.1038/oby.2011.292

Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.

Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC.
Authors
Osada, T; Chen, M; Yang, XY; Spasojevic, I; Vandeusen, JB; Hsu, D; Clary, BM; Clay, TM; Chen, W; Morse, MA; Lyerly, HK
MLA Citation
Osada, Takuya, et al. “Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations..” Cancer Res, vol. 71, no. 12, June 2011, pp. 4172–82. Pubmed, doi:10.1158/0008-5472.CAN-10-3978.
URI
https://scholars.duke.edu/individual/pub764958
PMID
21531761
Source
pubmed
Published In
Cancer Res
Volume
71
Published Date
Start Page
4172
End Page
4182
DOI
10.1158/0008-5472.CAN-10-3978