Kouros Owzar

Overview:

cancer pharmacogenomics
drug induced neuropathy, neutropenia and hypertension
statistical genetics
statistical methods for high-dimensional data
copulas
survival analysis
statistical computing

Positions:

Professor of Biostatistics & Bioinformatics

Biostatistics & Bioinformatics
School of Medicine

Director, DCI Bioinformatics

Biostatistics & Bioinformatics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2002

University of North Carolina - Chapel Hill

Grants:

Preoperative Breast Radiotherapy: A Tool to Provide Individualized and Biologically-Based Radiation Therapy

Administered By
Radiation Oncology
Awarded By
Gateway for Cancer Research
Role
Collaborator
Start Date
End Date

mTOR Therapy in Prostate Cancer: Signatures of Response and Biology of Resistance

Administered By
Institutes and Centers
Awarded By
National Institutes of Health
Role
Statistician
Start Date
End Date

Health Disparity in African Americans: A Meta-analysis of Six Phase III Trials in Metastatic Castration-Resistant Prostate Cancer Men treated with Docetaxel

Administered By
Biostatistics & Bioinformatics
Awarded By
Department of Defense
Role
Collaborator
Start Date
End Date

Profiling the Adenosine Axis in Metastatic Colorectal Cancer

Administered By
Medicine, Medical Oncology
Awarded By
MedImmune, Inc.
Role
Statistician
Start Date
End Date

Computational Resources and Dissemination Core

Administered By
Biostatistics & Bioinformatics
Awarded By
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
End Date

Publications:

APOBEC Mutagenesis Inhibits Breast Cancer Growth through Induction of T cell-Mediated Antitumor Immune Responses.

The APOBEC family of cytidine deaminases is one of the most common endogenous sources of mutations in human cancer. Genomic studies of tumors have found that APOBEC mutational signatures are enriched in the HER2 subtype of breast cancer and are associated with immunotherapy response in diverse cancer types. However, the direct consequences of APOBEC mutagenesis on the tumor immune microenvironment have not been thoroughly investigated. To address this, we developed syngeneic murine mammary tumor models with inducible expression of APOBEC3B. We found that APOBEC activity induced antitumor adaptive immune responses and CD4+ T cell-mediated, antigen-specific tumor growth inhibition. Although polyclonal APOBEC tumors had a moderate growth defect, clonal APOBEC tumors were almost completely rejected, suggesting that APOBEC-mediated genetic heterogeneity limits antitumor adaptive immune responses. Consistent with the observed immune infiltration in APOBEC tumors, APOBEC activity sensitized HER2-driven breast tumors to anti-CTLA-4 checkpoint inhibition and led to a complete response to combination anti-CTLA-4 and anti-HER2 therapy. In human breast cancers, the relationship between APOBEC mutagenesis and immunogenicity varied by breast cancer subtype and the frequency of subclonal mutations. This work provides a mechanistic basis for the sensitivity of APOBEC tumors to checkpoint inhibitors and suggests a rationale for using APOBEC mutational signatures and clonality as biomarkers predicting immunotherapy response in HER2-positive (HER2+) breast cancers.
Authors
DiMarco, AV; Qin, X; McKinney, BJ; Garcia, NMG; Van Alsten, SC; Mendes, EA; Force, J; Hanks, BA; Troester, MA; Owzar, K; Xie, J; Alvarez, JV
MLA Citation
DiMarco, Ashley V., et al. “APOBEC Mutagenesis Inhibits Breast Cancer Growth through Induction of T cell-Mediated Antitumor Immune Responses.Cancer Immunol Res, vol. 10, no. 1, Jan. 2022, pp. 70–86. Pubmed, doi:10.1158/2326-6066.CIR-21-0146.
URI
https://scholars.duke.edu/individual/pub1501810
PMID
34795033
Source
pubmed
Published In
Cancer Immunol Res
Volume
10
Published Date
Start Page
70
End Page
86
DOI
10.1158/2326-6066.CIR-21-0146

Correction: Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients.

Authors
Quintanilha, JCF; Wang, J; Sibley, AB; Jiang, C; Etheridge, AS; Shen, F; Jiang, G; Mulkey, F; Patel, JN; Hertz, DL; Dees, EC; McLeod, HL; Bertagnolli, M; Rugo, H; Kindler, HL; Kelly, WK; Ratain, MJ; Kroetz, DL; Owzar, K; Schneider, BP; Lin, D; Innocenti, F
MLA Citation
Quintanilha, Julia C. F., et al. “Correction: Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients.Br J Cancer, vol. 126, no. 1, Jan. 2022, p. 162. Pubmed, doi:10.1038/s41416-021-01617-1.
URI
https://scholars.duke.edu/individual/pub1502770
PMID
34853435
Source
pubmed
Published In
Br J Cancer
Volume
126
Published Date
Start Page
162
DOI
10.1038/s41416-021-01617-1

Plasma Protein Biomarkers in Advanced or Metastatic Colorectal Cancer Patients Receiving Chemotherapy With Bevacizumab or Cetuximab: Results from CALGB 80405 (Alliance).

PURPOSE: CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent. PATIENTS AND METHODS: In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment. RESULTS: In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10-2.06; cetuximab HR, 0.94; 95% CI, 0.71-1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19-2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68-1.24; Pinteraction = 0.0097). CONCLUSIONS: In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner. See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725.
Authors
Nixon, AB; Sibley, AB; Liu, Y; Hatch, AJ; Jiang, C; Mulkey, F; Starr, MD; Brady, JC; Niedzwiecki, D; Venook, AP; Baez-Diaz, L; Lenz, H-J; O'Neil, BH; Innocenti, F; Meyerhardt, JA; O'Reilly, EM; Owzar, K; Hurwitz, HI
MLA Citation
Nixon, Andrew B., et al. “Plasma Protein Biomarkers in Advanced or Metastatic Colorectal Cancer Patients Receiving Chemotherapy With Bevacizumab or Cetuximab: Results from CALGB 80405 (Alliance).Clin Cancer Res, vol. 28, no. 13, July 2022, pp. 2779–88. Pubmed, doi:10.1158/1078-0432.CCR-21-2389.
URI
https://scholars.duke.edu/individual/pub1504729
PMID
34965954
Source
pubmed
Published In
Clinical Cancer Research
Volume
28
Published Date
Start Page
2779
End Page
2788
DOI
10.1158/1078-0432.CCR-21-2389

P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.

Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment. We discover that selinexor activates PI3Kγ-dependent AKT signaling in AML by upregulating the purinergic receptor P2RY2. Inhibiting this axis potentiates the anti-leukemic effects of selinexor in AML cell lines, patient-derived primary cultures and multiple mouse models of AML. In a syngeneic, MLL-AF9-driven mouse model of AML, treatment with selinexor and ipatasertib outperforms both standard-of-care chemotherapy and chemotherapy with selinexor. Together, these findings establish drug-induced P2RY2-AKT signaling as an actionable consequence of XPO1 inhibition in AML.
Authors
Lin, KH; Rutter, JC; Xie, A; Killarney, ST; Vaganay, C; Benaksas, C; Ling, F; Sodaro, G; Meslin, P-A; Bassil, CF; Fenouille, N; Hoj, J; Washart, R; Ang, HX; Cerda-Smith, C; Chaintreuil, P; Jacquel, A; Auberger, P; Forget, A; Itzykson, R; Lu, M; Lin, J; Pierobon, M; Sheng, Z; Li, X; Chilkoti, A; Owzar, K; Rizzieri, DA; Pardee, TS; Benajiba, L; Petricoin, E; Puissant, A; Wood, KC
MLA Citation
Lin, Kevin H., et al. “P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.Nat Cancer, vol. 3, no. 7, July 2022, pp. 837–51. Pubmed, doi:10.1038/s43018-022-00394-x.
URI
https://scholars.duke.edu/individual/pub1523817
PMID
35668193
Source
pubmed
Published In
Nature Cancer
Volume
3
Published Date
Start Page
837
End Page
851
DOI
10.1038/s43018-022-00394-x

Re-Examination of the Exacerbating Effect of Inflammasome Components during Radiation Injury.

Radiation can be applied for therapeutic benefit against cancer or may result in devastating harm due to accidental or intentional release of nuclear energy. In all cases, radiation exposure causes molecular and cellular damage, resulting in the production of inflammatory factors and danger signals. Several classes of innate immune receptors sense the released damage associated molecules and activate cellular response pathways, including the induction of inflammasome signaling that impacts IL-1β/IL-18 maturation and cell death. A previous report indicated inflammasomes aggravate acute radiation syndrome. In contrast, here we find that inflammasome components do not exacerbate gamma-radiation-induced injury by examining heterozygous and gene-deletion littermate controls in addition to wild-type mice. Absence of some inflammasome genes, such as caspase-1/11 and Nlrp3, enhance susceptibility of treated mice to acute radiation injury, indicating importance of the inflammasome pathway in radioprotection. Surprisingly, we discover that the survival outcome may be sex-dependent as more inflammasome-deficient male mice are susceptible to radiation-induced injury. We discuss parameters that may influence the role of inflammasomes as radioprotective or radioexacerbating factors in recovery from radiation injury including the use of littermate controls, the sex of the animals, differences in microbiota within the colonies and other experimental conditions. Under the conditions tested, inflammasome components do not exacerbate radiation injury, but rather provide protective benefit.
Authors
Brickey, WJ; Thompson, MA; Sheng, Z; Li, Z; Owzar, K; Ting, JPY
MLA Citation
Brickey, W. June, et al. “Re-Examination of the Exacerbating Effect of Inflammasome Components during Radiation Injury.Radiat Res, vol. 197, no. 2, Feb. 2022, pp. 199–204. Pubmed, doi:10.1667/RADE-21-00142.1.
URI
https://scholars.duke.edu/individual/pub1502623
PMID
34855933
Source
pubmed
Published In
Radiat Res
Volume
197
Published Date
Start Page
199
End Page
204
DOI
10.1667/RADE-21-00142.1